Gene editing systems and methods for treating cardiovascular disease

Abstract

Provided are gene editing systems and methods for treating cardiovascular disease (CVD). Also provided are polynucleotides, vectors, cells, kits and compositions comprising the components of the gene editing systems, and methods related to treatment of CVD.

Description

FIELD OF DISCLOSURE

[0001] The present disclosure generally relates to gene editing systems and methods for treating cardiovascular disease (CVD). Also disclosed are polynucleotides, vectors, cells, kits, and compositions comprising components of the gene editing systems, and methods related to treatment of CVD. CROSS REFERENCE TO RELATED APPLICATION

[0002] This application claims the priority to and benefits of International Application No. PCT / CN2023 / 141841, filed December 26, 2023, which is incorporated herein by reference in its entirety. SEQUENCE LISTING

[0003] This application contains a Sequence Listing electronically submitted as an XML file entitled “sequence listing.xml” having a size of 1,356,492 bytes and created on December 25, 2024. The information contained in the Sequence Listing is incorporated by reference herein. BACKGROUND

[0004] Cardiovascular disease (CVD) remains a prominent cause of morbidity and mortality globally, with dyslipidemia emerging as a pivotal determinant influencing the risk of atherosclerosis. Elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) are a well-established risk factor for CVD. The intricate relationship between dyslipidemia and atherosclerosis plays a notable role in the progression of clinical CVD events such as coronary artery disease, peripheral artery disease, and stroke and their associated long-term sequelae. Therefore, current clinical guidelines stress the importance of lipid lowering, with a large emphasis on lowering Low-Density Lipoprotein cholesterol (LDL-C) levels.

[0005] The United States FDA has approved some PCSK9 inhibitors or siRNAs for the treatment of Atherosclerotic cardiovascular disease (ASCVD), such as Alirocumab or Inclisiran. However, the necessity for additional LDL-lowering therapeutics (LLT) is growing due to concerns about off-target events and poor patient compliance associated with conventional treatments. Conventional therapeutics exhibit limitations, especially in patients with genetically defined extreme levels of LDL-C, where maximum dosed LLT may prove insufficient to lower LDL-C to target levels. This challenge is further compounded by 1 prescribers who may be unaware of or reluctant to comply with guidelines. The emergence of novel gene-based therapeutics holds promise for minimizing off-target events and significantly reducing injection frequency, offering a potential breakthrough in addressing these limitations.

[0006] Recent advancements have established a link between Lp(a) levels and CVD, prompting the development of medications not solely targeting plasma LDL-C levels. Ongoing or recently completed clinical trials, such as Pelacarsen and Olpasiran, employ antisense oligonucleotide (ASO) or siRNA approaches against the LPA gene. These endeavors reflect a shift toward a more nuanced approach to medication, recognizing the importance of targeting specific factors beyond traditional LDL-C levels in mitigating cardiovascular risk.

[0007] In addition to the aforementioned treatment mechanisms, the pathways of Ang II generation and intracellular renin-angiotensin-aldosterone system (RAAS) signaling are considered crucial for cardiovascular and renal disease treatment. Uncontrolled hypertension serves as a significant contributor to cardiovascular risk, necessitating exploration into strategies to regulate blood pressure. The angiotensinogen gene (AGT) is a popular factor in this regard, as it is the source of all downstream angiotensin metabolites—a potent regulator of blood pressure. Recent clinical and preclinical data suggest that liver-selective AGT reduction presents a superior therapeutic profile in both blood pressure lowering and CVD treatment, offering a targeted and effective approach.

[0008] This dual approach, addressing both lipid levels and blood pressure regulation, tackles multiple facets of the CVD risk. However, there remains the need for the development of novel therapeutic strategies with potential applications in clinical practice for treating CVD. SUMMARY

[0009] In one aspect, the present disclosure provides gene editing systems, polynucleotides, vectors, cells, compositions, kits, and methods to disrupt the expression of genes selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT and APOC3, which contribute to lower Low-Density Lipoprotein cholesterol (LDL-C) levels, lower the level of triglyceride-rich remnant particles and / or lipoprotein(a) (Lp(a)), or regulate blood pressure, so that cardiovascular disease can be prevented or treated.

[0010] In some embodiments, the disruption of the PCSK9 gene regulates LDL metabolism. In some embodiments, the disruption of the PCSK9 gene reduces the level of LDL-C. In some embodiments, the disruption of the PCSK9 gene treats hypercholesterolemia. In some embodiments, the disruption of the PCSK9 gene treats cardiovascular diseases.

[0011] In some embodiments, the disruption of the ANGPTL3 gene regulates LDL metabolism. In some embodiments, the disruption of the ANGPTL3 gene reduces the level of LDL-C. In some embodiments, the disruption of the ANGPTL3 gene treats hypercholesterolemia. In some embodiments, the disruption of the ANGPTL3 gene treats cardiovascular diseases.

[0012] In some embodiments, the disruption of the ASGR1 gene regulates LDL metabolism. In some embodiments, the disruption of the ASGR1 gene reduces the level of LDL-C. In some embodiments, the disruption of the ASGR1 gene treats hypercholesterolemia. In some embodiments, the disruption of the ASGR1 gene treats cardiovascular diseases.

[0013] In some embodiments, the disruption of the LPA gene regulates triglyceride-rich remnant particles metabolism. In some embodiments, the disruption of the LPA gene regulates lipoprotein(a) (Lp(a)) metabolism. In some embodiments, the disruption of the LPA gene reduces the level of triglyceride-rich remnant particles. In some embodiments, the disruption of the LPA gene reduces the level of lipoprotein(a) (Lp(a)). In some embodiments, the disruption of the LPA gene treats cardiovascular diseases.

[0014] In some embodiments, the disruption of the AGT gene regulates expression of angiotensinogen. In some embodiments, the disruption of the AGT gene reduces the level of angiotensinogen. In some embodiments, the disruption of the AGT gene regulates blood pressure. In some embodiments, the disruption of the AGT gene treats hypertension. In some embodiments, the disruption of the AGT gene treats cardiovascular diseases.

[0015] In some embodiments, the disruption of the APOC3 gene regulates triglyceride-rich remnant particles metabolism. In some embodiments, the disruption of the APOC3 gene reduces the level of triglyceride-rich remnant particles. In some embodiments, the disruption of the APOC3 gene regulates LDL metabolism. In some embodiments, the disruption of the APOC3 gene reduces the level of LDL-C. In some embodiments, the disruption of the APOC3 gene treats the familial chylomicronemia syndrome and hypertriglyceridemia and reduces the risk of ischemic cardiovascular disease. In some embodiments, the disruption of the APOC3 gene treats cardiovascular diseases.

[0016] In some embodiments, the present disclosure provides a gene editing system for disrupting PCSK9 gene.

[0017] In some embodiments, the present disclosure provides a gene editing system for disrupting ANGPTL3 gene.

[0018] In some embodiments, the present disclosure provides a gene editing system for disrupting ASGR1 gene.

[0019] In some embodiments, the present disclosure provides a gene editing system for disrupting LPA gene.

[0020] In some embodiments, the present disclosure provides a gene editing system for disrupting AGT gene.

[0021] In some embodiments, the present disclosure provides a gene editing system for disrupting APOC3 gene.

[0022] In one aspect, the present disclosure a gene editing system comprising a base editor and at least one guide RNA that is capable of binding to one or more gene selected from: PCSK9 gene, ANGPTL3 gene, ASGR1 gene, LPA gene, AGT gene and APOC3 gene.

[0023] In some embodiments, the present disclosure a gene editing system comprising a base editor and at least one guide RNA that is capable of binding to PCSK9 gene.

[0024] In some embodiments, the present disclosure a gene editing system comprising a base editor and at least one guide RNA that is capable of binding to ANGPTL3 gene.

[0025] In some embodiments, the present disclosure a gene editing system comprising a base editor and at least one guide RNA that is capable of binding to ASGR1 gene.

[0026] In some embodiments, the present disclosure a gene editing system comprising a base editor and at least one guide RNA that is capable of binding to LPA gene.

[0027] In some embodiments, the present disclosure a gene editing system comprising a base editor and at least one guide RNA that is capable of binding to AGT gene.

[0028] In some embodiments, the present disclosure a gene editing system comprising a base editor and at least one guide RNA that is capable of binding to APOC3 gene.

[0029] In some embodiments, a highly specific base editor, transformer base editor (tBE), is used to induce efficient and precise gene editing at genomic sites for disrupting the PCSK9 gene. A tBE is used with a combination of main guide RNA (mgRNA) and helper guide RNA (hgRNA), wherein the mgRNA and hgRNA are capable of binding to the PCSK9 gene.

[0030] In some embodiments, a highly specific base editor, transformer base editor (tBE), is used to induce efficient and precise gene editing at genomic sites for disrupting the ANGPTL3 gene. A tBE is used with a combination of main guide RNA (mgRNA) and helper guide RNA (hgRNA), wherein the mgRNA and hgRNA are capable of binding to the ANGPTL3 gene.

[0031] In some embodiments, a highly specific base editor, transformer base editor (tBE), is used to induce efficient and precise gene editing at genomic sites for disrupting the ASGR1 gene. A tBE is used with a combination of main guide RNA (mgRNA) and helper guide RNA (hgRNA), wherein the mgRNA and hgRNA are capable of binding to the ASGR1 gene.

[0032] In some embodiments, a highly specific base editor, transformer base editor (tBE), is used to induce efficient and precise gene editing at genomic sites for disrupting the LPA gene. A tBE is used with a combination of main guide RNA (mgRNA) and helper guide RNA (hgRNA), wherein the mgRNA and hgRNA are capable of binding to the LPA gene.

[0033] In some embodiments, a highly specific base editor, transformer base editor (tBE), is used to induce efficient and precise gene editing at genomic sites for disrupting the AGT gene. A tBE is used with a combination of main guide RNA (mgRNA) and helper guide RNA (hgRNA), wherein the mgRNA and hgRNA are capable of binding to the AGT gene.

[0034] In some embodiments, a highly specific base editor, transformer base editor (tBE), is used to induce efficient and precise gene editing at genomic sites for disrupting the APOC3 gene. A tBE is used with a combination of main guide RNA (mgRNA) and helper guide RNA (hgRNA), wherein the mgRNA and hgRNA are capable of binding to the APOC3 gene.

[0035] In some embodiments, the present disclosure provides a gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA, wherein the mgRNA comprises an mgRNA spacer and the hgRNA comprises an hgRNA spacer, wherein the nucleic acid sequences of the mgRNA spacer and the hgRNA spacer comprises the respective sequences as set forth in Table 7A-7F. In some embodiments, the mgRNA and hgRNA comprises the respective sequences as set forth in Table 8A-8C.

[0036] In some embodiments, the mgRNA spacer and / or the hgRNA spacer are capable of binding to the PCSK9 gene. In some embodiments, the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 213-236, 317-328, and 1128.

[0037] In some embodiments, the hgRNA spacer is capable of binding to a site on the target gene that is close to a binding site of the mgRNA spacer. In some embodiments, the hgRNA is capable of binding to a site on the target gene that is within 200 bp upstream or downstream region from the binding site of the mgRNA spacer, preferably within 100 bp upstream or downstream region from the binding site of the mgRNA spacer, more preferably within 91 bp to 34 bp upstream or downstream region from the binding site of the mgRNA spacer, most preferably within 91 bp to 34 bp upstream region from the binding site of the mgRNA spacer.

[0038] In some embodiments, the mgRNA spacer and / or the hgRNA spacer are capable of binding to the ANGPTL3 gene. In some embodiments, the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 403-429 and 550-552.

[0039] In some embodiments, the mgRNA spacer and / or the hgRNA spacer are capable of binding to the ASGR1 gene. In some embodiments, the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 563-584 and 677-684.

[0040] In some embodiments, the mgRNA spacer and / or the hgRNA spacer are capable of binding to the LPA gene. In some embodiments, the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 717-750.

[0041] In some embodiments, the mgRNA spacer and / or the hgRNA spacer are capable of binding to the AGT gene. In some embodiments, the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 925-961.

[0042] In some embodiments, the mgRNA spacer and / or the hgRNA spacer are capable of binding to the APOC3 gene. In some embodiments, the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 1249-1251.

[0043] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 213, and the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 237-239, and 277-279.

[0044] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 214, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 240 and 280.

[0045] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 215, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 241242, and 281-282.

[0046] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 216, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 243245, and 283-285.

[0047] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 217, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 246247, and 286-287.

[0048] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 218, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 248250, and 288-290.

[0049] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 219, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 251253, and 291-293.

[0050] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 220, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 254 and 294.

[0051] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 221, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 255256, and 295-296.

[0052] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 222, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 257 and 297.

[0053] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 223, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 258259, and 298-299.

[0054] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 224, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 260 and 300.

[0055] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 225, the hgRNA spacer comprises a sequence selected from SEQ ID NO: 261 and 301.

[0056] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 226, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 262 and 302.

[0057] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 227, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 263 and 303.

[0058] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 228, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 264 and 304.

[0059] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 229, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 265 and 305.

[0060] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 230, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 266 and 306.

[0061] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 231, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 267 and 307.

[0062] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 232, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 268 and 308.

[0063] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 233, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 269 and 309.

[0064] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 234, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 270 and 310.

[0065] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 235, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 271274 and 311-314.

[0066] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 236, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 275276 and 315-316.

[0067] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 317, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 329331 and 366-368.

[0068] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 318, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 332333 and 369-370.

[0069] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 319, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 334335 and 371-372.

[0070] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 320, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 336337 and 373-374.

[0071] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 321, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 338340 and 375-377.

[0072] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 322, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 341344 and 378-381.

[0073] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 323, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 345349 and 382-386.

[0074] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 324, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 350354 and 387-391.

[0075] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 325, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 355356 and 392-393.

[0076] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 326, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 357359 and 394-396.

[0077] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 327, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 360363 and 397-400.

[0078] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 328, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 364365 and 401-402.

[0079] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1128, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1129 and 1130.

[0080] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 403, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 430432 and 490-492.

[0081] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 404, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 433434 and 493-494.

[0082] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 405, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 435436 and 495-496.

[0083] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 406, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 437 and 497.

[0084] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 407, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 438440 and 498-500.

[0085] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 408, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 441443 and 501-503.

[0086] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 409, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 444446 and 504-506.

[0087] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 410, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 447449 and 507-509.

[0088] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 411, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 450452 and 510-512.

[0089] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 412, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 453 and 513.

[0090] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 413, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 454456 and 514-516.

[0091] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 414, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 457458 and 517-518.

[0092] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 415, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 459461 and 519-521.

[0093] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 416, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 462463 and 522-523.

[0094] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 417, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 464465 and 524-525.

[0095] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 418, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 466468 and 526-528.

[0096] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 419, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 469470 and 529-530.

[0097] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 420, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 471472 and 531-532.

[0098] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 421, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 473 and 533.

[0099] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 422, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 474475 and 534-535.

[00100] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 423, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 476477 and 536-537.

[00101] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 424, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 478 and 538.

[00102] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 425, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 479481 and 539-541.

[00103] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 426, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 482484 and 542-544.

[00104] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 427, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 485 and 545.

[00105] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 428, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 486487 and 546-547.

[00106] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 429, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 488489 and 548-549.

[00107] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 550, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 553 and 558.

[00108] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 551, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 554555 and 559-560.

[00109] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 552, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 556557 and 561-562.

[00110] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 563, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 585 and 631.

[00111] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 564, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 586 and 632.

[00112] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 565, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 587588 and 633-634.

[00113] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 566, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 589590 and 635-636.

[00114] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 567, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 591593 and 637-639.

[00115] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 568, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 594596 and 640-642.

[00116] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 569, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 597598 and 643-644.

[00117] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 570, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 599601 and 645-647.

[00118] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 571, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 602604 and 648-650.

[00119] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 572, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 605606 and 651-652.

[00120] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 573, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 607608 and 653-654.

[00121] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 574, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 609610 and 655-656.

[00122] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 575, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 611612 and 657-658.

[00123] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 576, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 613614 and 659-660.

[00124] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 577, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 615616 and 661-662.

[00125] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 578, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 617619 and 663-665.

[00126] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 579, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 620622 and 666-668.

[00127] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 580, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 623625 and 669-671.

[00128] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 581, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 626 and 672.

[00129] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 582, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 627 and 673.

[00130] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 583, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 628 and 674.

[00131] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 584, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 629630 and 675-676.

[00132] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 677, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 685687 and 701-703.

[00133] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 678, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 688689 and 704-705.

[00134] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 679, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 690691 and 706-707.

[00135] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 680, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 692693 and 708-709.

[00136] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 681, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 694 and 710.

[00137] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 682, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 695696 and 711-712.

[00138] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 683, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 697698 and 713-714.

[00139] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 684, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 699700 and 715-716.

[00140] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 717, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 751755 and 838-842.

[00141] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 718, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 756760 and 843-847.

[00142] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 719, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 761765 and 848-852.

[00143] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 720, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 766769 and 853-856.

[00144] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 721, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 770773 and 857-860.

[00145] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 722, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 774775 and 861-862.

[00146] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 723, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 776778 and 863-865.

[00147] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 724, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 779 and 866.

[00148] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 725, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 780782 and 867-869.

[00149] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 726, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 783785 and 870-872.

[00150] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 727, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 786788 and 873-875.

[00151] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 728, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 789 and 876.

[00152] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 729, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 790792 and 877-879.

[00153] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 730, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 793 and 880.

[00154] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 731, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 794795 and 881-882.

[00155] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 732, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 796798 and 883-885.

[00156] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 733, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 799 and 886.

[00157] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 734, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 800802 and 887-889.

[00158] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 735, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 803804 and 890-891.

[00159] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 736, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 805806 and 892-893.

[00160] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 737, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 807 and 894.

[00161] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 738, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 808 and 895.

[00162] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 739, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 809810 and 896-897.

[00163] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 740, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 811813 and 898-900.

[00164] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 741, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 814815 and 901-902.

[00165] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 742, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 816818 and 903-905.

[00166] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 743, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 819820 and 906-907.

[00167] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 744, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 821823 and 908-910.

[00168] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 745, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 824825 and 911-912.

[00169] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 746, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 826828 and 913-915.

[00170] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 747, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 829831 and 916-918.

[00171] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 748, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 832833 and 919-920.

[00172] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 749, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 834 and 921.

[00173] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 750, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 835837 and 922-924.

[00174] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 925, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 962964 and 1034-1036.

[00175] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 926, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 965966 and 1037-1038.

[00176] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 927, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 967968 and 1039-1040.

[00177] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 928, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 969970 and 1041-1042.

[00178] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 929, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 971972 and 1043-1044.

[00179] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 930, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 973974 and 1045-1046.

[00180] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 931, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 975977 and 1047-1049.

[00181] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 932, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 978980 and 1050-1052.

[00182] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 933, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 981 and 1053.

[00183] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 934, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 982984 and 1054-1056.

[00184] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 935, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 985987 and 1057-1059.

[00185] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 936, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 988989 and 1060-1061.

[00186] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 937, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 990991 and 1062-1063.

[00187] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 938, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 992993 and 1064-1065.

[00188] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 939, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 994995 and 1066-1067.

[00189] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 940, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 996997 and 1068-1069.

[00190] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 941, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 998999 and 1070-1071.

[00191] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 942, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1000-1001 and 1072-1073.

[00192] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 943, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1002-1003 and 1074-1075.

[00193] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 944, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1004-1005 and 1076-1077.

[00194] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 945, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1006-1007 and 1078-1079.

[00195] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 946, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1008-1009 and 1080-1081.

[00196] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 947, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1010-1011 and 1082-1083.

[00197] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 948, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1012 and 1084.

[00198] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 949, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1013 and 1085.

[00199] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 950, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1014-1015 and 1086-1087.

[00200] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 951, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1016-1017 and 1088-1089.

[00201] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 952, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1018-1019 and 1090-1091.

[00202] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 953, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1020 and 1092.

[00203] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 954, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1021-1022 and 1093-1094.

[00204] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 955, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1023 and 1095.

[00205] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 956, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1024 and 1096.

[00206] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 957, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1025-1026 and 1097-1098.

[00207] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 958, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1027-1028 and 1099-1100.

[00208] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 959, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1029-1030 and 1101-1102.

[00209] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 960, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1031 and 1103.

[00210] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 961, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1032-1033 and 1104-1105.

[00211] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1249, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1252-1254 and 1259-1261.

[00212] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1250, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1255-1256 and 1262-1263.

[00213] In some embodiments, the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1251, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1257-1258 and 1264-1265.

[00214] In some embodiments, the mgRNA which is capable of binding to a target sequence located in PCSK9 gene, comprises a sequence selected from SEQ ID NOs: 1109, 1110, 1119, 1121, 1125, and 1127.

[00215] In some embodiments, the hgRNA which is capable of binding to PCSK9 gene comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122-1124, and 1126.

[00216] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1109, the hgRNA comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122 and 1123.

[00217] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1110, the hgRNA comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122 and 1123.

[00218] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1119, the hgRNA comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122 and 1123.

[00219] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1121, the hgRNA comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122 and 1123.

[00220] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1125, the hgRNA comprises a sequence represented by SEQ ID NOs: 1124.

[00221] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1127, the hgRNA comprises a sequence represented by SEQ ID NOs: 1126.

[00222] In some embodiments, the mgRNA which is capable of binding to a target sequence located in ANGPTL3 gene, comprises a sequence selected from SEQ ID NOs: 1132, 1134, and 1136.

[00223] In some embodiments, the hgRNA which is capable of binding to ANGPTL3 gene comprises a sequence selected from SEQ ID NOs: 1131, 1133, and 1135.

[00224] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1132, the hgRNA comprises a sequence represented by SEQ ID NO: 1131.

[00225] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1134, the hgRNA comprises a sequence represented by SEQ ID NO: 1133.

[00226] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1136, the hgRNA comprises a sequence represented by SEQ ID NOs: 1135.

[00227] In some embodiments, the mgRNA which is capable of binding to a target sequence located in APOC3 gene, comprises a sequence selected from SEQ ID NOs: 1266, 1268, 1270, 1272, 1274, and 1276.

[00228] In some embodiments, the hgRNA which is capable of binding to APOC3 gene comprises a sequence selected from SEQ ID NOs: 1267, 1269, 1271, 1273, 1275 and 1277.

[00229] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1266, the hgRNA comprises a sequence represented by SEQ ID NO: 1267.

[00230] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1268, the hgRNA comprises a sequence represented by SEQ ID NO: 1269.

[00231] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1270, the hgRNA comprises a sequence represented by SEQ ID NOs: 1271.

[00232] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1272, the hgRNA comprises a sequence represented by SEQ ID NOs: 1273.

[00233] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1274, the hgRNA comprises a sequence represented by SEQ ID NOs: 1275.

[00234] In some embodiments, the mgRNA comprises a sequence represented by SEQ ID NO: 1276, the hgRNA comprises a sequence represented by SEQ ID NOs: 1277.

[00235] In some embodiments, the gene editing system disclosed herein comprises (1) an hgRNA comprising a CRISPR motif, an hgRNA spacer, and a first protein-binding motif, or a DNA polynucleotide encoding the hgRNA, (2) an mgRNA comprising a second CRISPR motif and an mgRNA spacer, or a DNA polynucleotide encoding the mgRNA, (3) a first CRISPR-associated protein (Cas protein), or a polynucleotide encoding the first Cas protein, wherein the first Cas protein binds to the first CRISPR motif, (4) a second Cas protein, or a polynucleotide encoding the second Cas protein, wherein the second Cas protein binds to the second CRISPR motif, and (5) a first fusion protein comprising a nucleobase deaminase or a catalytic domain thereof and a first RNA binding domain, or a polynucleotide encoding the first fusion protein, wherein the nucleobase deaminase or the catalytic domain thereof and the first RNA binding domain are optionally connected by a linker, and wherein the first RNA binding domain binds to the first protein-binding motif, and wherein the first Cas protein and second Cas protein are the same or different.

[00236] In some embodiments, the gene editing system disclosed herein comprises (1) an hgRNA comprising a CRISPR motif, an hgRNA spacer, and a first protein-binding motif, or a DNA polynucleotide encoding the hgRNA, (2) an mgRNA comprising a second CRISPR motif and the mgRNA spacer, or a DNA polynucleotide encoding the mgRNA, (3) a first CRISPR-associated protein (Cas protein), or a polynucleotide encoding the first Cas protein, wherein the first Cas protein binds to the first CRISPR motif, (4) a second Cas protein, or a polynucleotide encoding the second Cas protein, wherein the second Cas protein binds to the second CRISPR motif, (5) a first fusion protein comprising a nucleobase deaminase or a catalytic domain thereof and a first RNA binding domain, or a polynucleotide encoding the first fusion protein, wherein the nucleobase deaminase or the catalytic domain thereof and the first RNA binding domain are optionally connected by a linker, and wherein the first RNA binding domain binds to the first protein-binding motif, (6) a protease, or a polynucleotide encoding the protease, and (7) a nucleobase deaminase inhibitor domain, wherein the first Cas protein and second Cas protein are the same or different, wherein the nucleobase deaminase inhibitor domain is connected to the nucleobase deaminase or the catalytic domain thereof in the first fusion protein optionally by a linker, and wherein there is a cleavage site for the protease between the nucleobase deaminase inhibitor domain and the nucleobase deaminase or the catalytic domain thereof.

[00237] In some embodiments, the gene editing system disclosed herein comprises (1) an hgRNA comprising a CRISPR motif, an hgRNA spacer, and a first protein-binding motif, or a DNA polynucleotide encoding the hgRNA, (2) an mgRNA comprising a second CRISPR motif and an mgRNA spacer, or a DNA polynucleotide encoding the mgRNA, (3) a first CRISPR-associated protein (Cas protein), or a polynucleotide encoding the first Cas protein, wherein the first Cas protein binds to the first CRISPR motif, (4) a second Cas protein, or a polynucleotide encoding the second Cas protein, wherein the second Cas protein binds to the second CRISPR motif, (5) a first fusion protein comprising a nucleobase deaminase or a catalytic domain thereof and a first RNA binding domain, or a polynucleotide encoding the first fusion protein, wherein the nucleobase deaminase or the catalytic domain thereof and the first RNA binding domain are optionally connected by a linker, and wherein the first RNA binding domain binds to the first protein-binding motif, (6) a protease, or a polynucleotide encoding the protease, (7) a nucleobase deaminase inhibitor domain, and (8) a second fusion protein comprising the protease and a second RNA binding domain, or a polynucleotide encoding the second fusion protein, wherein the first Cas protein and second Cas protein are the same or different, wherein the nucleobase deaminase inhibitor domain is connected to the nucleobase deaminase or the catalytic domain thereof in the first fusion protein optionally by a linker, and wherein there is a cleavage site for the protease between the nucleobase deaminase inhibitor domain and the nucleobase deaminase or the catalytic domain thereof, wherein the protease and the second RNA binding domain are optionally connected by a linker, wherein the mgRNA further comprises a second protein-binding motif, and wherein the second RNA binding domain binds to the second protein-binding motif.

[00238] In some embodiments, the protease is split into a first protease fragment and a second protease fragment, wherein the first or second protease fragment alone is not able to cleave the cleavage site.

[00239] In some embodiments, the gene editing system disclosed herein comprises (1) an hgRNA comprising a CRISPR motif, an hgRNA spacer, and a first protein-binding motif, or a DNA polynucleotide encoding the hgRNA, (2) an mgRNA comprising a second CRISPR motif and an mgRNA spacer, or a DNA polynucleotide encoding the mgRNA, (3) a first CRISPR-associated protein (Cas protein), or a polynucleotide encoding the first Cas protein, wherein the first Cas protein binds to the first CRISPR motif, (4) a second Cas protein, or a polynucleotide encoding the second Cas protein, wherein the second Cas protein binds to the second CRISPR motif, (5) a first fusion protein comprising a nucleobase deaminase or a catalytic domain thereof and a first RNA binding domain, or a polynucleotide encoding the first fusion protein, wherein the nucleobase deaminase or the catalytic domain thereof and the first RNA binding domain are optionally connected by a linker, and wherein the first RNA binding domain binds to the first protein-binding motif, (6) a protease, or a polynucleotide encoding the protease, (7) a nucleobase deaminase inhibitor domain, (8) a second fusion protein comprising the first protease fragment and a second RNA binding domain, or a polynucleotide encoding the second fusion protein, wherein the first protease fragment and the second RNA binding domain are optionally connected by a linker, and (9) a third fusion protein comprising the second protease fragment and a third RNA binding domain, or a polynucleotide encoding the third fusion protein, wherein the second protease fragment and the third RNA binding domain are optionally connected by a linker, wherein the first Cas protein and second Cas protein are the same or different, wherein the nucleobase deaminase inhibitor domain is connected to the nucleobase deaminase or the catalytic domain thereof in the first fusion protein optionally by a linker, and wherein there is a cleavage site for the protease between the nucleobase deaminase inhibitor domain and the nucleobase deaminase or the catalytic domain thereof, wherein the mgRNA further comprises a second proteinbinding motif and a third protein-binding motif, wherein the second RNA binding domain binds to the second protein-binding motif, and wherein the third RNA binding domain binds to the third protein-binding motif.

[00240] In some embodiments, the gene editing system disclosed herein comprises (1) an hgRNA comprising a CRISPR motif, an hgRNA spacer, and a first protein-binding motif, or a DNA polynucleotide encoding the hgRNA, (2) an mgRNA comprising a second CRISPR motif and an mgRNA spacer, or a DNA polynucleotide encoding the mgRNA, (3) a first CRISPR-associated protein (Cas protein), or a polynucleotide encoding the first Cas protein, wherein the first Cas protein binds to the first CRISPR motif, (4) a second Cas protein, or a polynucleotide encoding the second Cas protein, wherein the second Cas protein binds to the second CRISPR motif, (5) a first fusion protein comprising a nucleobase deaminase or a catalytic domain thereof and a first RNA binding domain, or a polynucleotide encoding the first fusion protein, wherein the nucleobase deaminase or the catalytic domain thereof and the first RNA binding domain are optionally connected by a linker, and wherein the first RNA binding domain binds to the first protein-binding motif, (6) a protease, or a polynucleotide encoding the protease, (7) a nucleobase deaminase inhibitor domain, (8) a second fusion protein comprising the first protease fragment and a second RNA binding domain, or a polynucleotide encoding the second fusion protein, wherein the first protease fragment and the second RNA binding domain are optionally connected by a linker, and (9) a third fusion protein comprising the second protease fragment and a third RNA binding domain, or a polynucleotide encoding the third fusion protein, wherein the second protease fragment and the third RNA binding domain are optionally connected by a linker, wherein the first Cas protein and second Cas protein are the same or different, wherein the nucleobase deaminase inhibitor domain is connected to the nucleobase deaminase or the catalytic domain thereof in the first fusion protein optionally by a linker, and wherein there is a cleavage site for the protease between the nucleobase deaminase inhibitor domain and the nucleobase deaminase or the catalytic domain thereof, wherein the mgRNA further comprises a second proteinbinding motif and a third protein-binding motif, wherein the second RNA binding domain binds to the second protein-binding motif, wherein the third RNA binding domain binds to the third protein-binding motif, wherein the second and third RNA binding domains are the same or different, and the second and third protein-binding motifs are the same or different.

[00241] In some embodiments, the gene editing system disclosed herein comprises (1) an hgRNA comprising a CRISPR motif, an hgRNA spacer, and a first protein-binding motif, or a DNA polynucleotide encoding the hgRNA, (2) the mgRNA comprising a second CRISPR motif and an mgRNA spacer, or a DNA polynucleotide encoding the mgRNA, (3) a first CRISPR-associated protein (Cas protein), or a polynucleotide encoding the first Cas protein, wherein the first Cas protein binds to the first CRISPR motif, (4) a second Cas protein, or a polynucleotide encoding the second Cas protein, wherein the second Cas protein binds to the second CRISPR motif, (5) a first fusion protein comprising a nucleobase deaminase or a catalytic domain thereof and a first RNA binding domain, or a polynucleotide encoding the first fusion protein, wherein the nucleobase deaminase or the catalytic domain thereof and the first RNA binding domain are optionally connected by a linker, and wherein the first RNA binding domain binds to the first protein-binding motif, (6) a protease, or a polynucleotide encoding the protease, (7) a nucleobase deaminase inhibitor domain, (8) a second fusion protein comprising the first protease fragment and a second RNA binding domain, or a polynucleotide encoding the second fusion protein, wherein the first Cas protein and second Cas protein are the same or different, wherein the nucleobase deaminase inhibitor domain is connected to the nucleobase deaminase or the catalytic domain thereof in the first fusion protein optionally by a linker, and wherein there is a cleavage site for the protease between the nucleobase deaminase inhibitor domain and the nucleobase deaminase or the catalytic domain thereof, wherein the first protease fragment and the second RNA binding domain are optionally connected by a linker, wherein the mgRNA further comprises a second proteinbinding motif, and wherein the second RNA binding domain binds to the second proteinbinding motif.

[00242] In some embodiments, the protease is a TEV protease, a TuMV protease, a PPV protease, a PVY protease, a ZIKV protease, or a WNV protease.

[00243] In some embodiments, the protease cleavage site is a self-cleaving peptide, such as the 2A peptides. “2A peptides” are 18-22 amino-acid-long viral oligopeptides that mediate “cleavage” of polypeptides during translation in eukaryotic cells. The designation “2A” refers to a specific region of the viral genome and different viral 2As have generally been named after the virus they were derived from. The first discovered 2A was F2A (foot-and-mouth disease virus), after which E2A (equine rhinitis A virus), P2A (porcine teschovirus-1 2A), and T2A (thosea asigna virus 2A) were also identified. A few non-limiting examples of 2A peptides are provided as GSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 210); GSGEGRGSLLTCGDVEENPGP (SEQ ID NO: 211); and GSGQCTNYALLKLAGDVESNPGP (SEQ ID NO: 212).

[00244] In some embodiments, the protease is a TEV protease. In some embodiments, the TEV protease comprises a sequence as set forth in SEQ ID NO: 195.

[00245] In some embodiments, the first and / or the second TEV protease fragment is not able to cleave the TEV cleavage site on its own. However, in the presence of the remaining portion of the TEV protease, this fragment will be able to effectuate the cleavage. The TEV fragment may be the TEV N-terminal domain (e.g., SEQ ID NO: 196) or the TEV C-terminal domain (e.g., SEQ ID NO: 197). In some embodiments, the first TEV protease fragment comprises a sequence of SEQ ID NO: 196. In some embodiments, the first TEV protease fragment comprises a sequence of SEQ ID NO: 197.

[00246] In some embodiments, the nucleobase deaminase inhibitor is an inhibitory domain of a nucleobase deaminase.

[00247] A “nucleobase deaminase inhibitor” or an “inhibitory domain” refers to a protein or a protein domain that inhibits the deaminase activity of a nucleobase deaminase.

[00248] In some embodiments, the nucleobase deaminase inhibitor is an inhibitory domain of a nucleobase deaminase. In some embodiments, the nucleobase deaminase inhibitor is an inhibitory domain of a human cytidine deaminase or mouse cytidine deaminase. In some embodiments, the nucleobase deaminase inhibitor is a mouse A3 cytidine deaminase domain 2 (mA3-CDA2) or human A3B cytidine deaminase domain 1 (hA3B-CDAl).

[00249] In some embodiments, the inhibitory domain of a cytidine deaminase comprises an amino acid sequence selected from SEQ ID NO: 1145-1234, preferably, the inhibitory domain of a cytidine deaminase comprises an amino acid sequence selected from SEQ ID NO: 1145 and 1146.

[00250] Table 1 shows proteins / domains that have significant sequence homology to mA3-CDA2 core sequence and / or hA3B-CDAl. All of these proteins and domains, as well as their variants and equivalents, are contemplated to have nucleobase deaminase inhibition activities.

[00251] Table 1 Name Sequence SEQ ID NO: mouse APOBEC3 cytidine deaminase domain 2 (mA3-CDA2) MSSSTLSNICLTKGLPETRFWVEGRRMDPLSEEEF YSQFYNQRVKHLCYYHRMKPYLCYQLEQFNGQA PLKGCLLSEKGKQHAEILFLDKIRSMELSQVTITC YLTWSPCPNCAWQLAAFKRDRPDLILHIYTSRLYF HWKRPFQKGLCSLWQSGILVDVMDLPQFTDCWT NFVNPKRPFWPWKGLEIISRRTQRRLRRIKESWGL QDLVNDFGNLQLGPPMS SEQ ID NO: 1145 human APOBEC3B cytidine deaminase domain 1 (hA3B-CDA1) MNPQIRNPMERMYRDTFYDNFENEPILYGRSYTW LCYEVKIKRGRSNLLWDTGVFRGQVYFKPQYHA EMCFLSWFCGNQLPAYKCFQITWFVSWTPCPDCV AKLAEFLSEHPNVTLTISAARLYYYWERDYRRAL CRLSQAGARVKIMDYEEFAYCWENFVYNEGQ SEQ ID NO: 1146 Mouse APOBEC3 cytidine deaminase domain 2 core (AA282-AA355) SEKGKQHAEILFLDKIRSMELSQVTITCYLTWSPC PNCAWQLAAFKRDRPDLILHIYTSRLYFHWKRPF QKGLC SEQ ID NO: 1147 Mus spicilegus A3 (AA248-AA321) SEKGKQHAEILFLDKIRSMELSQVTITCYLTWSPC PNCAWQLAAFKRDRPDLIPHIYTSRLYFHWKRPF QKGLC SEQ ID NO: 1148 Cricetulus longicaudatus A3 (AA249-AA322) SEKGKQHAEILFLDKIRSMELSQVTITCYLTWSPC PNCAWRLAAFKRDRPDLILHIYTSRLYFHWKRPF QKGLC SEQ ID NO: 1149 Mus terricolor A3 (AA248-AA321) SEKGKQHAEILFLNKIRSMELSQVTITCYLTWSPC PNCAWQLAAFKKDRPDLILHIYTSRLYFHWKRPF QKGLC SEQ ID NO: 1150 Mus caroli A3 (AA260-AA333) SKKGKQHAEILFLDKIRSMELSQVTITCYLTWSPC PNCAWQLAAFKRDHPDLILHIYTSRLYFHWKRPF QKGLC SEQ ID NO: 1151 Mus pahari A3 (AA263-AA336) SKKGKQHAEILFLEKIRSMELSQMRITCYLTWSPC PNCAWQLAAFQKDRPDLILHIYTSRLYFHWRRIFQ KGLC SEQID NO: 1152 Mus shortridgei A3 (AA233-AA306) SKKGKQHAEILFLEKIRSMELSQMRITCYLTWSPC PNCAWQLAAFQKDRPDLILHIYTSRLYFHWRRIFQ KGLC SEQID NO: 1153 Mus setulosus A3 (AA29-AA302) SKKGKQHAEILFLDKIRSMELSQVRITCYLTWSPC PNCAWQLETFKKDRPDLILHIYTSRLYFHWKRAF QEGLC SEQID NO: 1154 Grammomys surdaster A3 (AA270-AA344) SKKGKPHAEILFLDKMWSMEELSQVRITCYLTWS PCPNCARQLAAFKKDHPGLILRIYTSRLYFYWRR KFQKGLC SEQID NO: 1155 Rattus norvegicus A3 (AA256-AA328) KKGEQHVEILFLEKMRSMELSQVRITCYLTWSPCP NCARQLAAFKKDHPDLILRIYTSRLYFYWRKKFQ KGLC SEQID NO: 1156 Mastomys coucha A3 (AA258-AA331) SKKGRQHAEILFLEKVRSMQLSQVRITCYLTWSPC PNCAWQLAAFKMDHPDLILRIYASRLYFHWRRAF QKGLC SEQID NO: 1157 Cricetulus griseus A3B (AA235-AA307) NKKGKHAEILFIDEMRSLELGQVQITCYLTWSPCP NCAQELAAFKSDHPDLVLRIYTSRLYFHWRRKYQ EGLC SEQID NO: 1158 Peromyscus leucopus A3 (AA266-AA338) NKKGKHAEILFIDEMRSLELGQARITCYLTWSPCP NCAQKLAAFKKDHPDLVLRVYTSRLYFHWRRKY QEGLC SEQID NO: 1159 Mesocricetus auratus A3 (AA268-AA340) NKKDKHAEILFIDKMRSLELCQVRITCYLTWSPCP NCAQELAAFKKDHPDLVLRIYTSRLYFHWRRKY QEGLC SEQID NO: 1160 Micro tus ochrogaster A3B (AA266-AA338) NKKGKHAEILFIDEMRSLKLSQERITCYLTWSPCP NCAQELAAFKRDHPGLVLRIYASRLYFHWRRKY QEGLC SEQID NO: 1161 Nannospalax galili A3 (AA231-AA302) NKRAKHAEILLIDMMRSMELGQVQITCYITWSPC PTCAQELAAFKQDHPDLVLRIYASRLYFHWKRKF QKGL SEQID NO: 1162 Meriones unguiculatus A3 (AA233-AA3O5) NKKGRHAEICLIDEMRSLGLGKAQITCYLTWSPC RKCAQELATFKKDHPDLVLRVYASRLYFHWSRK YQQGLC SEQID NO: 1163 Dipodomys ordii A3 (AA256-AA33O) NKKGHHAEIRFIERIRSMGLDPSQDYQITCYLTWS PCLDCAFKLAKLKKDFPRLTLRIFTSRLYFHWIRK FQKGL SEQID NO: 1164 Jaculus jaculus A3 (AA3O3-AA374) NKKGKHAEARFVDKMRSMQLDHALITCYLTWSP CLDCSQKLAALKRDHPGLTLRIFTSRLYFHWVKK FQEGL SEQID NO: 1165 Chinchilla lanigera A3H (AA86-AA161) SPQKGHHAESRFIKRISSMDLDRSRSYQITCFLTWS PCPSCAQELASFKRAHPHLRFQIFVSRLYFHWKRS YQAGL SEQID NO: 1166 Heterocephalus glaber A3 (AA277-AA350) KKGYHAESRFIKRICSMDLGQDQSYQVTCFLTWS PCPHCAQELVSFKRAHPHLRLQIFTARLFFHWKRS YQEGL SEQID NO: 1167 Octodon degus A3 (AA256-AA329) KKGQHAEIRFIERIHSMALDQARSYQITCFLTWSP CPFCAQELASFKSTHPRVHLQIFVSRLYFHWKRSY QEGL SEQID NO: 1168 Urocitellus parryii A3 (AA256-AA330) NKKGHHAEIRFIKKIRSLDLDQSQNYEVTCYLTWS PCPDCAQELVALTRSHPHVRLRLFTSRLYFHWFW SFQEGL SEQID NO: 1169 Aotus nancymaae A3H (AA75-AA146) NRHAEICFIDEIESMGLDKTQCYEVTCYLTWSPCP SCAQKLAAFTKAQVHLNLRIFASRLYYHWRSSYQ KGL SEQID NO: 1170 Cebus capucinus imitator A3H (AA55-AA126) NRHAEICFIDEIESMGLDKTQCYEVTCYLTWSPCP SCAQKLVAFAKAQDHLNLRIFASRLYYHWRRRY KEGL SEQID NO: 1171 Saimiri boliviensis boliviensis A3H (AA56-AA125) HVEICFIDKIASMELDKTQCYDVTCYLTWSPCPSC AQKLAAFAKAQDHLNLRIFASRLYYHWRRSYQK GL SEQID NO: 1172 Homo sapiens A3H (AA49-AA123) NKKKCHAEICFINEIKSMGLDETQCYQVTCYLTW SPCSSCAWELVDFIKAHDHLNLGIFASRLYYHWC KPQQKGL SEQID NO: 1173 Homo sapiens ARP10 (AA48-AA123) ENKKKCHAEICFINEIKSMGLDETQCYQVTCYLT WSPCSSCAWELVDFIKAHDHLNLGIFASRLYYHW CKPQQKGL SEQID NO: 1174 Pan paniscus A3H (AA49- AA123) NKKKCHAEICFINEIKSMGLDETQCYQVTCYLTW SPCSSCAWKLVDFIQAHDHLNLRIFASRLYYHWC KPQQEGL SEQID NO: 1175 Symphalangy s syndactylus A3H (AA49-AA123) NKKKRHAEIRFINKIKSMGLDETQCYQVTCYLTW SPCPSCAWELVDFIKAHDHLNLGIFASRLYYHWC RHQQEGL SEQID NO: 1176 Macaca mulatta A3H (AA49-AA123) NKKKDHAEIRFINKIKSMGLDETQCYQVTCYLTW SPCPSCAGELVDFIKAHRHLNLRIFASRLYYHWRP NYQEGL SEQID NO: 1177 Theropithecus gelada A3H (AA54-AA128) NKKKEHAEIRFINKIKSMGLDETQCYQVTCYLTW SPCPSCAGKLVDFIKAHHHLNLRIFASRLYYHWRP NYQEGL SEQID NO: 1178 Mandrillus leucophaeus A3H (AA49-AA123) NKKKHHAEIHFINKIKSMGLDETQCYQVTCYLTW SPCPSCARELVDFIKAHRHLNLRIFASRLYYHWRP HYQEGL SEQID NO: 1179 Bos grunniens A3 (AA74-AA148) NKKQRHAEIRFIDKINSLDLNPSQSYKIICYITWSP CPNCANELVNFITRNNHLKLEIFASRLYFHWIKPF KMGL SEQID NO: 1180 Bubalus bubalis A3 (AA74-AA148) NKKQRHAEIRFIDKINSLDLNPSQSYKIICYITWSP CPNCASELVDFITRNDHLDLQIFASRLYFHWIKPF KRGL SEQID NO: 1181 Odocoileus virginianus texanus A3H (AA209-AA283) NKKQRHAEIRFIDKINSLNLDRRQSYKIICYITWSP CPRCASELVDFITGNDHLNLQIFASRLYFHWKKPF QRGL SEQID NO: 1182 Sus scrofa A3 (AA51-AA125) NKKKRHAEIRFIDKINSLNLDQNQCYRIICYVTWS PCHNCAKELVDFISNRHHLSLQLFASRLYFHWVR CYQRGL SEQID NO: 1183 Ceratotherium simum simum A3B (AA232-AA306) NKKKRHAEIRFIDKIKSLGLDRVQSYEITCYITWSP CPTCALELVAFTRDYPRLSLQIFASRLYFHWRRRS IQGL SEQID NO: 1184 Equus caballus A3H (AA79-AA153) NKKKRHAEIRFIDKINSLGLDQDQSYEITCYVTWS PCATCACKLIKFTRKFPNLSLRIFVSRLYYHWFRQ NQQGL SEQID NO: 1185 Enhydra lutris kenyoni A3B (AA243-AA316) KKKRHAEIRFIDSIRALQLDQSQRFEITCYLTWSPC PTCAKELAMFVQDHPHISLRLFASRLYFHWRWKY QEGL SEQID NO: 1186 Leptonychotes weddellii A3H (AA50-AA123) KKKRHAEIRFIDNIKALRLDTSQRFEITCYVTWSPC PTCAKELVAFVRDHRHISLRLFASRLYFHWLREN KKGL SEQID NO: 1187 Ursus arctos horribilis A3F (AA552-AA626) NKKKRHAEIRFIDKIRSLQRDSSQTFEITCYVTWSP CFTCAEELVAFVRDHPHVRLRLFASRLYFHWLRK YQEGL SEQID NO: 1188 Panthera leo bleyenberghi A3H (AA50-AA124) NKKKRHAEICFIDKIKSLTRDTSQRFEIICYITWSPC PFCAEELVAFVKDNPHLSLRIFASRLYVHWRWKY QQGL SEQID NO: 1189 Panthera tigris sumatrae A3H (AA50-AA124) NKKKRHAEICFIDKIKSLTRDTSQRFEIICYITWSPC PFCAEELVAFVKDNPHLSLRIFASRLYVHWRWKY QQGL SEQID NO: 1190 Tupaia belangeri A3 (AA46-AA120) NKKHRHAEVRFIAKIRSMSLDLDQKHQLTCYLTW SPCPSCAQELVTFMAESRHLNLQVFVSRLYFHWQ RDFQQGL SEQID NO: 1191 Gorilla A3B (AA29-AA138) GRSYNWLCYEVKIKRGRSNLLWNTGVFRGQMYS QPEHHAEMCFLSWFCGNQLPAYKCFQITWFVSW TPCPDCVAKLAEFLAEYPNVTLTISTARLYYYWE RDYRRALCRL SEQID NO: 1192 Pan paniscus A3B (AA29- AA138) GRSYTWLCYEVKIRRGHSNLLWDTGVFRGQMYS QPEHHAEMYFLSWFCGNQLPAYKCFQITWFVSW TPCPDCVAKLAEFLAEHPNVTLTISAARLYYYWE RDYRRALCRL SEQID NO: 1193 Pan troglodytes A3B (AA29-AA138) GRSYTWLCYEVKIRRGHSNLLWDTGVFRGQMYS QPEHHAEMCFLSWFCGNQLSAYKCFQITWFVSW TPCPDCVAKLAKFLAEHPNVTLTISAARLYYYWE RDYRRALCRL SEQID NO: 1194 Gorilla A3F (AA30-AA137) RNTVWLCYEVKTKGPSRPPLDAKIFRGQVYFEPQ YHAEMCFLSWFCGNQLPAYKCFQITWFVSWTPCP DCVAKLAEFLAEHPNVTLTISAARLYYYWE SEQID NO: 1195 Pan troglodytes A3F (AA30-AA137) RNTVWLCYEVKTKGPSRPRLDTKIFRGQVYFEPQ YHAEMCFLSWFCGNQLPAYKCFQITWFVSWTPCP DCVAKLAEFLAEHPNVTLTISAARLYYYWERDYR RALCRL SEQID NO: 1196 Human sapiens A3F (AA30-AA137) RNTVWLCYEVKTKGPSRPRLDAKIFRGQVYSQPE HHAEMCFLSWFCGNQLPAYKCFQITWFVSWTPCP DCVAKLAEFLAEHPNVTLTISAARLYYYWERDYR RALCRL SEQID NO: 1197 Macaca leonine A3F (AA30-AA137) RNTVWLCYEVKTRGPSMPTWGTKIFRGQVCFEPQ YHAEMCFLSRFCGNQLPAYKRFQITWFVSWTPCP DCVAKVAEFLAEHPNVTLTISAARLYYYWETDYR RALCRL SEQID NO: 1198 Macaca nemestrina A3F (AA30-AA137) RNTVWLCYEVKTRGPSMPTWGTKIFRGQVCFEPQ YHAEMCFLSRFCGNQLPAYKRFQITWFVSWTPCP DCVAKVAEFLAEHPNVTLTISAARLYYYWETDYR RALCRL SEQID NO: 1199 Rhinopithecus roxellana A3F (AA30-AA137) RNTVWLCYEVKTRGPSMPTWGAKIFRGQVYFEP QYHAEMCFLSWFCGNQLPAYKRFQITWFVSWTP CPDCVAKVAEFLAEHPNVTLTISAARLYYYWETD YRRALCRL SEQID NO: 1200 Mandrillus leucophaeus A3F (AA30-AA130) RNTVWLCYKVKTRGPSMPTWGTKIFRGQVYFQP QYHAEMCFLSWFCGNQLPAYKRFQITWFVSWTP CPDCVVKVAEFLAEHPNVTLTISAARLYYYWETD Y SEQID NO: 1201 Macaca mulatta A3F (AA30-AA137) RNTVWLCYEVKTRGPSMPTWDTKIFRGQVYSKP EHHAEMCFLSRFCGNQLPAYKRFQITWFVSWTPC PDCVAKVAEFLAEHPNVTLTISAARLYYYWETDY RRALCRL SEQID NO: 1202 Theropithecus gelada A3F (AA30-AA137) RNTVWLCYEVKTRGPSMPTWGTKIFRGQVYFQP QYHAEMCFLSRFCGNQLPAYKRFQITWFVSWNPC PDCVAKVIEFLAEHPNVTLTISAARLYYYWGRDW RRALRRL SEQID NO: 1203 Cercocebus atys A3B (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWYTGVFRGQVYS KPEHHAEMCFLSRFCGNQLPAYKRFQITWFVSWN PCPDCVAKVIEFLAEHPNVTLTISAARLYYYWSRD WQRALCRL SEQID NO: 1204 Macaca fascicularis A3B (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVYS KPEHHAEMCFLSRFCGNQLPAYKRFQITWFVSWN PCPDCVAKVIEFLAEHPNVTLTISTARLYYYWGR DWQRALCRL SEQID NO: 1205 Macaca mulatta A3B (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVYS KPEHHAEMCFLSRFCGNQLPAYKRFQITWFVSWN PCPDCVAKVIEFLAEHPNVTLTISTARLYYYWGR DWQRALCRL SEQID NO: 1206 Macaca leonina A3B (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVYS KPEHHAEMCFLSRFCGNQLPAYKRFQITWFVSWN PCPDCVVKVIEFLAEHPNVTLTISTARLYYYWGR DWQRALCRL SEQID NO: 1207 Mandrillus leucophaeus A3B (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWYTGVFRGQVYS KPEHHAEMCFLSRFCGNQLPAYKRFQITWFVSWN SEQID NO: 1208 PCPDCVAKVIEFLAEHPNVTLTIFTARLYYYWGR DWQRALCRL Macaca nemestrina A3B (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVYS KPEHHAEMCFLSRFCGNQLPAYKRFQITWFVSWN PCPDCVAKVTEFLAEHPNVTLTISTARLYYYWGR DWQRALCRL SEQID NO: 1209 Rhinopithecus bieti A3F (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVYSE PEHHAEMYFLSWFCGNQLPAYKRFQITWFVSWTP CPDCVAKVAEFLTEHPNVTLTISAARLYYYRGRD WRRALCRL SEQID NO: 1210 Rhinopithecus roxellana A3B (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVYSE PEHHAEMYFLSWFCGNQLPAYKRFQITWFVSWTP CPDCVAKVAEFLTEHPNVTLTISAARLYYYRGRD WRRALCRL SEQID NO: 1211 Chlorocebus sabaeus A3B (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQMYS KPEHHAEMCFLSWFCGNQLPAHKRFQITWFVSW TPCPDCVAKVAEFLAEYPNVTLTISAARLYYYWE TDYRRALCRL SEQID NO: 1212 Nomascus leucogenys A3B (AA30-AA138) RSYTWLCYEVKIRKDPSKLPWDTGVFRGQMYFQ PEYHAEMCFLSWFCGNQLPAYKRFQITWFVSWTP CPDCVAKVAVFLAEHPNVTLTISAARLYYYWEK DWQRALCRL SEQID NO: 1213 Cercocebus atys A3F (AA29-AA138) GRSYTWLCYEVKIKKYPSKLLWDTGVFQGQVYF QPQYHAEMCFLSRFCGNQLPAYKRFQITWFVSW NPCPDCVAKVTEFLAEHPNVTLTISAARLYYYWE KDXRRALRRL SEQID NO: 1214 Papio anubis A3F (AA29-AA138) GRSYTWLCYEVKIKEDPSKLLWDTGVFQGQVYF QPQYHAEMCFLSRFCGNQLPAYKRFQITWFVSW NPCPDCVAKVTEFLAEHPNVTLTISAARLYYYWG RDWRRALRRL SEQID NO: 1215 Chlorocebus aethiops A3D (AA29-AA150) GRRYTWLCYEVKIKKDPSKLPWDTGVFPGQVRP KFQSNRRYEVYFQPQYHAEMYFLSWFCGNQLPA YKHFQITWFVSWNPCPDCVAKVTEFLAEHRNVTL TISAARLYYYWGKDWRRALCRL SEQID NO: 1216 Chlorocebus sabaeus A3D (AA29-AA134) GRRYTWLCYEVKIKKDPSKLPWDTGVFPGQPQY HAEMYFLSWFCGNQLPAYKHFQITWFVSWNPCP DCVAKVTEFLAEHRNVTLTISAARLYYYWGKDW RRALCRL SEQID NO: 1217 Chlorocebus sabaeus A3F (AA29-AA150) GRRYTWLCYEVKIKKDPSKLPWDTGVFPGQVRP KFQSNRRQKVYFQPQYHAEMYFLSWFCGNQLPA YKHFQITWFVSWNPCPDCVAKVTEFLAEHRNVTL TISAARLYYYWGKDWRRALCRL SEQID NO: 1218 Erythrocebus patas A3D (AA29-AA150) GRRYTWLCYEVKIKKDPSKLPWDTGVFQGQVRP KFQSNRRYEVYFQPQYHAEMCFLSWFCGNQLPA YKHFQITWFVSWNPCPDCVAKVTEFLAEHPNVTL TISAARLYYYWGKDWRRALCRL SEQID NO: 1219 Macaca fascicularis A3D (AA29-AA159) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVRP KLQSNRRYELSNWECRKRVYFQPQYHAEMYFLS WFCGNQLPANKRFQITWFASWNPCPDCVAKVTE FLAEHPNVTLTISVARLYYYRGKDWRRALRRL SEQID NO: 1220 Macaca fascicularis A3F (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVYF QPQYHAEMYFLSWFCGNQLPANKRFQITWFASW NPCPDCVAKVTEFLAEHPNVTLTISVARLYYYRG KDWRRALRRL SEQID NO: 1221 Macaca nemestrina A3D (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRDQVYF QPQYHAEMCFLSWFCGNQLPANKRFQITWFVSW NPCPDCVTKVTEFLAEHPNVTLTISVARLYYYRG KDWRRALRRL SEQID NO: 1222 Macaca leonina A3D (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWYTGVFRGQVYF QPQYHAEMCFLSWFCGNQLPANKRFQITWFVSW NPCPDCVAKVTEFLAEHPNVTLTISVARLYYYRG KDWRRALRRL SEQID NO: 1223 Macaca mulatta A3D (AA29-AA138) GRSYTWLCYEVKIRKDPSKLPWDTGVFRGQVYF QPQYHAEMCFLSWFCGNQLPAYKRFQITWFVSW NPCPDCVAKVTEFLAEHPNVTLTISVARLYYYRG KDWRRALCRL SEQID NO: 1224 Gorilla A3D (AA29-AA150) GRSYTWLCYEVKIRRGSSNLLWNTGVFRGPVPPK LQSNHRQEVYFQFENHAEMCFLSWFCGNRLPAN RRFQITWFVSWNPCLPCVVKVTKFLAEHPNVTLTI SAARLYYYRDREWRRVLRRL SEQID NO: 1225 Pan paniscus A3D (AA29- AA150) GRSYTWLCYEVKIKRGCSNLIWDTGVFRGPVLPK LQSNHRQEVYFQFENHAEMCFFSWFCGNRLPAN RRFQITWFVSWNPCLPCVVKVTKFLAEHPNVTLTI SAARLYYYQDREWRRVLRRL SEQID NO: 1226 Pan troglodytes A3D (AA29-AA150) GRSYTWLCYEVKIKRGCSNLIWDTGVFRGPVLPK LQSNHRQEVYFQFENHAEMCFFSWFCGNRLPAN SEQID NO: 1227 RRFQITWFVSWNPCLPCVVKVTKFLAEHPNVTLTI SAARLYYYQDREWRRVLRRL Homo sapiens A3D (AA29-AA150) GRSYTWLCYEVKIKRGRSNLLWDTGVFRGPVLPK RQSNHRQEVYFRFENHAEMCFLSWFCGNRLPAN RRFQITWFVSWNPCLPCVVKVTKFLAEHPNVTLTI SAARLYYYRDRDWRWVLLRL SEQID NO: 1228 Nomascus leucogenys A3D (AA29-AA150) GRSYTWLCYEVKIRKDPSKLPWDKGVFRGQVLP KFQSNHRQEVYFQLENHAEMCFLSWFCGNQLPA NRRFQITWFVSWNPCLPCVAKVTEFLAEHPNVTL TISAARLYYYRGRDWRRALRRL SEQID NO: 1229 Saimiri boliviensis A3C (AA29-AA138) GKKYTWLCYEVKIKKDTSKLPWNTGVFRGQVNF NPEHHAEMYFLSWFRGKLLPACKRSQrrWFVSW NPCLYCVAKVAEFLAEHPNVTLTVSTARLYCYW KKDWRRALRKL SEQID NO: 1230 Saimiri boliviensis A3F (AA29-AA138) GKKYTWLCYEVKIKKDTSKLPWNTGVFRGQVNF NPEHHAEMYFLSWFRGKLLPACKRSQrrWFVSW NPCLYCVAKVAEFLAEHPNVTLTVSTARLYCYW KKDWRRALRKL SEQID NO: 1231 Piliocolobus tephrosceles A3F (AA36-AA145) GRRYTWLCYEVKIMKDHSKLPWYTGVFRGQVYF EPQNHAEMCFLSWFCGNQLPAYECCQITWFVSW TPCPDCVAKVTEFLAEHPNVTLTISAARLYYYRG RDWRRALRRL SEQID NO: 1232 Colobus angolensis palliatus A3F (AA29-AA138) GRRYTWLCYEVKISKDPSKLPWDTGIFRGQVYFE PQYHAEMCFLSWYCGNQLPAYKCFQITWFVSWT PCPDCVGKVAEFLAEHPNVTLTISAARLYYYWET DYRRALCRL SEQID NO: 1233 Pongo abelii A3F (AA30-AA150) RNYTWLCYEVKIRKDPSKLAWDTGVFRGQVLPK LQSNHRREVYFEPQYHAEMCFLSWFCGNQLSAY ERFQITWFVSWTPCPDCVAMLAEFLAEHPNVTLT VSAARLYYYWERDYRGALRRL SEQID NO: 1234

[00252] In some embodiments, the nucleotide deaminase of the first fusion protein is a cytidine deaminase or an adenosine deaminase.

[00253] In some embodiments, the nucleotide deaminase of the first fusion protein is a 5 cytidine deaminase selected from the group consisting of APOBEC3A (A3A), APOBEC3B (A3B), APOBEC3C (A3C), APOBEC3D (A3D), APOBEC3F (A3F), APOBEC3G (A3G), APOBEC3H (A3H), APOBEC 1 (Al), APOBEC3 (A3), APOBEC2 (A2), APOBEC4 (A4), and AICDA (AID).

[00254] In some embodiments, the nucleotide deaminase of the first fusion protein is a cytidine deaminase comprising an amino acid sequence of any one of SEQ ID NOs: 159-194 and 1143-1144. Table 2 Exemplary sequences of cytidine deaminase Name Sequence SEQ ID NO: Felis catus APOBEC3H MNPLQEVIFCRQFGNQHRVPKPYYRRKTYLCYQLKLP EGTLIHKDCLRNKKKRHAEMCFIDKIKALTRDTSQRF EIICYITWSPCPFCAEELVAFVKDNPHLSLRIFASRLYV HWRWKYQQGLRHLHASGIPVAVMSLPEFEDCWRNF VDHQDRSFQPWPNLDQYSKSIKRRLGKILTPLNDLRN DFRNLKLE SEQ ID NO: 159 Human APOBEC3A MEASPASGPRHLMDPHIFTSNFNNGIGRHKTYLCYEV ERLDNGTSVKMDQHRGFLHNQAKNLLCGFYGRHAEL RFLDLVPSLQLDPAQIYRVTWFISWSPCFSWGCAGEV RAFLQENTHVRLRIFAARIYDYDPLYKEALQMLRDAG AQVSIMTYDEFKHCWDTFVDHQGCPFQPWDGLDEHS QALSGRLRAILQNQGN SEQ ID NO: 160 Cricetulus longicaudatus A3 MGPFCLGCSHRKCYSPIRNLISQETFKFHFKNLGYAKG RKDTFLCYEVTRKDCDSPVSLHHGVFKNKGNIHAEVC FLYWFHDKVLKVLSPREEFKITWYMSWSPCFECAEQI VRFLATHHYLSLDIFSSRLYNVQDPETQQNLCRLVQE GAQVAAMDLYEFKKCWKKFVTMVAGDSGLGKRLLT NFRYQDSKLQEILRRMDPLSEEEFYSQFYNQRVKHLC YYHRMKPYLCYQLEQFNGQAPLKGCLLSEKGKQHAE ILFLDKIRSMELSQVTITCYLTWSPCPNCAWRLAAFKR DRPDLILHIYTSRLYFHWKRPFQKGLCSLWQSGILVDV MDLPQFTDCWTNFVNPKRPFWPWKGLEIISRRTQRRL RRIKESWGLQDLVNDFGNLQLGPPMS SEQ ID NO: 161 Rattus norvegicus APOBEC3 MGPFCLGCSHRKCYSPIRNLISQETFKFHFKNLRYAID RKDTFLCYEVTRKDCDSPVSLHHGVFKNKDNIHAEIC FLYWFHDKVLKVLSPREEFKITWYMSWSPCFECAEQ VLRFLATHHNLSLDIFSSRLYNIRDPENQQNLCRLVQE GAQVAAMDLYEFKKCWKKFVDNGGRRFRPWKKLLT NFRYQDSKLQEILRPCYIPVPSSSSSTLSNICLTKGLPET RFCVERRRVHLLSEEEFYSQFYNQRVKHLCYYHGVKP YLCYQLEQFNGQAPLKGCLLSEKGKQHAEILFLDKIRS MELSQVIITCYLTWSPCPNCAWQLAAFKRDRPDLILHI YTSRLYFHWKRPFQKGLCSLWQSGILVDVMDLPQFT DCWTNFVNPKRPFWPWKGLEIISRRTQRRLHRIKESW GLQDLVNDFGNLQLGPPMS SEQ ID NO: 162 Pongo pygmaeus APOBEC3H MALLTAKTFSLQFNNKRRIKRPYYPRKALLCYQLTPQ NGSTPTRGYFKNKKKCHAEIRFINEIKSMGLDETQCY QVTCYLTWSPCPSCVRELVAFIKAHDHLNLRIFASRLY CHWCRRQQEGLRLLCGSQVPVEVMGSREFADCWENF VDHEKPLSFNPSEMLEELDKNSRAIKRRLERIKQSWSV DVLENGLRSLQLGPVSSSLSRSNSR SEQ ID NO: 163 Felis catus APOBEC3Ca MEPWRPSPRNPMDRIDPNTFRFHFPNLLYASGRKLCY LCFQVETEDYFSCDDSDRGVFRNKVHPWARCHAEQC FLSWFRDQYPYRDEYYNVTWFLSWSPCPTCAEEVVE FLEEYRNLTLSIFTSRLYYFWDPNYQEGLCKLWDAGV QLDIMSCDDFKHCWDNFVDHKGMRFQRRNLLKDYD FLAAELQEILR SEQ ID NO: 164 Human APOBEC3H MALLTAETFRLQFNNKRRLRRPYYPRKALLCYQLTPQ NGSTPTRGYFENKKKCHAEICFINEIKSMGLDETQCYQ VTCYLTWSPCSSCAWELVDFIKAHDHLNLGIFASRLY YHWCKPQQKGLRLLCGSQVPVEVMGFPEFADCWENF VDHEKPLSFNPYKMLEELDKNSRAIKRRLERIKIPGVR AQGRYMDILCDAEV SEQ ID NO: 165 Macaca mulatta APOBEC3G MVEPMDPRTFVSNFNNRPILSGLNTVWLCCEVKTKDP SGPPLDAKIFQGKVYSKAKYHPEMRFLRWFHKWRQL HHDQEYKVTWYVSWSPCTRCANSVATFLAKDPKVTL TIFVARLYYFWKPDYQQALRILCQKRGGPHATMKIM NYNEFQDCWNKFVDGRGKPFKPRNNLPKHYTLLQAT LGELLRHLMDPGTFTSNFNNKPWVSGQHETYLCYKV ERLHNDTWVPLNQHRGFLRNQAPNIHGFPKGRHAEL CFLDLIPFWKLDGQQYRVTCFTSWSPCFSCAQEMAKF ISNNEHVSLCIFAARIYDDQGRYQEGLRALHRDGAKIA MMNYSEFEYCWDTFVDRQGRPFQPWDGLDEHSQAL SGRLRAI SEQ ID NO: 166 Pan troglodytes APOBEC3G MKPHFRNPVERMYQDTFSDNFYNRPILSHRNTVWLC YEVKTKGPSRPPLDAKIFRGQVYSKLKYHPEMRFFHW FSKWRKLHRDQEYEVTWYISWSPCTKCTRDVATFLA EDPKVTLTIFVARLYYFWDPDYQEALRSLCQKRDGPR ATMKIMNYDEFQHCWSKFVYSQRELFEPWNNLPKYY ILLHIMLGEILRHSMDPPTFTSNFNNELWVRGRHETYL CYEVERLHNDTWVLLNQRRGFLCNQAPHKHGFLEGR HAELCFLDVIPFWKLDLHQDYRVTCFTSWSPCFSCAQ EMAKFISNNKHVSLCIFAARIYDDQGRCQEGLRTLAK AGAKISIMTYSEFKHCWDTFVDHQGCPFQPWDGLEE HSQALSGRLRAILQNQGN SEQ ID NO: 167 Chlorocebus aethiops APOBEC3G MNPQIRNMVEQMEPDIFVYYFNNRPILSGRNTVWLCY EVKTKDPSGPPLDANIFQGKLYPEAKDHPEMKFLHWF RKWRQLHRDQEYEVTWYVSWSPCTRCANSVATFLA SEQ ID NO: 168 EDPKVTLTIFVARLYYFWKPDYQQALRILCQERGGPH ATMKIMNYNEFQHCWNEFVDGQGKPFKPRKNLPKH YTLLHATLGELLRHVMDPGTFTSNFNNKPWVSGQRE TYLCYKVERSHNDTWVLLNQHRGFLRNQAPDRHGFP KGRHAELCFLDLIPFWKLDDQQYRVTCFTSWSPCFSC AQKMAKFISNNKHVSLCIFAARIYDDQGRCQEGLRTL HRDGAKIAVMNYSEFEYCWDTFVDRQGRPFQPWDGL DEHSQALSGRLRAI Human AP0BEC3F MKPHFRNTVERMYRDTFSYNFYNRPILSRRNTVWLC YEVKTKGPSRPRLDAKIFRGQVYSQPEHHAEMCFLSW FCGNQLPAYKCFQITWFVSWTPCPDCVAKLAEFLAEH PNVTLTISAARLYYYWERDYRRALCRLSQAGARVKI MDDEEFAYCWENFVYSEGQPFMPWYKFDDNYAFLH RTLKEILRNPMEAMYPHIFYFHFKNLRKAYGRNESWL CFTMEVVKHHSPVSWKRGVFRNQVDPETHCHAERCF LSWFCDDILSPNTNYEVTWYTSWSPCPECAGEVAEFL ARHSNVNLTIFTARLYYFWDTDYQEGLRSLSQEGASV EIMGYKDFKYCWENFVYNDDEPFKPWKGLKYNFLFL DSKLQEILE SEQ ID NO: 169 Human AP0BEC3G MKPHFRNTVERMYRDTFSYNFYNRPILSRRNTVWLC YEVKTKGPSRPPLDAKIFRGQVYSELKYHPEMRFFHW FSKWRKLHRDQEYEVTWYISWSPCTKCTRDMATFLA EDPKVTLTIFVARLYYFWDPDYQEALRSLCQKRDGPR ATMKIMNYDEFQHCWSKFVYSQRELFEPWNNLPKYY ILLHIMLGEILRHSMDPPTFTFNFNNEPWVRGRHETYL CYEVERMHNDTWVLLNQRRGFLCNQAPHKHGFLEG RHAELCFLDVIPFWKLDLDQDYRVTCFTSWSPCFSCA QEMAKFISKNKHVSLCIFTARIYDDQGRCQEGLRTLA EAGAKISIMTYSEFKHCWDTFVDHQGCPFQPWDGLD EHSQDLSGRLRAILQNQEN SEQ ID NO: 170 Human AP0BEC3C MNPQIRNPMKAMYPGTFYFQFKNLWEANDRNETWL CFTVEGIKRRSVVSWKTGVFRNQVDSETHCHAERCFL SWFCDDILSPNTKYQVTWYTSWSPCPDCAGEVAEFLA RHSNVNLTIFTARLYYFQYPCYQEGLRSLSQEGVAVEI MDYEDFKYCWENFVYNDNEPFKPWKGLKTNFRLLK RRLRESLQ SEQ ID NO: 171 Human AP0BEC3B MNPQIRNPMERMYRDTFYDNFENEPILYGRSYTWLC YEVKIKRGRSNLLWDTGVFRGQVYFKPQYHAEMCFL SWFCGNQLPAYKCFQITWFVSWTPCPDCVAKLAEFLS EHPNVTLTISAARLYYYWERDYRRALCRLSQAGARV TIMDYEEFAYCWENFVYNEGQQFMPWYKFDENYAFL HRTLKEILRYLMDPDTFTFNFNNDPLVLRRRQTYLCY EVERLDNGTWVLMDQHMGFLCNEAKNLLCGFYGRH SEQ ID NO: 172 AELRFLDLVPSLQLDPAQIYRVTWFISWSPCFSWGCA GEVRAFLQENTHVRLRIFAARIYDYDPLYKEALQMLR DAGAQVSIMTYDEFEYCWDTFVYRQGCPFQPWDGLE EHSQALSGRLRAILQNQGN Macaca mulatta AP0BEC3H MALLTAKTFSLQFNNKRRVNKPYYPRKALLCYQLTP QNGSTPTRGHLKNKKKDHAEIRFINKIKSMGLDETQC YQVTCYLTWSPCPSCAGELVDFIKAHRHLNLRIFASRL YYHWRPNYQEGLLLLCGSQVPVEVMGLPEFTDCWEN FVDHKEPPSFNPSEKLEELDKNSQAIKRRLERIKSRSV DVLENGLRSLQLGPVTPSSSIRNSR SEQ ID NO: 173 Human AP0BEC3D MNPQIRNPMERMYRDTFYDNFENEPILYGRSYTWLC YEVKIKRGRSNLLWDTGVFRGPVLPKRQSNHRQEVY FRFENHAEMCFLSWFCGNRLPANRRFQITWFVSWNPC LPCVVKVTKFLAEHPNVTLTISAARLYYYRDRDWRW VLLRLHKAGARVKIMDYEDFAYCWENFVCNEGQPF MPWYKFDDNYASLHRTLKEILRNPMEAMYPHIFYFHF KNLLKACGRNESWLCFTMEVTKHHSAVFRKRGVFRN QVDPETHCHAERCFLSWFCDDILSPNTNYEVTWYTS WSPCPECAGEVAEFLARHSNVNLTIFTARLCYFWDTD YQEGLCSLSQEGASVKIMGYKDFVSCWKNFVYSDDE PFKPWKGLQTNFRLLKRRLREILQ SEQ ID NO: 174 Mus musculus AP0BEC3 MQPQRLGPRAGMGPFCLGCSHRKCYSPIRNLISQETFK FHFKNLGYAKGRKDTFLCYEVTRKDCDSPVSLHHGV FKNKDNIHAEICFLYWFHDKVLKVLSPREEFKITWYM SWSPCFECAEQIVRFLATHHNLSLDIFSSRLYNVQDPE TQQNLCRLVQEGAQVAAMDLYEFKKCWKKFVDNGG RRFRPWKRLLTNFRYQDSKLQEILRPCYISVPSSSSSTL SNICLTKGLPETRFWVEGRRMDPLSEEEFYSQFYNQR VKHLCYYHRMKPYLCYQLEQFNGQAPLKGCLLSEKG KQHAEILFLDKIRSMELSQVTITCYLTWSPCPNCAWQL AAFKRDRPDLILHIYTSRLYFHWKRPFQKGLCSLWQS GILVDVMDLPQFTDCWTNFVNPKRPFWPWKGLEIISR RTQRRLRRIKESWGLQDLVNDFGNLQLGPPMS SEQ ID NO: 175 Rattus norvegicus APOBEC1 MSSETGPVAVDPTLRRRIEPHEFEVFFDPRELRKETCL LYEINWGGRHSIWRHTSQNTNKHVEVNFIEKFTTERY FCPNTRCSITWFLSWSPCGECSRAITEFLSRYPHVTLFI YIARLYHHADPRNRQGLRDLISSGVTIQIMTEQESGYC WRNFVNYSPSNEAHWPRYPHLWVRLYVLELYCIILGL PPCLNILRRKQPQLTFFTIALQSCHYQRLPPHILWATGL K SEQ ID NO: 176 Human APOBEC1 MTSEKGPSTGDPTLRRRIEPWEFDVFYDPRELRKEACL LYEIKWGMSRKIWRSSGKNTTNHVEVNFIKKFTSERD FHPSMSCSITWFLSWSPCWECSQAIREFLSRHPGVTLV SEQ ID NO: 177 IYVARLFWHMDQQNRQGLRDLVNSGVTIQIMRASEY YHCWRNFVNYPPGDEAHWPQYPPLWMMLYALELHC IILSLPPCLKISRRWQNHLTFFRLHLQNCHYQTIPPHILL ATGLIHPSVAWR Oryctolagus cuniculus APOBEC1 MASEKGPSNKDYTLRRRIEPWEFEVFFDPQELRKEAC LLYEIKWGASSKTWRSSGKNTTNHVEVNFLEKLTSEG RLGPSTCCSITWFLSWSPCWECSMAIREFLSQHPGVTL IIFVARLFQHMDRRNRQGLKDLVTSGVTVRVMSVSEY CYCWENFVNYPPGKAAQWPRYPPRWMLMYALELYC IILGLPPCLKISRRHQKQLTFFSLTPQYCHYKMIPPYILL ATGLLQPSVPWR SEQ ID NO: 178 Mus musculus APOBEC1 MSSETGPVAVDPTLRRRIEPHEFEVFFDPRELRKETCL LYEINWGGRHSVWRHTSQNTSNHVEVNFLEKFTTER YFRPNTRCSITWFLSWSPCGECSRAITEFLSRHPYVTLF IYIARLYHHTDQRNRQGLRDLISSGVTIQIMTEQEYCY CWRNFVNYPPSNEAYWPRYPHLWVKLYVLELYCIIL GLPPCLKILRRKQPQLTFFTITLQTCHYQRIPPHLLWAT GLK SEQ ID NO: 179 Mesocricetus auratus APOBEC1 MSSETGPVVVDPTLRRRIEPHEFDAFFDQGELRKETCL LYEIRWGGRHNIWRHTGQNTSRHVEINFIEKFTSERYF YPSTRCSIVWFLSWSPCGECSKAITEFLSGHPNVTLFIY AARLYHHTDQRNRQGLRDLISRGVTIRIMTEQEYCYC WRNFVNYPPSNEVYWPRYPNLWMRLYALELYCIHLG LPPCLKIKRRHQYPLTFFRLNLQSCHYQRIPPHILWAT GFI SEQ ID NO: 180 Monodelphis domestica APOBEC1 MNSKTGPSVGDATLRRRIKPWEFVAFFNPQELRKETC LLYEIKWGNQNIWRHSNQNTSQHAEINFMEKFTAERH FNSSVRCSITWFLSWSPCWECSKAIRKFLDHYPNVTLA IFISRLYWHMDQQHRQGLKELVHSGVTIQIMSYSEYH YCWRNFVDYPQGEEDYWPKYPYLWIMLYVLELHCII LGLPPCLKISGSHSNQLALFSLDLQDCHYQKIPYNVLV ATGLVQPFVTWR SEQ ID NO: 181 Pongo pygmaeus APOBEC1 MTSEKGPSTGDPTLRRRIESWEFDVFYDPRELRKETCL LYEIKWGMSRKIWRSSGKNTTNHVEVNFIKKFTSERR FHSSISCSITWFLSWSPCWECSQAIREFLSQHPGVTLVI YVARLFWHMDQRNRQGLRDLVNSGVTIQIMRASEYY HCWRNFVNYPPGDEAHWPQYPPLWMMLYALELHCII LSLPPCLKISRRWQNHLAFFRLHLQNCHYQTIPPHILL ATGLIHPSVTWR SEQ ID NO: 182 Bos taurus APOBEC2 MAQKEEAAAAAEPASQNGEEVENLEDPEKLKELIELP PFEIVTGERLPAHYFKFQFRNVEYSSGRNKTFLCYVVE AQSKGGQVQASRGYLEDEHATNHAEEAFFNSIMPTFD SEQ ID NO: 183 PALRYMVTWYVSSSPCAACADRIVKTLNKTKNLRLLI LVGRLFMWEEPEIQAALRKLKEAGCRLRIMKPQDFEY IWQNFVEQEEGESKAFEPWEDIQENFLYYEEKLADILK Mus musculus AP0BEC2 MAQKEEAAEAAAPASQNGDDLENLEDPEKLKELIDLP PFEIVTGVRLPVNFFKFQFRNVEYSSGRNKTFLCYVVE VQSKGGQAQATQGYLEDEHAGAHAEEAFFNTILPAF DPALKYNVTWYVSSSPCAACADRILKTLSKTKNLRLL ILVSRLFMWEEPEVQAALKKLKEAGCKLRIMKPQDFE YIWQNFVEQEEGESKAFEPWEDIQENFLYYEEKLADIL K SEQ ID NO: 184 Human AP0BEC2 MAQKEEAAVATEAASQNGEDLENLDDPEKLKELIELP PFEIVTGERLPANFFKFQFRNVEYSSGRNKTFLCYVVE AQGKGGQVQASRGYLEDEHAAAHAEEAFFNTILPAF DPALRYNVTWYVSSSPCAACADRIIKTLSKTKNLRLLI LVGRLFMWEEPEIQAALKKLKEAGCKLRIMKPQDFEY VWQNFVEQEEGESKAFQPWEDIQENFLYYEEKLADIL K SEQ ID NO: 185 Pongo pygmaeus APOBEC2 MAQKEEAAAATEAASQNGEDLENLDDPEKLKELIELP PFEIVTGERLPANFFKFQFRNVEYSSGRNKTFLCYVVE AQGKGGQVQASRGYLEDEHAAAHAEEAFFNTILPAF DPALRYNVTWYVSSSPCAACADRIIKTLSKTKNLRLLI LVGRLFMWEELEIQDALKKLKEAGCKLRIMKPQDFE YVWQNFVEQEEGESKAFQPWEDIQENFLYYEEKLADI LK SEQ ID NO: 186 Human APOBEC4 MEPIYEEYLANHGTIVKPYYWLSFSLDCSNCPYHIRTG EEARVSLTEFCQIFGFPYGTTFPQTKHLTFYELKTSSGS LVQKGHASSCTGNYIHPESMLFEMNGYLDSAIYNNDS IRHIILYSNNSPCNEANHCCISKMYNFLITYPGITLSIYF SQLYHTEMDFPASAWNREALRSLASLWPRVVLSPISG GIWHSVLHSFISGVSGSHVFQPILTGRALADRHNAYEI NAITGVKPYFTDVLLQTKRNPNTKAQEALESYPLNNA FPGQFFQMPSGQLQPNLPPDLRAPVVFVLVPLRDLPP MHMGQNPNKPRNIVRHLNMPQMSFQETKDLGRLPTG RSVEIVEITEQFASSKEADEKKKKKGKK SEQ ID NO: 187 Rattus norvegicus APOBEC4 MEPLYEEYLTHSGTIVKPYYWLSVSLNCTNCPYHIRT GEEARVPYTEFHQTFGFPWSTYPQTKHLTFYELRSSSG NLIQKGLASNCTGSHTHPESMLFERDGYLDSLIFHDSN IRHIILYSNNSPCDEANHCCISKMYNFLMNYPEVTLSV FFSQLYHTENQFPTSAWNREALRGLASLWPQVTLSAI SGGIWQSILETFVSGISEGLTAVRPFTAGRTLTDRYNA YEINCITEVKPYFTDALHSWQKENQDQKVWAASENQ PLHNTTPAQWQPDMSQDCRTPAVFMLVPYRDLPPIHV NPSPQKPRTVVRHLNTLQLSASKVKALRKSPSGRPVK SEQ ID NO: 188 KEEARKGSTRSQEANETNKSKWKKQTLFIKSNICHLL EREQKKIGILSSWSV Mus musculus AP0BEC4 MEPLYEEILTQGGTIVKPYYWLSLSLGCTNCPYHIRTG EEARVPYTEFHQTFGFPWSTYPQTKHLTFYELRSSSKN LIQKGLASNCTGSHNHPEAMLFEKNGYLDAVIFHNSN IRHIILYSNNSPCNEAKHCCISKMYNFLMNYPEVTLSV FFSQLYHTEKQFPTSAWNRKALQSLASLWPQVTLSPIC GGLWHAILEKFVSNISGSTVPQPFIAGRILADRYNTYEI NSIIAAKPYFTDGLLSRQKENQNREAWAAFEKHPLGS AAPAQRQPTRGQDPRTPAVLMLVSNRDLPPIHVGSTP QKPRTVVRHLNMLQLSSFKVKDVKKPPSGRPVEEVE VMKESARSQKANKKNRSQWKKQTLVIKPRICRLLER SEQ ID NO: 189 Macaca fascicularis AP0BEC4 MEPTYEEYLANHGTIVKPYYWLSFSLDCSNCPYHIRT GEEARVSLTEFCQIFGFPYGTTYPQTKHLTFYELKTSS GSLVQKGHASSCTGNYIHPESMLFEMNGYLDSAIYNN DSIRHIILYCNNSPCNEANHCCISKVYNFLITYPGITLSI YFSQLYHTEMDFPASAWNREALRSLASLWPRVVLSPI SGGIWHSVLHSFVSGVSGSHVFQPILTGRALTDRYNA YEINAITGVKPFFTDVLLHTKRNPNTKAQMALESYPL NNAFPGQSFQMTSGIPPDLRAPVVFVLLPLRDLPPMH MGQDPNKPRNIIRHLNMPQMSFQETKDLERLPTRRSV ETVEITERFASSKQAEEKTKKKKGKK SEQ ID NO: 190 Human AICDA MDSLLMNRRKFLYQFKNVRWAKGRRETYLCYVVKR RDSATSFSLDFGYLRNKNGCHVELLFLRYISDWDLDP GRCYRVTWFTSWSPCYDCARHVADFLRGNPNLSLRIF TARLYFCEDRKAEPEGLRRLHRAGVQIAIMTFKDYFY CWNTFVENHERTFKAWEGLHENSVRLSRQLRRILLPL YEVDDLRDAFRTLGL SEQ ID NO: 191 Mus musculus AICDA MDSLLMKQKKFLYHFKNVRWAKGRHETYLCYVVKR RDSATSCSLDFGHLRNKSGCHVELLFLRYISDWDLDP GRCYRVTWFTSWSPCYDCARHVAEFLRWNPNLSLRIF TARLYFCEDRKAEPEGLRRLHRAGVQIGIMTFKDYFY CWNTFVENRERTFKAWEGLHENSVRLTRQLRRILLPL YEVDDLRDAFRMLGF SEQ ID NO: 192 Canis lupus familiaris (Dog) AICDA MDSLLMKQRKFLYHFKNVRWAKGRHETYLCYVVKR RDSATSFSLDFGHLRNKSGCHVELLFLRYISDWDLDP GRCYRVTWFTSWSPCYDCARHVADFLRGYPNLSLRIF AARLYFCEDRKAEPEGLRRLHRAGVQIAIMTFKDYFY CWNTFVENREKTFKAWEGLHENSVRLSRQLRRILLPL YEVDDLRDAFRTLGL SEQ ID NO: 193 Bos taurus (Bovine) AICDA MDSLLKKQRQFLYQFKNVRWAKGRHETYLCYVVKR RDSPTSFSLDFGHLRNKAGCHVELLFLRYISDWDLDP GRCYRVTWFTSWSPCYDCARHVADFLRGYPNLSLRIF TARLYFCDKERKAEPEGLRRLHRAGVQIAIMTFKDYF YCWNTFVENHERTFKAWEGLHENSVRLSRQLRRILLP LYEVDDLRDAFRTLGL SEQ ID NO: 194 mouse APOBEC3 cytidine deaminase domain 1 (mA3-CDAl) MGPFCLGCSHRKCYSPIRNLISQETFKFHFKNLGYAKG RKDTFLCYEVTRKDCDSPVSLHHGVFKNKDNIHAEIC FLYWFHDKVLKVLSPREEFKITWYMSWSPCFECAEQI VRFLATHHNLSLDIFSSRLYNVQDPETQQNLCRLVQE GAQVAAMDLYEFKKCWKKFVDNGGRRFRPWKRLLT NFRYQDSKLQEILRPCYISVPSS SEQ ID NO: 1143 human APOBEC3B cytidine deaminase domain 2 (hA3B-CDA2) MQFMPWYKFDENYAFLHRTLKEILRYLMDPDTFTFN FNNDPLVLRRRQTYLCYEVERLDNGTWVLMDQHMG FLCNEAKNLLCGFYGRHAELRFLDLVPSLQLDPAQIY RVTWFISWSPCFSWGCAGEVRAFLQENTHVRLRIFAA RIYDYDPLYKEALQMLRDAGAQVSIMTYDEFEYCWD TFVYRQGCPFQPWDGLEEHSQALSGRLRAILQNQGN SEQ ID NO: 1144

[00255] In some embodiments, the nucleotide deaminase of the first fusion protein is a human cytidine deaminase, a monkey cytidine deaminase, or mouse cytidine deaminase.

[00256] In some embodiments, the catalytic domain of the nucleotide deaminase of the 5 first fusion protein is a mouse A3 cytidine deaminase domain 1 (mA3-CDAl) or a human A3B cytidine deaminase domain 2 (hA3B-CDA2).

[00257] In some embodiments, the nucleotide deaminase of the first fusion protein is an adenosine deaminase selected from tRNA-specific adenosine deaminase (TadA), adenosine deaminase tRNA specific 1 (ADAT1), adenosine deaminase tRNA specific 2 (ADAT2), 10 adenosine deaminase tRNA specific 3 (ADAT3), adenosine deaminase RNA specific B1 (ADARBI), adenosine deaminase RNA specific B2 (ADARB2), adenosine monophosphate deaminase 1 (AMPD1), adenosine monophosphate deaminase 2 (AMPD2), adenosine monophosphate deaminase 3 (AMPD3), adenosine deaminase (ADA), adenosine deaminase 2 (ADA2), adenosine deaminase like (ADAL), adenosine deaminase domain containing 1 15 (ADADI), adenosine deaminase domain containing 2 (ADAD2), and adenosine deaminase RNA specific (ADAR).

[00258] In some embodiments, the adenosine deaminase comprises an amino acid sequence selected from SEQ ID NO: 66-158. Table 3 Exemplary sequences of adenosine deaminase Name Sequence SEQ ID NO: Agrobacteriu m fabrum TadA MAERTHFMELALVEARSAGERDEVPIGAVLVLDGRVI ARSGNRTRELNDVTAHAEIAVIRMACEALGQERLPGA DLYVTLEPCTMCAAAISFARIRRLYYGAQDPKGGAVE SGVRFFSQPTCHHAPDVYSGLAESESAEILRQFFREKR LDD SEQ ID NO: 66 Arabidopsis thaliana TadA MFNTYTNSLQWPIRSRNQQDYCSLLPERSESYKLSKA YTSSRCYCVSSRSSCCCCCSTPSSSSFVKPKVLINPGFV LYGVRQSTLIQWPSFQRRLLVGGGRLMGCEVYSSCD GIRRKNRSFKLRCLEESDECCGGRSCSDDVEAMISFLS EELIDEERKWNLVSRVKEKKKVGNVRKVSVEGSNSY GNGRVSQRVKKPEGFGRRKEIKEDVKLNERYDCEHC GRRKKSSELESESRRGSKLVTGEYIGKSYRGDEEREVR PRRRKSSSCSSYYSLASSGEFESDTEDQEEDVEIYREN VRSSEKKVVDQSAKRLKSRKEASQMHSRKKRDESST GVDSRYQKQIFEEGENSNQAVTLNQRRRKKFSQTENR VSESTGNYEEDMEIHEVHVNDAETSSQNQKLFNERED YRVHSIRNDSGNENIESSQHQLKERLETRYSSEDRVSE MRRRTKYSSSQEEGINVLQNFPEVTNNQQPLVEERISK QAGTRRTTEHISESSEIHDIDIRNTYVSQREDQIRNQEV HAGLVSGLQSERKQQDYHIEHNPLQTTQSDRTSVSVS HTSDAVRYTEIQRKSEKRLIGQGSTTAVQSDSKVEKN GAQKEDSRLDHANSKKDGQTTLGLQSYQSKLSEEASS SQSSLMASRTKLQLVDLVSEEMQGSETTLIPPSSQLVS RRSGQSYRTGGVSIQEISHGTSESGYTTAFEHPRAGAS VNSQSAGELMGFTSHEDAMGSAHRLEQASEKYVGEF VKKAKHGVINPETEEQRAESNQLKRRDSRRSSGGSGA KGPSDEMWVTDSAQGTPHPGATEGNAAVGNAIFKRN GRSLWNVIADIARLRWGSRAGSPDSSAKPAGRSSPNE SVSSATWFSGREHDGSSDDNTKGDKVLPQEAPSLHQV EVGQTSPRSQSEYPGTTKLKQRSERHEGVVSSPSSTILE GGSVSNRMSSTSGNQIVGVDEEEGGNFEFRLPETALTE VPMKLPSRNLIRSPPIKESSESSLTEASSDQNFTVGEGR RYPRMDAGQNPLLFPGRNLRSPAVMEPPVPRPRMVS GSSSLREQVEQQQPLSAKSQEETGSVSADSALIQRKLQ RNKQVVRDSFEEWEEAYKVEAERRTVDEIFMREALV EAKKAADTWEVPVGAVLVHDGKIIARGYNLVEELRD STAHAEMICIREGSKALRSWRLADTTLYVTLEPCPMC AGAILQARVNTLVWGAPNKLLGADGSWIRLFPGGEG NGSEASEKPPPPVHPFHPKMTIRRGVLESECAQTMQQ FFQLRRKKKDKNSDPPTPTDHHHHHLPKLLNKMHQV LPFFCL SEQ ID NO: 67 Aquifex aeolicus Tad A MGKEYFLKVALREAKRAFEKGEVPVGAIIVKEGEIISK AHNSVEELKDPTAHAEMLAIKEACRRLNTKYLEGCEL YVTLEPCIMCSYALVLSRIEKVIFSALDKKHGGVVSVF NILDEPTLNHRVKWEYYPLEEASELLSEFFKKLRNNII SEQ ID NO: 68 Streptococcus pyogenes serotype M3 TadA MPYSLEEQTYFMQEALKEAEKSLQKAEIPIGCVIVKD GEIIGRGHNAREESNQAIMHAEMMAINEANAHEGNW RLLDTTLFVTIEPCVMCSGAIGLARIPHVIYGASNQKF GGADSLYQILTDERLNHRVQVERGLLAADCANIMQTF FRQGRERKKIAKHLIKEQSDPFD SEQ ID NO: 69 Bacillus subtilis TadA MTQDELYMKEAIKEAKKAEEKGEVPIGAVLVINGEIIA RAHNLRETEQRSIAHAEMLVIDEACKALGTWRLEGAT LYVTLEPCPMCAGAVVLSRVEKVVFGAFDPKGGCSG TLMNLLQEERFNHQAEVVSGVLEEECGGMLSAFFREL RKKKKAARKNLSE SEQ ID NO: 70 Haemophilus influenzae TadA MDAAKVRSEFDEKMMRYALELADKAEALGEIPVGA VLVDDARNIIGEGWNLSIVQSDPTAHAEIIALRNGAKN IQNYRLLNSTLYVTLEPCTMCAGAILHSRIKRLVFGAS DYKTGAIGSRFHFFDDYKMNHTLEVTSGVLAEECSQK LSTFFQKRREEKKIEKALLKSLSDK SEQ ID NO: 71 Buchnera aphidicola TadA MKYEKDKNWMKIALKYAYYAKEKGEIPIGAILVFKE RIIGIGWNSSISKNDPTAHAEIIALRGAGKKIKNYRLLN TTLYVTLQPCIMCCGAIIQSRIKRLVFGANCNSSDHRFS LKNLFCDPQKDYKLDIKKNVMQRECSDILINFFQKKR KNKIHICKKI SEQ ID NO: 72 Escherichia coli TadA MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLV HNNRVIGEGWNRPIGRHDPTAHAEIMALRQGGLVMQ NYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARD AKTGAAGSLMDVLHHPGMNHRVEITEGILADECAAL LSDFFRMRRQEIKAQKKAQSSTD SEQ ID NO: 73 Streptococcus pyogenes serotype Ml TadA MPYSLEEQTYFMQEALKEAEKSLQKAEIPIGCVIVKD GEIIGRGHNAREESNQAIMHAEMMAINEANAHEGNW RLLDTTLFVTIEPCVMCSGAIGLARIPHVIYGASNQKF GGVDSLYQILTDERLNHRVQVERGLLAADCANIMQTF FRQGRERKKIAKHLIKEQSDPFD SEQ ID NO: 74 Rickettsia bellii TadA MREALKQAEIAFSKNEVPVGAVIVDRENQKIISKSYNN TEEKNNALYHAEIIAINEACRIISSKNLSDYDIYVTLEP CAMCAAAIAHSRLKRLFYGASDSKHGAVESNLRYFN SKACFHRPEIYSGIFAEDSALLMKGFFKKIRD SEQ ID NO: 75 Rickettsia felis TadA MEQALKQAGIAFDKNEVPVGAVIVDRLNQKIIVSSHN NTEEKNNALYHAEIIAINEACNLISSKNLNDYDIYVTL EPCAMCAAAIAHSRLKRLFYGASDSKHGAVESNLRYF NSSVCFYRPEIYSGILAEDSRLLMKEFFKRIR SEQ ID NO: 76 Salmonella typhimurium TadA MSDVELDHEYWMRHALTLAKRAWDEREVPVGAVLV HNHRVIGEGWNRPIGRHDPTAHAEIMALRQGGLVLQ NYRLLDTTLYVTLEPCVMCAGAMVHSRIGRVVFGAR DAKTGAAGSLIDVLHHPGMNHRVEIIEGVLRDECATL LSDFFRMRRQEIKALKKADRAEGAGPAV SEQ ID NO: 77 Escherichia coli 06 TadA MSEVEFSHEYWMRHAMTLAKRAWDEREVPVGAVLV HNNRVIGEGWNRPIGRHDPTAHAEIMALRQGGLVMQ NYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARD AKTGAAGSLMDVLHHPGMNHRVEITEGILADECAAL LSDFFRMRRQEIKAQKKAQSSTD SEQ ID NO: 78 Buchnera aphidicola subsp. Baizongia pistaciae (strain Bp) TadA MKSNRDSYWMKIALKYAYYAEENGEVPIGAILVFQE KIIGTGWNSVISQNDSTAHAEIIALREAGRNIKNYRLV NTTLYVTLQPCMMCCGAIINSRIKRLVFGASYKDLKK NPFLKKIFINLEKNKLKIKKHIMRNECAKILSNFFKNKR F SEQ ID NO: 79 Streptococcus pyogenes serotype Ml8 TadA MPYSLEEQTYFMQEALKEAEKSLQKAEIPIGCVIVKD GEIIGRGHNAREESNQAIMHAEMMAINEANAHEGNW RLLDTTLFVTIEPCVMCSGAIGLARIPHVIYGASNQKF GGADSLYQILTDERLNHRVQVERGLLAADCANIMQTF FRQGRERKKNS SEQ ID NO: 80 Rickettsia prowazekii TadA MEQALKQARLAFDKNEVPVGVVIVCRLNQKIIVSSHN NIEEKKNPLCHAEIIAINTACNLISSKNLNDYDIYVTLE PCAMCASAISHSRLKRLFYGASDSKHGAVESNLRYFN SNSCFYRPEIYSGILSEHSRFLMQEFFQRIRSAID SEQ ID NO: 81 Rickettsia typhi TadA MEQALKQARLAFDKNEVPVGVVIVYRLNQKIIVSSHN NIEEKNNALCHAEIIAINEACNLISSKNLNDYDIYVTLE PCAMCASAISHSRLKRLFYGASDSKQGAVESNLRYFN SSACFHRPEIYSGILSEHSRFLMKEFFQKMRSTID SEQ ID NO: 82 Buchnera aphidicola subsp. Schizaphis graminum (strain Sg) TadA MHDSDKYFMKCAIFLAKISEMIGEVPVGAVLVFNNTII GKGLNSSILNHDPTAHAEIKALRNGAKFLKNYRLLHT TLYVTLEPCIMCYGAIIHSRISRLVFGAKYKNLQKYIC CKNHFFINKNFRKISITQEVLESECSNLLSSFFKRKRKI ATKYFNNNII SEQ ID NO: 83 Rickettsia conorii TadA MEQALKQAKIAFDKNEVPVGAVVVDRLHQKIIASTH NNTEEKNNALYHAEIIAINEACNLISSKNLNDYDIYVT LEPCAMCAAAIAHSRLKRLFYGASDSKHGVVESNLRY FNSSACFHRPEIYSGILAEDSGLLMKEFFKRIRTVISSH RMT SEQ ID NO: 84 Staphylococc us aureus TadA MTNDIYFMTLAIEEAKKAAQLGEVPIGAIITKDDEVIA RAHNLRETLQQPTAHAEHIAIERAAKVLGSWRLEGCT LYVTLEPCVMCAGTIVMSRIPRVVYGADDPKGGCSGS LMNLLQQSNFNHRAIVDKGVLKEACSTLLTTFFKNLR ANKKSTN SEQ ID NO: 85 Arabidopsis thaliana ADAT1 MEEDWGKTVSEKVISAYMSLPKKGKPQGREVTVLSA FLVSSPSQDPKVIALGTGTKCVSGSLLSPRGDIVNDSH AEVVARRALIRFFYSEIQRMQLTSGKSNEAKRQRIDSE TSSILESADSSCPGEVKYKLKSGCLLHLYISQLPCGYAS TSSPLYALKKIPSTQVDDSLLVQASDICSSRHSDVPEIG SNSNKGNGSQVADMVQRKPGRGETTLSVSCSDKIAR WNVLGVQGALLYQVLQPVYISTITVGQSLHSPDNFSL ADHLRRSLYERILPLSDELLTSFRLNKPLFFVAPVPPSE FQHSETAQATLTCGYSLCWNYSGLHEVILGTTGRKQG TSAKGALYPSTQSSICKQRLLELFLKETHGHKRESSKS KKSYRELKNKATEYYLMSKIFKGKYPFNNWLRKPLN CEDFLIN SEQ ID NO: 86 Schizosacchar omyces pombe ADAT1 MEEFTLDRNSNVGNLIALAVLNKFDELARHGKPIIRA NGVREWTTLAGVVIQKKMENEFICVCLATGVKCTPA GIIKNEQLGSVLHDCHAEILALRCFNRLLLEHCILIKES KKDTWLLEVADNGKFTLNSNLLIHLYVSECPCGDAS MELLASRLENNKPWNLTVDSEKLMRGRADFGLLGIV RTKPGRPDAPVSWSKSCTDKLAAKQYLSILNSQTSLIC EPIYLSCVVLYKKVIVKSAIDRAFGPFGRCAPLAEFGE KDNPYYFHPFTVLETDENFLYSRPLNQAEKTATSTNV LIWIGDKMQCTQVIHNGIKAGTKAKDVEKSQTLICRK SMMNLLHQLSQSLTNEKNYYEWKKLNIKRCQQKQIL RNILKNWIPNGGNEFQWI SEQ ID NO: 87 Saccharomyce s cerevisiae ADAT1 MVSCQGTRPCIVNLLTMPSEDKLGEEISTRVINEYSKL KSACRPIIRPSGIREWTILAGVAAINRDGGANKIEILSIA TGVKALPDSELQRSEGKILHDCHAEILALRGANTVLL NRIQNYNPSSGDKFIQHNDEIPARFNLKENWELALYIS RLPCGDASMSFLNDNCKNDDFIKIEDSDEFQYVDRSV KTILRGRLNFNRRNVVRTKPGRYDSNrrLSKSCSDKLL MKQRSSVLNCLNYELFEKPVFLKYIVIPNLEDETKHHL EQSFHTRLPNLDNEIKFLNCLKPFYDDKLDEEDVPGL MCSVKLFMDDFSTEEAILNGVRNGFYTKSSKPLRKHC QSQVSRFAQWELFKKIRPEYEGISYLEFKSRQKKRSQL IIAIKNILSPDGWIPTRTDDVK SEQ ID NO: 88 Macaca fascicularis ADAT1 MWTADEIALLCYEHYGIRLPKKGKPEPNHEWTLLAA VVKIQSPADQDCDTPDKPAQVTKEVVSMGTGTKCIG QSKMRKSGDILNDSHAEVIARRNFQRYLLHQLQLAAT LKEDSIFVPGTQKGLWKLRRDLFFVFFSSHTPCGDASII SEQ ID NO: 89 PMLEFEDQPCCPVIRDWASSSSVEASSNLEAPGNERKC EDLDSPVTKKMRLEPMTAAREVTNGATHHQSFGKQE SGPISPGINSCNLTVEGLAAVTRIAPGSAKVIDVYRTG AKCVPGEAGDSRKPGAAFHQVGLLRVKPGRGDRTRS MSCSDKMARWNVLGCQGALLMHFLEEPIYLSAVVIG KCPYSQEAMQRALTGRRQNVSALPKGFGVQELKILQS DLLFEQSRCAVQAKRADSPGRLVPCGAAISWSAVPEQ PLDVTANGFPQGTTKKTIGSLQARSQISKVELLRSFQK LLSRIARDKWPDSLRVQKLDTYQDYKEAASSYQEAW STLRKQAFGSWIRNPPDYHQFK Gallus gallus ADAT1 MWTADEIAELCYEHYRSRLPKQGKPDPSREWTSLAA VVKVESAANEAGSAVLGTLQVAKEVVALGTGTKCIG LNKMRKTGDVLNDSHAEVVAKRSFQRYLLHQMRLA TSYQQCSIFIPGTETGKWKLKPNIIFIFFCSHTPCGDASII PIRETENHLSKSVDGHDIAGQSVLCSSSNCDHRGPEDK RKSEKMASSHMIKRMKNADGGFFSTITEDMAVQQVF AKPEGNVNPECCESSEEMQAANKETNAGKLKAVGVY RTGAKFVPGELSDTLIPGIEYHCVGLLRVKPGRGDRTC SMSCSDKLARWNVLGCQGALLMHFLQYPVYLSAVIV GKCPYSQEAMQRAVIERCRHISLLPDGFLTQEVQLLQS DLQFEHSRQAIQEGQTSSKRKLVPCSAAISWSAVPEGP LDVTSDGFRQGTTKKGIGSPQSRSKICKVELFHEFQKL VTSISKENLPDTLRMKTLETYWDYKEAALNYQEAWK ALRSQALLGWIKNAQEYLLFM SEQ ID NO: 90 Human ADAT1 MWTADEIAQLCYEHYGIRLPKKGKPEPNHEWTLLAA VVKIQSPADKACDTPDKPVQVTKEVVSMGTGTKCIG QSKMRKNGDILNDSHAEVIARRSFQRYLLHQLQLAAT LKEDSIFVPGTQKGVWKLRRDLIFVFFSSHTPCGDASII PMLEFEDQPCCPVFRNWAHNSSVEASSNLEAPGNERK CEDPDSPVTKKMRLEPGTAAREVTNGAAHHQSFGKQ KSGPISPGIHSCDLTVEGLATVTRIAPGSAKVIDVYRTG AKCVPGEAGDSGKPGAAFHQVGLLRVKPGRGDRTRS MSCSDKMARWNVLGCQGALLMHLLEEPIYLSAVVIG KCPYSQEAMQRALIGRCQNVSALPKGFGVQELKILQS DLLFEQSRSAVQAKRADSPGRLVPCGAAISWSAVPEQ PLDVTANGFPQGTTKKTIGSLQARSQISKVELFRSFQK LLSRIARDKWPHSLRVQKLDTYQEYKEAASSYQEAW STLRKQVFGSWIRNPPDYHQFK SEQ ID NO: 91 Mus musculus ADAT1 MWTADEIAQLCYAHYNVRLPKQGKPEPNREWTLLAA VVKIQASANQACDIPEKEVQVTKEVVSMGTGTKCIGQ SKMRESGDILNDSHAEIIARRSFQRYLLHQLHLAAVLK EDSIFVPGTQRGLWRLRPDLSFVFFSSHTPCGDASIIPM LEFEEQPCCPVIRSWANNSPVQETENLEDSKDKRNCE SEQ ID NO: 92 DPASPVAKKMRLGTPARSLSNCVAHHGTQESGPVKP DVSSSDLTKEEPDAANGIASGSFRVVDVYRTGAKCVP GETGDLREPGAAYHQVGLLRVKPGRGDRTCSMSCSD KMARWNVLGCQGALLMHFLEKPIYLSAVVIGKCPYS QEAMRRALTGRCEETLVLPRGFGVQELEIQQSGLLFE QSRCAVHRKRGDSPGRLVPCGAAISWSAVPQQPLDVT ANGFPQGTTKKEIGSPRARSRISKVELFRSFQKLLSSIA DDEQPDSIRVTKKLDTYQEYKDAASAYQEAWGALRR IQPFASWIRNPPDYHQFK Drosophila melanogaster ADAT1 MCDNKKPTVKEIAELCLKKFESLPKTGKPTANQWTIL AGIVEFNRNTEACQLVSLGCGTKCIGESKLCPNGLILN DSHAEVLARRGFLRFLYQELKQDRIFHWNSTLSTYDM DEHVEFHFLSTQTPCGDACILEEEQPAARAKRQRLDE DSEMVYTGAKLISDLSDDPMLQTPGALRTKPGRGERT LSMSCSDKIARWNVIGVQGALLDVLISKPIYFSSLNFC CDDAQLESLERAIFKRFDCRTFKHTRFQPQRPQINIDP GIRFEFSQRSDWQPSPNGLIWSQVPEELRPYEISVNGK RQGVTKKKMKTSQAALAISKYKLFLTFLELVKFNPKL SEMFDQQLSDPERIAYASCKDLARDYQFAWREIKEKY FLQWTKKPHELLDFNPMSNK SEQ ID NO: 93 Xenopus tropicalis ADAT1 MQAKGLWSADEIAALSYGHYTTQLPKQGLPDPSREW TLMAAVIQIESVEDTKVIKKVVAMGTGTKCIGQAKLR KTGDVLQDSHAEIIAKRSFQRYLLHQLSLAVSDTKDC LFIPGTEKGKWMLRPEISFVFFTSHTPCGDASIIPVISHE DELGHPLPSEVTEKDHSSNNVCESVNTTYKRKVRSEE DIGFISKKMKHSIDEILTRPENYEEENRHDFPSTCQKAL DVHRTGAKCVAGELQDSYSPGVNYHTVGVLRIKPGR GDRTMSMSCSDKMARWNVLGCQGALLMHFLQQPIY LSAVVVGKCPFSQDAMERALYNRCHKVLSLPCAFRL NRVQIIQSDLEFQHGRHALTKKDATRKLVPCGAAVS WSAVPHHPLDVTANGYRQGTTRKAIGSPQCRSRICKA EIFNTFRELVQRLSEKQRSESLSSQGLKTYWDYKAAAI TYQEAWNCLRQQAFTSWIQTPRDFLMFS SEQ ID NO: 94 Dictyostelium discoideum ADAT1 MSWKLDKQFSDKICNFSHDFFNKKLIKKGKPISGEWT VLATLVLVVENTSSYEIKQVLSLGTGNRCLGKSSLSN QGDVLNDSHAEIICKRSFQKFCYNEILNLLQSKYYNSI LFNIEYHDSNNNNKDNDNNGSLPTISIKKGHSLHFYVN QTPCGDCSIFPFKKETQPENFIEKEKLEKDGKDKIENH EKKEQKDIIKQVDKDKDEENYEDEESKRKLKKVKDD NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN NNNINNNNNQYDDIQRTGAKTVFGEPEDKKLIGVDY HQIGVLRVKPGRGDPTVSMSCSDKIARWNVLGIQGSL LSHFIKEQIFLSSITIGDLFNHSSIYRGLIGRLLPNPTTTT SEQ ID NO: 95 TETSSSSSSSSSSSNTIPNFKLNSDLEIFSTNIQFQFSKLL LESDQQNNNKSTSSGLAISFCYPNQHEVTIAINGKKMG TNQKNFNAISQRSSICKFNLFKLFHQLVLIIKNKNSNEE NEKNNQIVLIDSLFNYYECKHLSKKYYQEYEKLKEFK FKNWLTNSSDLENFVLDN Schizosacchar omyces pombe ADAT2 MAGDSVKSAIIGIAGGPFSGKTQLCEQLLERLKSSAPS TFSKLIHLTSFLYPNSVDRYALSSYDIEAFKKVLSLISQ GAEKICLPDGSCIKLPVDQNRIILIEGYYLLLPELLPYY TSKIFVYEDADTRLERCVLQRVKAEKGDLTKVLNDFV TLSKPAYDSSIHPTRENADIILPQKENIDTALLFVSQHL QDILAEMNKTSSSNTVKYDTQHETYMKLAHEILNLGP YFVIQPRSPGSCVFVYKGEVIGRGFNETNCSLSGIRHA ELIAIEKILEHYPASVFKETTLYVTVEPCLMCAAALKQ LHIKAVYFGCGNDRFGGCGSVFSINKDQSIDPSYPVYP GLFYSEAVMLMREFYVQENVKAPVPQSKKQRVLKRE VKSLDLSRFK SEQ ID NO: 96 Saccharomyce s cerevisiae ADAT2 MQHIKHMRTAVRLARYALDHDETPVACIFVHTPTGQ VMAYGMNDTNKSLTGVAHAEFMGIDQIKAMLGSRG VVDVFKDITLYVTVEPCIMCASALKQLDIGKVVFGCG NERFGGNGTVLSVNHDTCTLVPKNNSAAGYESIPGIL RKEAIMLLRYFYVRQNERAPKPRSKSDRVLDKNTFPP MEWSKYLNEEAFIETFGDDYRTCFANKVDLSSNSVD WDLIDSHQDNIIQELEEQCKMFKFNVHKKSKV SEQ ID NO: 97 Xenopus tropicalis ADAT2 MTEEIQNWMHKAFQMAQDALNNGEVPVGCLMVYD NQVVGKGRNEVNETKNATRHAEMVAIDQVLDWCEK NSKKSRDVFENIVLYVTVEPCIMCAGALRLLKIPLVVY GCRNERFGGCGSVLNVAGDNIPDTGTEFKYIGGYQAE KAVELLKTFYKQENPNAPRSKVRKKE SEQ ID NO: 98 Bos taurus ADAT2 MEAKAGPTAATDGAYSVSAEETEKWMEQAMQMAK DALDNTEVPVGCLMVYNNEVVGKGRNEVNQTKNAT RHAEMVAIDQALDWCRRRGRSPSEVFEHTVLYVTVE PCIMCAAALRLMRIPLVVYGCQNERFGGCGSVLDIAS ADLPSTGKPFQCTPGYRAEEAVEMLKTFYKQENPNAP KSKVRKKECHKS SEQ ID NO: 99 Danio rerio ADAT2 MQEVGVDPEKNDFLQPSDSEVQTWMAKAFDMAVEA LENGEVPVGCLMVYNNEIIGKGRNEVNETKNATRHA EMVALDQVLDWCRLREKDCKEVCEQTVLYVTVEPCI MCAAALRLLRIPFVVYGCKNERFGGCGSVLDVSSDHL PHTGTSFKCIAGYRAEEAVEMLKTFYKQENPNAPKPK VRKDSINPQDGAAVIQVMRGPPDEETETIAHLS SEQ ID NO: 100 Arabidopsis thaliana ADAT2 MEEDHCEDSHNYMGFALHQAKLALEALEVPVGCVFL EDGKVIASGRNRTNETRNATRHAEMEAIDQLVGQWQ KDGLSPSQVAEKFSKCVLYVTCEPCIMCASALSFLGIK EVYYGCPNDKFGGCGSILSLHLGSEEAQRGKGYKCRG GIMAEEAVSLFKCFYEQGNPNAPKPHRPVVQRERT SEQ ID NO: 101 Mus musculus ADAT2 MEEKVESTTTPDGPCVVSVQETEKWMEEAMRMAKE ALENIEVPVGCLMVYNNEVVGKGRNEVNQTKNATRH AEMVAIDQVLDWCHQHGQSPSTVFEHTVLYVTVEPCI MCAAALRLMKIPLVVYGCQNERFGGCGSVLNIASAD LPNTGRPFQCIPGYRAEEAVELLKTFYKQENPNAPKSK VRKKDCQKS SEQ ID NO: 102 Human ADAT2 MEAKAAPKPAASGACSVSAEETEKWMEEAMHMAKE ALENTEVPVGCLMVYNNEVVGKGRNEVNQTKNATR HAEMVAIDQVLDWCRQSGKSPSEVFEHTVLYVTVEP CIMCAAALRLMKIPLVVYGCQNERFGGCGSVLNIASA DLPNTGRPFQCIPGYRAEEAVEMLKTFYKQENPNAPK SKVRKKECQKS SEQ ID NO: 103 Arabidopsis thaliana ADAT3 MDSDAWEIIHIPEKPSLSPDHQPTVKVYASLIKPRFAN TIVRHLCKIAPLEDLRHVKRVKKKILPDCGETQLTVIL CLAPEHNDQLSDMPPDVQRLVDPYELSPFITQVCKYA AVSKEEWEEQSKIWPTSFHPPTYNIDGIGGFSEEETQSI CKFMRVVIDMAVSGHTPLVNAAVIVDPSVRRIIASETD QVYASSAPRDMTSAETRPFEETGEICLNDTLEKQNGSL SALSCLNPWQWSLQPHDTENCSQWHPLRHASMVAIE SSSARDRNLFPNPSKIFDQDHVPPSNTDSPAKKQKTSS QSPDVQNDSREETVRDPSMERPYLCTGYDIFLLLEPCT MCAMALVHQRIKRIFYAFPNTTAGGLGSVHRLQGEKS LNHHYAVFRVLLPDDALRQMTTV SEQ ID NO: 104 Mus musculus ADAT3 MEPTSGFAEQPGPVKAESEEQEPAQWQALPVLSEQQS GAVELILAYAAPVLDKRQTSRLLREVSAVYPLPAQPH LKRVRPSRSAGGAQSSDLLLCLAGPSAGPRSLAELLPR PAVDPRGLGTPFLVPVPARPPLTRSQFEEARAHWPTSF HEDKQVTSALAGQLFSTQERAAMQTHMERAVCAAQ RAAAQGLRAVGAVVVDPASDRVLATGHDCSSVASPL LHAVMVCIDLVAQGQGRGSCDLRSHPACSFTQATAT QGARAGSVRKLDEDSLPYVCTGYDLYVTREPCVMCA MALVHARIQRVFYGAPSPDGALGTLFRVHARPDLNH RFQVFRGILEDQCRQLDPDP SEQ ID NO: 105 Danio rerio ADAT3 MEPQAKRKKEMDDYDDTWEVLPVLSDEQSQDPELLP AYAAPILERRETSRLVKELSLIHPLPNLQHIKRVRPCKH KDSPHPLEVIVCLVSDVQCTDPKKVTLSHLLHTQCFNS NGLGDPFIVQIPANPPLTRPQFEKASKHWPTSFHEDKL VTFALKGQLFTAHQKTKMREYMCVAVKAAKSGREL SEQ ID NO: 106 GMDAVGAVIVDPKTEQIIAVAHDCKRGSHPLHHAVM VCIDLVACGQDGGAYNYEKYPACRFSCSNSVCDGKE TGLPYICTGYDLYVTREPCVMCAMALVHSRISRVFYG ASTADGAFGSRYKIHCQKDLNHRFEVFKGVMVNACE DLCKE Schizosacchar omyces pombe ADAT3 MVKTNISKNSPKEATVPELDWPFKLIKSHLETRKLETE NVWIACFEPKYASKVTQYVKQIRSKQKESLLHCNRLR RIQDENGSLELQIIICPEKSMTANEIGKDFEDLGIVSKMI FLYAVPAFPPLTDEQFHEWNSVWPVSYRKHVQRQDV FTVHELKRIESILEDLINAAGASHKHGEIGCAAAIYDPT TDTVLAVSVDERSKLKNPINHCVMNAINLVAKRELSR RQNRTDGSKDRYLCKDLTVVMTHEPCVMCSMGLLH SRIRRLIYCKKQPLTGGIESLYGIHWRAELNHRYLAYS GWNKPVPSIKENIHV SEQ ID NO: 107 Saccharomyce s cerevisiae ADAT3 MVKKVNNPLKIDYQNGIIENRLLQIRNFKDVNTPKLIN VWSIRIDPRDSKKVIELIRNDFQKNDPVSLRHLKRIRK DIETSTLEVVLCSKEYICDEGEINNKLKSIWVGTKKYE LSDDIEVPEFAPSTKELNNAWSVKYWPLIWNGNPNDQ ILNDYKIDMQEVRNELSRASTLSVKMATAGKQFPMVS VFVDPSRKKDKVVAEDGRNCENSLPIDHSVMVGIRAV GERLREGVDEDANSYLCLDYDVYLTHEPCSMCSMAL IHSRVRRVVFLTEMQRTGSLKLTSGDGYCMNDNKQL NSTYEAFQWIGEEYPVGQVDRDVCC SEQ ID NO: 108 Human ADAT3 MEPAPGLVEQPKCLEAGSPEPEPAPWQALPVLSEKQS GDVELVLAYAAPVLDKRQTSRLLKEVSALHPLPAQPH LKRVRPSRDAGSPHALEMLLCLAGPASGPRSLAELLP RPAVDPRGLGQPFLVPVPARPPLTRGQFEEARAHWPT SFHEDKQVTSALAGRLFSTQERAAMQSHMERAVWA ARRAAARGLRAVGAVVVDPASDRVLATGHDCSCAD NPLLHAVMVCVDLVARGQGRGTYDFRPFPACSFAPA AAPQAVRAGAVRKLDADEDGLPYLCTGYDLYVTREP CAMCAMALVHARILRVFYGAPSPDGALGTRFRIHARP DLNHRFQVFRGVLEEQCRWLDPDT SEQ ID NO: 109 Rattus norvegicus ADAT3 MEPTSGFAEQPGPEKVESEEQEPAQWQALPVLSEQQS GAVELVLAYAAPVLDKRQTSRLLREVSAVYPLPAQPH LKRVRPSRSAGGAHSSDLLLCLAGPSAGPRSLAELLPR PAVDPRGLGTPFLVPVPARPPLTRSQFEEARAHWPTSF HEDKQVTSALAGQLFSAQARAAMQTHMERAVRAAQ RAAAQGLRAVGAVVVDPASDHVLATGHDCCSEASPL LHAVMVCIDLVAQGQGRGSCDLRRHPACSFTQATAT QSARAGSVRKLDEDSLPYVCTGYDLYVTREPCVMCA MALVHARIQRVFYGAPSPDGALGTRFRVHARPDLNH RFQVFRGILEDQCRQLDPDP SEQ ID NO: 110 Rattus norvegicus ADARB1 MDIEDEENMSSSSIDVKENRNLDNMPPKDSSTPGPGE GIPLSNGGGGSTSRKRPLEEGSNGHSKYRLKKRRKTP GPVLPKNALMQLNEIKPGLQYMLLSQTGPVHAPLFV MSVEVNGQVFEGSGPTKKKAKLHAAEKALRSFVQFP NASEAHLAMGRTLSVNTDFTSDQADFPDTLFNGFETP DKSEPPFYVGSNGDDSFSSSGDVSLSASPVPASLTQPP LPIPPPFPPPSGKNPVMILNELRPGLKYDFLSESGESHA KSFVMSVVVDGQFFEGSGRNKKLAKARAAQSALATV FNLHLDQTPSRQPVLSEGLQLHLPQVLADAVSRLVLG KFSDLTDNFSSPHARRKVLSGVVMTTGTDVKDAKVIS VSTGTKCINGEYMSDRGLALNDCHAEIISRRSLLRFLY AQLELYLNNKEDQKKSIFQKSERGGFRLKDTVQFHLY ISTSPCGDARIFSPHEPVLEGMAPDSHQLTEPADRHPN RKARGQLRTKIESGEGTIPVRSNASIQTWDGVLQGERL LTMSCSDKIARWNVVGIQGALLSIFVEPIYFSSIILGSLY HGDHLSRAMYQRISNIEDLPPLYTLNKPLLSGISNAEA RQPGKAPNFSVNWTVGDTAIEVINATTGKDELGRPSR LCKHALYCRWMRVHGKVPPHLLRTKITKPTTYHESK LAAKEYQAAKARLFTAFIKAGLGAWVEKPTEQDQFS FTP SEQ ID NO: 111 Human ADAR MNPRQGYSLSGYYTHPFQGYEHRQLRYQQPGPGSSPS SFLLKQIEFLKGQLPEAPVIGKQTPSLPPSLPGLRPRFPV LLASSTRGRQVDIRGVPRGVHLRSQGLQRGFQHPSPR GRSLPQRGVDCLSSHFQELSIYQDQEQRILKFLEELGE GKATTAHDLSGKLGTPKKEINRVLYSLAKKGKLQKE AGTPPLWKIAVSTQAWNQHSGVVRPDGHSQGAPNSD PSLEPEDRNSTSVSEDLLEPFIAVSAQAWNQHSGVVRP DSHSQGSPNSDPGLEPEDSNSTSALEDPLEFLDMAEIK EKICDYLFNVSDSSALNLAKNIGLTKARDINAVLIDME RQGDVYRQGTTPPIWHLTDKKRERMQIKRNTNSVPET APAAIPETKRNAEFLTCNIPTSNASNNMVTTEKVENG QEPVIKLENRQEARPEPARLKPPVHYNGPSKAGYVDF ENGQWATDDIPDDLNSIRAAPGEFRAIMEMPSFYSHG LPRCSPYKKLTECQLKNPISGLLEYAQFASQTCEFNMI EQSGPPHEPRFKFQVVINGREFPPAEAGSKKVAKQDA AMKAMTILLEEAKAKDSGKSEESSHYSTEKESEKTAE SQTPTPSATSFFSGKSPVTTLLECMHKLGNSCEFRLLS KEGPAHEPKFQYCVAVGAQTFPSVSAPSKKVAKQMA AEEAMKALHGEATNSMASDNQPEGMISESLDNLESM MPNKVRKIGELVRYLNTNPVGGLLEYARSHGFAAEF KLVDQSGPPHEPKFVYQAKVGGRWFPAVCAHSKKQG KQEAADAALRVLIGENEKAERMGFTEVTPVTGASLRR TMLLLSRSPEAQPKTLPLTGSTFHDQIAMLSHRCFNTL SEQ ID NO: 112 TNSFQPSLLGRKILAAIIMKKDSEDMGVVVSLGTGNR CVKGDSLSLKGETVNDCHAEIISRRGFIRFLYSELMKY NSQTAKDSIFEPAKGGEKLQIKKTVSFHLYISTAPCGD GALFDKSCSDRAMESTESRHYPVFENPKQGKLRTKVE NGEGTIPVESSDIVPTWDGIRLGERLRTMSCSDKILRW NVLGLQGALLTHFLQPIYLKSVTLGYLFSQGHLTRAIC CRVTRDGSAFEDGLRHPFIVNHPKVGRVSIYDSKRQS GKTKETSVNWCLADGYDLEILDGTRGTVDGPRNELS RVSKKNIFLLFKKLCSFRYRRDLLRLSYGEAKKAARD YETAKNYFKKGLKDMGYGNWISKPQEEKNFYLCPV Rattus norvegicus ADAR MSQGFRGPTGVFPHQTQPCLDPSYEHSKWRYLQPRGS ESYLRSFQLQQIEFLKGRLPEAPLIGAQTQSLPPFLPGH WPRFPGPPAQGKQPEIWGFPRSVTLRNQGFHIGPPLPP PHSRGPPWRGAEGLCSHFQELSISQNPEQKVLNRLEEL GEGKATTAYALARELRTPKKDINRILYSLERKGKLHR GVGKPPLWSLVPLSQACTQPPRAVNSDKEVPRGEPDL DSEDGDPASDLEGPSELLDMAEIKEKICDYLFNVSKSS ALNLAKNIGLAKARDVNAVLIDLERQGDVYREGATPP IWYLTDKKRERLQMKRSTHSGPAATPAAVSEATQSTS FPTCHPPQSGGSSSMATSKRVENGQEPVTKYESRHEA RPGPVRLRPHAYHNGPSRAGYVASENGPWATDDIPD NLNSIHTAPGEFRAIMEMPSFYSPTLPRCSPYKKLTEC QLKNPVSGLLEYAQFTSQTCDFNLIEQSGPSHEPRFKF QVVINGREFPPAEAGSKKVAKQDAAVKAMAILLREA KAKDSGQPEELSNCPMEEDPEKPAESQPPSSSATSLFS GKSPVTTLLECMHKLGNSCEFRLLSKEGPAHDPKFQY CVAVGAQTFPSVSAPSKKVAKQMAAEEAMKALQEE AANSADDQSGGANTDSLDESVAPNKIRRIGELVRYLN TNPVGGLLEYARSHGFAAEFKLIDQSGPPHEPKFVYQ AKVGGRWFPAVCAHSKKQGKQDAADAALRVLIGESE KAEQLGFAEVTPVTGASLRRTMLLLSRSPDAHPKTLP LTGSTFHDQIAMLSHRCFNALTNSFQPSLLGRKILAAII MKRDPEDMGVVVSLGTGNRCVKGDSLSLKGETVND CHAEIISRRGFIRFLYSELMKYNHHTAKNSIFELARGG EKLQIKKTVSFHLYISTAPCGDGAHFDKSCSDRAVEST ES RHYPVFENPKQGKLRTKVENGEGTIP VESS DIVPT W DGIRLGERLRTMSCSDKILRWNVLGLQGALLTHFLQP VYLKSVTLGYLFSQGHLTRAICCRVTRDGNAFEDGLR YPFIVNHPKVGRVSVYDSKRQSGKTKETSVNWCLAD GYDLEILDGTRGTVDGPGKELSRVSKKNIFLQFKKLCS FRARRDLLQLSYGEAKKAARDYDLAKNYFKKSLRDM GYGNWISKPQEEKNFYLCPVPND SEQ ID NO: 113 Human ADARB1 MDIEDEENMSSSSTDVKENRNLDNVSPKDGSTPGPGE GSQLSNGGGGGPGRKRPLEEGSNGHSKYRLKKRRKT PGPVLPKNALMQLNEIKPGLQYTLLSQTGPVHAPLFV MSVEVNGQVFEGSGPTKKKAKLHAAEKALRSFVQFP NASEAHLAMGRTLSVNTDFTSDQADFPDTLFNGFETP DKAEPPFYVGSNGDDSFSSSGDLSLSASPVPASLAQPP LPVLPPFPPPSGKNPVMILNELRPGLKYDFLSESGESHA KSFVMSVVVDGQFFEGSGRNKKLAKARAAQSALAAI FNLHLDQTPSRQPIPSEGLQLHLPQVLADAVSRLVLGK FGDLTDNFSSPHARRKVLAGVVMTTGTDVKDAKVIS VSTGTKCINGEYMSDRGLALNDCHAEIISRRSLLRFLY TQLELYLNNKDDQKRSIFQKSERGGFRLKENVQFHLY ISTSPCGDARIFSPHEPILEGSRSYTQAGVQWCNHGSL QPRPPGLLSDPSTSTFQGAGTTEPADRHPNRKARGQL RTKIESGEGTIPVRSNASIQTWDGVLQGERLLTMSCSD KIARWNVVGIQGSLLSIFVEPIYFSSIILGSLYHGDHLSR AMYQRISNIEDLPPLYTLNKPLLSGISNAEARQPGKAP NFSVNWTVGDSAIEVINATTGKDELGRASRLCKHALY CRWMRVHGKVPSHLLRSKITKPNVYHESKLAAKEYQ AAKARLFTAFIKAGLGAWVEKPTEQDQFSLTP SEQ ID NO: 114 Mus musculus ADARB1 MDIEDEENMSSSSTDIKENRNLDNMPPKDSSTPGPGEG IPLSNGGGGSTSRKRPLEEGSNGHSKYRLKKRRKTPGP VLPKNALMQLNEIKPGLQYMLLSQTGPVHAPLFVMS VEVNGQVFEGSGPTKKKAKLHAAEKALRSFVQFPNA SEAHLAMGRTLSVNTDFTSDQADFPDTLFNGFETPDK SEPPFYVGSNGDDSFSSSGDVSLSASPVPASLTQPPLPI PPPFPPPSGKNPVMILNELRPGLKYDFLSESGESHAKSF VMSVVVDGQFFEGSGRNKKLAKARAAQSALATVFNL HLDQTPSRQPVLSEGLQLHLPQVLADAVSRLVLGKFS DLTDNFSSPHARRKVLSGVVMTTGTDVKDAKVISVST GTKCINGEYMSDRGLALNDCHAEIISRRSLLRFLYAQL ELYLNNKEDQKKSIFQKSERGGFRLKDTVQFHLYISTS PCGDARIFSPHEPVLEGMTPDSHQLTEPADRHPNRKA RGQLRTKIESGEGTIPVRSNASIQTWDGVLQGERLLTM SCSDKIARWNVVGIQGSLLSIFVEPIYFSSIILGSLYHGD HLSRAMYQRISNIEDLPPLYTLNKPLLSGISNAEARQP GKAPNFSVNWTVGDATIEVINATTGKDELGRPSRLCK HALYCRWMRVHGKVPPHLLRTKITKPTTYHESKLAA REYQAAKARLFTAFIKAGLGAWVEKPTEQDQFSFTP SEQ ID NO: 115 Mus musculus ADAR MSQGFRGPTGVFPHQTQSYLDPSHEHSKWRYPQPQGP ESYPRSFQLQQIEFLKGRLPEAPLIGIQTQSLPPFLPGH WPRFPGPPAQDRQLEIWEFPRSVTLRNQGFHIGPPLPP PHSRGTPWRGADGLCSHFRELSISQSPEQKVLNRLEEL SEQ ID NO: 116 GEGKATTAHVLARELRIPKRDINRILYSLEKKGKLHRG RGKPPLWSLVPLSQAWTQPPGVVNPDSCIQEFPRGEP GLDSEDGDPASDLEGPSEPLDMAEIKEKICDYLFNVSN SSALNLAKNIGLTKARDVTSVLIDLERQGDVYRQGAT PPIWYLTDKKRERLQMKRSTHSAPAPTPTAVPEATRSP SFPACHPPPAGASSSVAASKRVENGQEPAIKHESRHEA RPGPMRLRPHAYHNGPSRAGYVASENGQWATDDIPD NLNSIHTAPGEFRAIMEMPSFYSPTLPRCSPYKKLTEC QLKNPVSGLLEYAQFTSQTCDFNLIEQSGPSHEPRFKF QVVINGREFPPAEAGSKKVAKQDAAVKAMAILLREA KAKDSGQPEDLSHCPMEEDSEKPAEAQAPSSSATSLFS GKSPVTTLLECMHKLGNSCEFRLLSKEGPAHDPKFQY CVAVGAQTFPPVSAPSKKVAKQMAAEEAMKALQEE AASSADDQSGGANTDSLDESMAPNKIRRIGELVRYLN TNPVGGLLEYARSHGFAAEFKLIDQSGPPHEPKFVYQ AKVGGRWFPAVCAHSKKQGKQDAADAALRVLIGESE KAEQLGFAEVTPVTGASLRRTMLLLSRSPDAHPKTLP LSGSTFHDQIAMLSHRCFNALTNSFQPSLLGRKILAAII MKRDPEDMGVVVSLGTGNRCVKGDSLSLKGETVND CHAEIISRRGFIRFLYSELMKYNHHTAKNSIFELARGG EKLQIKKTVSFHLYISTAPCGDGALFDKSCSDRAVEST ES RHYPVFENPKQGKLRTKVENGEGTIP VESS DIVPT W DGIRLGERLRTMSCSDKILRWNVLGLQGALLTHFLQP VYLKSVTLGYLFSQGHLTRAICCRVTRDGKAFEDGLR YPFIVNHPKVGRVSVYDSKRQSGKTKETSVNWCMAD GYDLEILDGTRGTVDGPGKELSRVSKKNIFLQFKKLCS FRARRDLLQLSYGEAKKAARDYDLAKNYFKKSLRDM GYGNWISKPQEEKNFYLCPVPND Human ADARB2- AS1 MKQLFPPPPGTSLTHALGAWRGRERAQAATSLLASSA SQFPTAVEDALMSVLTSHCAPSTPAATRAQQTGTRGH IHPACPCQQSCVGASRPPGRPQIFLPLTTALSLEAYAA DTCSAADFLHNPSSWGKVWYLNEASFDLYSYHYFW SEQ ID NO: 117 Rattus norvegicus ADARB2 MASVLGSGRGSGGLSSQLKCKSKRRRRRRSKRKDKV SILSTFLAPFKYLSPGTTNTEDEDNLSTSSAEVKENRN VSNLGTRPLPPGDWARGGSTPSVKRKRPLEEGNGGHF CKLQLIWKKLSWSMTPKNALVQLHELKPGLQYRMVS QTGPVHAPVFAVAVEVNGLTFEGTGPTKKKAKMRAA EMALKSFVQFPNAFQAHLAMGSSTSPCTDFTSDQADF PDTLFKEFEPSSRNEDFPGCCPVDTEFLSSAYRRGRLL YHTLDLMGQALPDRSRLAPGALGERNPVVVLNELRS GLRYVCLSETAEKPRVKSFVMAVCVDGRTFEGSGRS KKLAKGQAAQAALQALFDIRLPGHIPSRSKSNLLPQDF ADSVSQLVTQKFRELTVGLTSVYARHKTLAGIVMTK SEQ ID NO: 118 GLDTKQAQVIVLSSGTKCISGEHISDQGLVVNDCHAEI VARRAFLHFLYTQLELHLSKHQEDPERSIFIRVKEGGY RLRENILFHLYVSTSPCGDARLNSPYEITIDLNSSKHIV RKFRGHLRTKIESGEGTVPVRGPSAVQTWDGILLGEQ LVTMSCTDKIASWNVLGLQGALLCHFIEPVYLHSIIVG SLHHTGHLARVMSHRMEGIGQLPASYRQNRPLLSGVS NAEARQPGKSPHFSANWVVGSADLEIINATTGKRSCG GSSRLCKHVFSARWARLHGRLSTRIPGHGDTPSMYCE AKRGAHTYQSVKQQLFKAFQKAGLGTWVRKPPEQD QFLLSL Mus musculus ADARB2 MASVLGSGRGSGGLSSQLKCKSKRRRRRRSKRKDKV SILSTFLAPFKYLSPGTTNTEDEDNLSTSSAEVKENRN VSNLGTRPLPPGDWARGSTPSVKRKRPLEEGNGGHFC KLQLIWKKLSWSVTPKNALVQLHELKPGLQYRMVSQ TGPVHAPVFAVAVEVNGLTFEGTGPTKKKAKMRAAE MALKSFVQFPNAFQAHLAMGSSTSPCTDFTSDQADFP DTLFKEFEPSSKNEDFPGCHPVDTEFLSSAYRRGRLLY HTLDLMGQALPDRSRLAPGALGERNPVVVLNELRSG LRYVCLSETAEKPRVKSFVMAVCVDGRTFEGSGRSK KLAKGQAAQAALQALFDIRLPGHIPSRSKSNLLPQDFA DSVSQLVTQKFRELTVGLTSVYARHKTLAGIVMTKGL DTKQAQVIVLSSGTKCISGEHISDQGLVVNDCHAEIVA RRAFLHFLYSQLELHLSKHQEDPERSIFIRLKEGGYRL RENILFHLYVSTSPCGDARVNSPYEITTDLNSSKHIVRK FRGHLRTKIESGEGTVPVRGPSAVQTWDGILLGEQLIT MSCTDKIASWNVLGLQGALLCHFIEPVYLHSnVGSLH HTGHLARVMSHRMEGIGQLPASYRQNRPLLSGVSHA EARQPGKSPHFSANWVVGSADLEIINATTGKRSCGGS SRLCKHVFSAWWARLHGRLSTRIPSHGDTPSMYCEA KQGAHTYQSVKQQLFKAFQKAGLGTWVRKPPEQDQ FLLSL SEQ ID NO: 119 Human ADARB2 MASVLGSGRGSGGLSSQLKCKSKRRRRRRSKRKDKV SILSTFLAPFKHLSPGITNTEDDDTLSTSSAEVKENRNV GNLAARPPPSGDRARGGAPGAKRKRPLEEGNGGHLC KLQLVWKKLSWSVAPKNALVQLHELRPGLQYRTVSQ TGPVHAPVFAVAVEVNGLTFEGTGPTKKKAKMRAAE LALRSFVQFPNACQAHLAMGGGPGPGTDFTSDQADFP DTLFQEFEPPAPRPGLAGGRPGDAALLSAAYGRRRLL CRALDLVGPTPATPAAPGERNPVVLLNRLRAGLRYVC LAEPAERRARSFVMAVSVDGRTFEGSGRSKKLARGQ AAQAALQELFDIQMPGHAPGRARRTPMPQEFADSISQ LVTQKFREVTTDLTPMHARHKALAGIVMTKGLDARQ AQVVALSSGTKCISGEHLSDQGLVVNDCHAEVVARR SEQ ID NO: 120 AFLHFLYTQLELHLSKRREDSERSIFVRLKEGGYRLRE NILFHLYVSTSPCGDARLHSPYEITTDLHSSKHLVRKF RGHLRTKIESGEGTVPVRGPSAVQTWDGVLLGEQLIT MSCTDKIARWNVLGLQGALLSHFVEPVYLQSIVVGSL HHTGHLARVMSHRMEGVGQLPASYRHNRPLLSGVSD AEARQPGKSPPFSMNWVVGSADLEIINATTGRRSCGG PSRLCKHVLSARWARLYGRLSTRTPSPGDTPSMYCEA KLGAHTYQSVKQQLFKAFQKAGLGTWVRKPPEQQQF LLTL Rattus norvegicus AMPD1 MPLFKLTGQGKQIDDAMRSFAEKVFASEVKDEGGRH EISPFDVDEICPISLREMQAHIFHMENLSMSMDGRRKR RFQGRKTVNLSIPQSETSSTKLSHIEEFISSSPTYESVPD FQRVQITGDYASGVTVEDFEVVCKGLYRALCIREKYM QKSFQRFPKTPSKYLRNIDGEALVAIESFYPVFTPPPKK GEDPFRREDLPANLGYHLKMKGGVIYIYPDEAAASRD EPKPYPYPNLDDFLDDMNFLLALIAQGPVKTYTHRRL KFLSSKFQVHQMLNEMDELKELKNNPHRDFYNCRKV DTHIHAAACMNQKHLLRFIKKSYHIDADRVVYSTKEK NLTLKELFAQLNMHPYDLTVDSLDVHAGRQTFQRFD KFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEV GADLVDAKYQHAEPRLSIYGRSPDEWSKLSSWFVGN RIYCPNMTWMIQVPRIYDVFRSKNFLPHFGKMLENIFL PVFEATINPQTHPDLSVFLKHITGFDSVDDESKHSGHM FSSKSPKPEEWTMENNPSYTYYAYYMYANIMVLNCL RKERGMNTFLFRPHCGEAGALTHLMTAFMIADNISHG LNLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAKNPF LDFLQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQV FKLSTCDMCEVARNSVLQCGISHEEKAKFLGNNYLEE GPVGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLKS TE SEQ ID NO: 121 Human AMPD1 MPLFKLPAEEKQIDDAMRNFAEKVFASEVKDEGGRQ EISPFDVDEICPISHHEMQAHIFHLETLSTSTEARRKKR FQGRKTVNLSIPLSETSSTKLSHIDEYISSSPTYQTVPDF QRVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQ KSFQRFPKTPSKYLRNIDGEAWVANESFYPVFTPPVK KGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVS KDEPKPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHR RLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYNCR KVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYST KEKNLTLKELFAKLKMHPYDLTVDSLDVHAGRQTFQ RFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIK EVGADLVEAKYQHAEPRLSIYGRSPDEWSKLSSWFVC NRIHCPNMTWMIQVPRIYDVFRSKNFLPHFGKMLENI SEQ ID NO: 122 FMPVFEATINPQADPELSVFLKHITGFDSVDDESKHSG HMFSSKSPKPQEWTLEKNPSYTYYAYYMYANIMVLN SLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDIS HGLNLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAK NPFLDFLQKGLMISLSTDDPMQFHFTKEPLMEEYAIAA QVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNYL EEGPAGNDIRRTNVAQIRMAYRYETWCYELNLIAEGL KSTE Oryctolagus cuniculus AMPD1 MNQKHLLRFIKKSYQVDADRVVYSTK SEQ ID NO: 123 Gallus gallus AMPD1 MNQKHLLRFIKKSYRVDADRVVYDAK SEQ ID NO: 124 Mus musculus AMPD1 MPLFKLTGQGKQIDDAMRSFAEKVFASEVKDEGGRH EISPFDVDEICPISLHEMQAHIFHMENLSMDGRRKRRF QGRKTVNLSIPQSETSSTKLSHIEEFISSSPTYESVPDFQ RVQITGDYASGVTVEDFEVVCKGLYRALCIREKYMQ KSFQRFPKTPSKYLRNIDGEALVGNESFYPVFTPPPKK GEDPFRTEDLPANLGYHLKMKAGVIYIYPDEAAANRD EPKPYPYPNLDDFLDDMNFLLALIAQGPVKTYAHRRL KFLSSKFQVHQMLNEMDELKELKNNPHRDFYNCRKV DTHIHAAACMNQKHLLRFIKKSYHIDADRVVYSTKEK SLTLKELFAKLNMHPYDLTVDSLDVHAGRQTFQRFD KFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEV GADLVEAKYQHAEPRLSIYGRSPDEWNKLSSWFVCN RIYCPNMTWMIQVPRIYDVFRSKNFLPHFGKMLENIFL PVFEATINPQAHPDLSVFLKHITGFDSVDDESKHSGHM FSSKSPKPEEWTMENNPSYTYYAYYMYANITVLNSLR KERGMNTFLFRPHCGEAGALTHLMTAFMIADNISHGL NLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAKNPFL DFLQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVF KLSTCDMCEVARNSVLQCGISHEEKAKFLGNNYLEEG PVGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLKAT E SEQ ID NO: 125 Dictyostelium discoideum AMPD1 MSTPLRGSSPQVSFYESELDQEGGSDASHFTYRNYME DDKINSFTFNMARKDQTQLFQRIILTNESESEIEEYAEV AEQLLDAINLREKYVFHPKIWKADAPVGEKPPYSPFES DESTNCATEHMFKEVNGVYFVYSNETDMKSNKALFS VPHTLASYYKDINNLMMLSSYGPAKTFTFKRLQLLES KFNMHTLLNDSLELFQQKTAPHRDFYNVRKVDTHVH HSSSMNQKHLLKFIKRKLKENPNEIVIFRDDKYLTLAE VFKSLNLDVDELSVDTLDVHADNNTFHRFDKFNLKY NPCGQSRLREIFLKTDNLIKGKYLAEISKEVFTDLESSK SEQ ID NO: 126 YQCAEYRLSIYGRKMSEWDTLASWIVDNDLFSTKVR WLIQVPRLYDVYRETSTTTFQDFLNNVFHPLFEVTKD PSSHPKLHLFLQQVVGIDCVDDESKFEKKFTEKFPVPG EWSSEHNPPYTYYLYYLYANLYTLNQFREEKGLNILT LRPHSGEAGEVDHMGAAFYLAHGINHGINLRKTPVLQ YLYYLTQIGIAMSPLSNNSLFLTYNRNPFPAFFARGLN VSISTDDPLQFHYTKEPLMEEYSIATQVWRLSVCDICEI ARNSVLQSGFEHNVKSHWLGPDYANSGGNDIKKTNIS DIRVCFRNETLIEELHLILKSLQTLPNFKNLNINFLLDK LPSEITTGNDYKLKKAQLKLNGANKLRNSSVGSTPNN GTPSSSGTPSLSSPGAIVHLMKTKPYIPPPLSLNIKQEN NNNNNNNNNNNNNNNNNNTNTNTNSNSTTTNQDDN SKSDK Human AMPD3 MPRQFPKLNISEVDEQVRLLAEKVFAKVLREEDSKDA LSLFTVPEDCPIGQKEAKERELQKELAEQKSVETAKR KKSFKMIRSQSLSLQMPPQQDWKGPPAASPAMSPTTP VVTGATSLPTPAPYAMPEFQRVTISGDYCAGITLEDYE QAAKSLAKALMIREKYARLAYHRFPRITSQYLGHPRA DTAPPEEGLPDFHPPPLPQEDPYCLDDAPPNLDYLVH MQGGILFVYDNKKMLEHQEPHSLPYPDLETYTVDMS HILALITDGPTKTYCHRRLNFLESKFSLHEMLNEMSEF KELKSNPHRDFYNVRKVDTHIHAAACMNQKHLLRFI KHTYQTEPDRTVAEKRGRKITLRQVFDGLHMDPYDL TVDSLDVHAGRQTFHRFDKFNSKYNPVGASELRDLY LKTENYLGGEYFARMVKEVARELEESKYQYSEPRLSI YGRSPEEWPNLAYWFIQHKVYSPNMRWIIQVPRIYDIF RSKKLLPNFGKMLENIFLPLFKATINPQDHRELHLFLK YVTGFDSVDDESKHSDHMFSDKSPNPDVWTSEQNPP YSYYLYYMYANIMVLNNLRRERGLSTFLFRPHCGEA GSITHLVSAFLTADNISHGLLLKKSPVLQYLYYLAQIPI AMSPLSNNSLFLEYSKNPLREFLHKGLHVSLSTDDPM QFHYTKEALMEEYAIAAQVWKLSTCDLCEIARNSVLQ SGLSHQEKQKFLGQNYYKEGPEGNDIRKTNVAQIRM AFRYETLCNELSFLSDAMKSEEITALTN SEQ ID NO: 127 Human AMPD2 MRNRGQGLFRLRSRCFLHQSLPLGAGRRKGLDVAEP GPSRCRSDSPAVAAVVPAMASYPSGSGKPKAKYPFK KRASLQASTAAPEARGGLGAPPLQSARSLPGPAPCLK HFPLDLRTSMDGKCKEIAEELFTRSLAESELRSAPYEF PEESPIEQLEERRQRLERQISQDVKLEPDILLRAKQDFL KTDSDSDLQLYKEQGEGQGDRSLRERDVLEREFQRVT ISGEEKCGVPFTDLLDAAKSVVRALFIREKYMALSLQS FCPTTRRYLQQLAEKPLETRTYEQGPDTPVSADAPVH PPALEQHPYEHCEPSTMPGDLGLGLRMVRGVVHVYT SEQ ID NO: 128 RREPDEHCSEVELPYPDLQEFVADVNVLMALIINGPIK SFCYRRLQYLSSKFQMHVLLNEMKELAAQKKVPHRD FYNIRKVDTHIHASSCMNQKHLLRFIKRAMKRHLEEI VHVEQGREQTLREVFESMNLTAYDLSVDTLDVHADR NTFHRFDKFNAKYNPIGESVLREIFIKTDNRVSGKYFA HIIKEVMSDLEESKYQNAELRLSIYGRSRDEWDKLAR WAVMHRVHSPNVRWLVQVPRLFDVYRTKGQLANFQ EMLENIFLPLFEATVHPASHPELHLFLEHVDGFDSVDD ESKPENHVFNLESPLPEAWVEEDNPPYAYYLYYTFAN MAMLNHLRRQRGFHTFVLRPHCGEAGPIHHLVSAFM LAENISHGLLLRKAPVLQYLYYLAQIGIAMSPLSNNSL FLSYHRNPLPEYLSRGLMVSLSTDDPLQFHFTKEPLME EYSIATQVWKLSSCDMCELARNSVLMSGFSHKVKSH WLGPNYTKEGPEGNDIRRTNVPDIRVGYRYETLCQEL ALITQAVQSEMLETIPEEAGITMSPGPQ Mus musculus AMPD2 MASEARSGLGASPLQSARSLPGNAPCLKHFPLDLRTS MDGKCKEIAEELFSRSLAESELRSAPYEFPEESPIEQLE ERRQRLERQISQDVKLEPDILLRAKQDFLKTDSDSDLQ LYKEQGEGQGDRGLWERDVVLEREFQRVIISGEEKCG VPFTDLLDAAKSVVRALFIREKYMALSLQSFCPTTRR YLQQLAEKPLETRTYEQSPDTPVSADAPVHPPALEQH PYEHCEPSAMPGDLGLGLRMVRGVVHVYTRRDPDEH CPEVELPYPDLQEFVADVNVLMALIINGPIKSFCYRRL QYLSSKFQMHVLLNEMKELAAQKKVPHRDFYNIRKV DTHIHASSCMNQKHLLRFIKRAMKRHLEEIVHVEQGR EQTLREVFESMNLTAYDLSVDTLDVHADRNTFHRFD KFNAKYNPIGESVLREIFIKTDNKISGKYFAHIIKEVMA DLEESKYQNAELRLSIYGRSRDEWDKLARWAVNHKV HSPNVRWLVQVPRLFDVYRTKGQLANFQEMLENIFLP LFEATVHPASHPELHLFLEHVDGFDSVDDESKPENHV FNLESPLPEAWVEEDNPPYAYYLYYTFANMAMLNHL RRQRGFHTFVLRPHCGEAGPIHHLVSAFMLAENISHG LLLRKAPVLQYLYYLAQIGIAMSPLSNNSLFLSYHRNP LPEYLSRGLMVSLSTDDPLQFHFTKEPLMEEYSIATQV WKLSSCDMCELARNSVLMSGFSHKVKSHWLGPNYT KEGPEGNDIRRTNVPDIRVGYRYETLCQELALITQAVQ SEMLETIPEEVGIVMSPGP SEQ ID NO: 129 Rattus norvegicus AMPD2 MASYPGPGKSKAKYPFKKRASLQASAAAPEARSGLG ASPLQSARSLPGTAPCLKHFPLDLRTSMDGKCKEIAEE LFSRSLAESELRSAPYEFPEESPIEQLEERRQRLERQISQ DVKLEPDILLRAKQDFLKTDSDSDLQLYKEQGEGQGD RGLWERDVVLEREFQRVIISGEEKCGVPFTDLLDAAK SVVRALFIREKYMALSLQSFCPTTRRYLQQLAEKPLET SEQ ID NO: 130 RTYEQSPDTPVSADAPVHPPALEQHPYEHCEPSTMPG DLGLGLRMVRGVVHVYTRRDPDEHCPEVELPYPDLQ EFVADVNVLMALIINGPIKSFCYRRLQYLSSKFQMHV LLNEMKELAAQKKVPHRDFYNIRKVDTHIHASSCMN QKHLLRFIKRAMKRHLEEIVHVEQGREQTLREVFESM NLTAYDLSVDTLDVHADRNTFHRFDKFNAKYNPIGES VLREIFIKTDNKISGKYFAHIIKEVMSDLEESKYQNAEL RLSIYGRSRDEWDKLARWAVNHRVHSPNVRWLVQV PRLFDVYRTKGQLANFQEMLENIFLPLFEATVHPASHP ELHLFLEHVDGFDSVDDESKPENHVFNLESPLPEAWV EEDNPPYAYYLYYTFANMAMLNHLRRQRGFHTFVLR PHCGEAGPIHHLVSAFMLAENISHGLLLRKAPVLQYL YYLAQIGIAMSPLSNNSLFLSYHRNPLPEYLSRGLMVS LSTDDPLQFHFTKEPLMEEYSIATQVWKLSSCDMCEL ARNSVLMSGFSHKVKSHWLGPNYTKEGPEGNDIRRT NVPDIRVGYRYETLCQELALITQAVQSEMLETIPEEVG IVMSPGP Plasmodium gallinaceum ADA MTILHEEINFLKKDELNINLKCLDKKERYKIWRRIPKC ELHCHLDLCFSLEFFLKCVRKYNLQPDLTDDEVVDYY LFKDKGKSLNEFIERSRRVTDIFINYDIIKDIAKNAVFN KYKEGVILIEFRYSPSYIAYKYNLCIDLIHKTIVEGINEA VEKLNHKIHVGLICIGETGISEESLRKAAEFCVKNKKD FVGFDHAGHERDLKPYKEIYDYVRENGIPLTIHAGED LTLPNLNTIYSAIEVLKAKRIGHGIRVIESEDLINLIKKN DILLEICPISNLLLNNVKSMDTHPIKKLYDSGIKVSVNT DDPGMFLTEINDEYEELYLNLNFNLEDFMKMNLWAL EKSFVKSEIKDKLKKLYF SEQ ID NO: 131 Plasmodium knowlesi ADA MNILQEPIDFLKKDELKNIDLSQMDKKERYKIWKRIPK CELHCHLDLCFSADFFLSCVRKYNLQPNLSDEEVLDY YLFAKGGKSLGEFVEKAIRVADIFQDYEMIEDLAKHA VFNKYKEGVVLMEFRYSPTFVAFKHNLDIELIHQAIV KGIKEVVELLDHKIDVTLLCIGDTGHRAADIKASADFC LKHKADFVGFDHGGHEVDLKPYKEIFDYVKEGGMHL TVHAGEDVTLPNLNTLYSAIQVLKVERIGHGIRVSESQ ELIDMVKENNILLEVCPISNVLLKNAKSFDTHPIRKLY DAGVKVSVSSDDPGMFLTNINDDYEKLYTHLHFTLED FMKMNEWALEKSFIGCDIKEKIKKLYF SEQ ID NO: 132 Plasmodium berghei ADA MEIPNEEIKFLKKEDIKNINLNGMNKKERYEIWKKIPK VELHCHLDLTFSGKFFLKWVRKYNLQPNMTDDQVLD HYLFTKEGKSLAEFIRKAISVSDIYRDYDILEDLAKWA VIEKYKEGVVLMEFRYSPTFVSSSHGLDIELIHKAFVK GIKNATEMLNNKIYVALICISDTGHSAASIKHSGDFAIK HKHDFVGFDHGGREIDLKDHKDVYHSVRNHGLHLTV SEQ ID NO: 133 HAGEDATLPNLNTLYTAINILNVERIGHGIRVSESEELI ELVKKNNILLEVCPISNLLLNNVKSMDTHPIRKLFDAG VKVSVNSDDPGMFLTDINDNYEKLYIHLNFTLEEFMT MNNWALEKSFVNDDIKSKLKTMYF Plasmodium vivax ADA MNILQEPIDFLKKEELKNIDLSQMSKKERYKIWKRIPK CELHCHLDLCFSADFFVSCIRKYNLQPNLSDEEVLDY YLFAKGGKSLGEFVEKAIKVADIFHDYEVIEDLAKHA VFNKYKEGVVLMEFRYSPTFVAFKYNLDIELIHQAIV KGIKEVVELLDHKIHVALMCIGDTGHEAANIKASADF CLKHKADFVGFDHGGHEVDLKEYKEIFDYVRESGVP LSVH AGED VTLPNLNTLYSAIQVLKVERIGHGIRV AES QELIDMVKEKNILLEVCPISNVLLKNAKSMDTHPIRQL YDAGVKVSVNSDDPGMFLTNINDDYEELYTHLNFTLE DFMKMNEWALEKSFMDSNIKDKIKNLYF SEQ ID NO: 134 Plasmodium cynomolgi ADA MNILQEPIDFLKKDEIKNIDLSQMSKKERYKIWKRIPK CELHCHLDLCFSADFFLSCIRKYNLQPNLSDEEVLDYY LFAKGGKSLGEFVEKAIRVADIFHDYEVIEDLAKHAV FNKYKEGVVLMEFRYSPTFVAFKYKLDIELIHQAIVK GIKEVVELLDHKIHVALMCIGDTGHEAANIKASADFC LKHRADFVGFDHGGHEVDLKQYKEIFDYVRESGIPLS VHAGEDVTLPNLNTLYSAIQVLKVERIGHGIRVSESQE LIDMVKEKNILLEVCPISNVLLKNAKSMDTHPIRQLYD AGVKVSVNSDDPGMFLTNINDDYEELYTHLNFTLEDF MKMNEWALEKSFMDSNIKDKVKNLYF SEQ ID NO: 135 Human ADA MAQTPAFDKPKVELHVHLDGSIKPETILYYGRRRGIAL PANTAEGLLNVIGMDKPLTLPDFLAKFDYYMPAIAGC REAIKRIAYEFVEMKAKEGVVYVEVRYSPHLLANSKV EPIPWNQAEGDLTPDEVVALVGQGLQEGERDFGVKA RSILCCMRHQPNWSPKVVELCKKYQQQTVVAIDLAG DETIPGSSLLPGHVQAYQEAVKSGIHRTVHAGEVGSA EVVKEAVDILKTERLGHGYHTLEDQALYNRLRQENM HFEICPWSSYLTGAWKPDTEHAVIRLKNDQANYSLNT DDPLIFKSTLDTDYQMTKRDMGFTEEEFKRLNINAAK SSFLPEDEKRELLDLLYKAYGMPPSASAGQNL SEQ ID NO: 136 Mus musculus ADA MAQTPAFNKPKVELHVHLDGAIKPETILYFGKKRGIA LPADTVEELRNIIGMDKPLSLPGFLAKFDYYMPVIAGC REAIKRIAYEFVEMKAKEGVVYVEVRYSPHLLANSKV DPMPWNQTEGDVTPDDVVDLVNQGLQEGEQAFGIKV RSILCCMRHQPSWSLEVLELCKKYNQKTVVAMDLAG DETIEGSSLFPGHVEAYEGAVKNGIHRTVHAGEVGSP EVVREAVDILKTERVGHGYHTIEDEALYNRLLKENM HFEVCPWSSYLTGAWDPKTTHAVVRFKNDKANYSLN SEQ ID NO: 137 TDDPLIFKSTLDTDYQMTKKDMGFTEEEFKRLNINAA KSSFLPEEEKKELLERLYREYQ Bos taurus ADA MAQTPAFNKPKVELHVHLDGAIKPETILYYGRKRGIA LPADTPEELQNIIGMDKPLSLPEFLAKFDYYMPAIAGC REAVKRIAYEFVEMKAKDGVVYVEVRYSPHLLANSK VEPIPWNQAEGDLTPDEVVSLVNQGLQEGERDFGVK VRSILCCMRHQPSWSSEVVELCKKYREQTVVAIDLAG DETIEGSSLFPGHVKAYAEAVKSGVHRTVHAGEVGSA NVVKEAVDTLKTERLGHGYHTLEDATLYNRLRQENM HFEVCPWSSYLTGAWKPDTEHPVVRFKNDQVNYSLN TDDPLIFKSTLDTDYQMTKNEMGFTEEEFKRLNINAA KSSFLPEDEKKELLDLLYKAYGMPSPASAEQCL SEQ ID NO: 138 Gallus gallus ADA MERGVRVFGEPKVELHIHLDGAIRPETILHFGKKRGVP LPGSTVDELMKHVSYQTPLSLKLFLEKFNHYMPAIAG DREAVRRIAYELVETKAKEGVVYVEVRYSPHLLANC RVEPIPWGQAEGDLTPEEVVNLVNQGLQDGERNFRIK ARSILCCMRHMPSWSPEVVELCKKYQNNSVVAIDLA GDELLMASSDHKAAYEEAERCGIHRTVHAGEAGPAT MIKEAVYLLKAERIGHGYHVLEDPELYRELLRTRMHF EVCPWSSYLTGACLPDFRKHPVVQFKKDQANYSINTD DPLIFNSNIDKDYGIVKEYMDFTEEDFKRVNINAAQSS FLPEKEKQELLNTLYEAYGMVPATS SEQ ID NO: 139 Danio rerio ADA MNGKPAFDKPKVELHVHLDGAIRLKTVLDVAKRRGI SLPVSMEEELKELCTVNEPATLTEFLGKFSHFMHVIAG DREAIKRIAYEFVETKAKEGVIYVEARYSPHFLANKG VEPLPWDQKPGDITPDDVVDLVNQGFKEGEQAFKTK ARSILCCMRHMPNWSMEVVELCKKFHKDGVVAIDLA GDESMNCESYPGHKKAFEEAVRSNVHRTVHAGEVGP ASVVREAVEVLKAERIGHGYHTLEDQNLYKQLLHQN MHFEMCPVSSRLTGACEPDFTKHPLITFKKDKANYSL NTDDPTIFNSTLNSDYEVVQKYMDFTEEEFKRLNINA AKSCFLPEKEKEKLLNQLYEAYGMRKSTSF SEQ ID NO: 140 Xenopus laevis ADA MESKAFNKPKVELHVHLDGSIKPETIIHFAKKRQIKLP ADTVEGLLEHVSYKEPLSLTEFLQKFNHYMPAIAGDR EAIKRIAYEFVEMKAKEGVIYVEVRYSPHFLANSKVD PIPWGQKEGDITPDEVVDLVNQGLRKGEKTFNIKARSI LCCMRHMPNWSSEVIELCKKYQNDTVVAIDLAGDES LNCESYPGHRKAYEEAVKCGIHRTVHAGEVGPPSVV KEAVEVLKAERIGHGYHTTEDPNLYKELLENNMHFE VCPWSSYLTSACHPDFTKHPATQFRKDKANFSLNTDD PLIFGSTLDVDYSIAVQHMGFTEDEFKRVNINAAKSSF LPDNEKKELLYKLYEAYGMILSTGL SEQ ID NO: 141 Plasmodium falciparum ADA MNCKNMDTSYEIINYLTKDELDIDLSCMDKKERYKIW KRLPKCELHCHLDVCFSVDFFLNVIRKYNIQPNMSDE EIIDYYLFSKPGKSLDEFVEKALRLTDIYIDYTVVEDLA KHAVFNKYKEGVVLMEFRYSPSFMSFKHNLDKDLIH EAIVKGLNEAVALLEYKIQVGLLCTGDGGLSHERMKE AAEFCIKHKKDFVGYDHAGHEVDLKPFKDIFDNIREE GISLSVHAGEDVSIPNLNSLYTAINLLHVKRIGHGIRVS ESQELIDLVKEKDILLEVCPISNVLLNNVKSMDTHPIR MLYDAGVKVSVNSDDPGMFLTNITDNYEELYTHLNF TLADFMKMNLWAVQKSFVDPDIKNKIISKYF SEQ ID NO: 142 Drosophila melanogaster ADA MEQFLKGLPKVELHAHLNGSLGIKSLCDLGERLYGTS CKDFLKLCAHFSRFEKDMDACFEKFAFVHELTSTREG LRFATELAIRDFAEDNVQYVEMRTTPKANENYSRRDY LQIVIDAIKAASETYPEITVKLLPSINRAEPVDVAEETV SLAVELARAHPNLILGIDLSGNPGKGRFSDFAPILAQA RDKGLKLAIHCAEIENPSEVKEMLHFGMSRCGHGTFL TPEDIGQLKQRNIAIECCLTSNVKSGTVPSLEEHHLKRI MEADAPKVICTDDSGVFDTTLTKEFLIAAETFGLTREQ CIDLTLEAVHHSFASEQEQIQMADRVGNYADILVK SEQ ID NO: 143 Xenopus tropicalis ADA MESKAFNKPKVELHVHLDGSIKPETIIHFAKKRQIKLP ADTVEGLLEHVSYKEPLSLTEFLSKFNHYMPAIAGDR EAIKRIAYEFVEMKAKEGVIYVEVRYSPHFLANSKVEP IPWGQKEGDITPDEVVDLVNQGLRKGEKAFNIKARSIL CCMRHMPSWSTEVVELCKKYQNDTVVAIDLAGDESL NCESYPGHRKAYEEAVKCGIHRTVHAGEVGPSSVVK EAVEVLKAERIGHGYHTTEDPNLYKELLEKNMHFEV CPWSSYLTGACHPDFTKHPATQFRKDKANYSLNTDD PLIFGSTLDVDYSIAAKHMGFTEEEFKRVNINAAKSSF LPESEKKELLYKLYEAYGMILSTGL SEQ ID NO: 144 Rattus norvegicus ADA MAQTPAFNKPKVELHVHLDGAIKPETILYYGKKRGID LPADTVEGLRNIIGMDKPLSLPDFLAKFDYYMPAIAGC REAIKRIAYEFVEMKAKEGVVYVEVRYSPHLLANSKV DPIPWNQAEGDLTPDEVVDLVNQGLQEGEQAFGIKVR SILCCMRHQPSWSPEVLELCKKYHQKTVVAMDLAGD ETIEGSSLFPGHVEAYEGAVKDGIHRTVHAGEVGSAE VVREAVDILKTERVGHGYHTIEDEALYNRLLKENMHF EVCPWSSYLTGAWNPKTTHAVVRFKDDQANYSLNSD DPLIFKSTVDTDYQMVKKDMGFTEEEFKRLNINAAKS SFLPEDEKKELLERLYKEYQ SEQ ID NO: 145 Mus musculus AD ADI MATAGGSRRAPVPGPRLGLPLAAHLPASLGGEGAKD SVGGEKTSGNNDWFQSSRVPSFAQMLKKNLPVQPSA QTVTLPTGYSSESCSLSNMASKVTQVTGNFPEPLLSKG LSSISNPVLPPKKLPKEFIMKYKRGEINPVSALHQFAQ SEQ ID NO: 146 MQRVQLDLKETVTTGNVMGPYFAFCAVVDGIQYKTG LGQNKKESRSNAAKLALDELLQLDEPEPRVLEPAGPP PIPAEPVVTPEAAYVSKVQYEGRQVQYAKISQLVKET FGQLISNHSQYLKCSSSLAAFIIERAGHHEVVAIGTGEY NYSQCIKPNGRVLHDTHAVVTARRSLLRYFYRQLLLF YSKNPAMMEKSIFCTEPASNLLTLKQNINLYLYMNQL PKGSAQIKSQLRLNPHSISAFEANEELSLHVAVEGKIY LTVYCSADGVNRVNSMSSSDKLTRWEVLGVQGALLS HFIQPVYISSILVGDGNCNDTRGLEIAINQRVDDALTSK LPMFYLVNRPHISLVPTAYPLQINLDHKSLSLNWAQG DNSLEIVDGLNGKITESSPFKSGLSMASRLCKAAMLSR FNLLAKEAKTDDLLEARTYHAAKCMSGPYQEAKALL KAYLQQHGYGSWIVKSPCIEQFSM Rattus norvegicus AD ADI MATAGGSRRAPVPGPRLGLPLAAHLPASLGGEGAKD SLGGEKTSGNNDWFQSSRVPSFAQMLKKNLPVQSSA QTVTLPTGYSSESCSLSNMASKVTQVTGNFPEPLLSKG LSSISNPVLPPKKIPKEFIMKYRRGEINPVSALHQFAQM QRVQLDLKETVTTGNVMGPYFAFCAVVDGIQYKTGL GQNKKESRSNAAKLALDELLQLDEPEPRALEPAGPPPI PAEPIVTPEAAYISKVQYEGRQVQYAKISQLVKETFSQ LISSHSQYLKCSSSLAAFIIERGGHHEVVAIGTGEYNYS QCIKPNGRVLHDTHAVVTARRSLLRYFYRQLLLFYSK NPAMMEKSIFCTEPASNLLTLKQNINLYLYMNQLPKG SAQIKSQLRLNPHSISAFEANEELSLHVAVEGKIYLTV YCSADGVNRVNSMSSSDKLTRWEVLGVQGALLSHFI QPVYISSILVGDGNCNDTRGLEIAINQRVDDALTSKLP MFYLVNRPHISLVPTAYPLQINLDHKSLSLNWAQGDN SLEIVDGLSGKITESSPFKSGLSMASRLCKAAMLSRFN LLAKEAKTDDLLEARTYHAAKCLSGPYQEAKALLKA YLQQHGYGSWIVKSPCIEQFSM SEQ ID NO: 147 Xenopus laevis AD ADI MASNRNWSQHSSVPSFAQMLKKNLPDPGTSPAVNQT STLSTCCLYNQPDCGTARVTRITGNFPEPFLSKMIVPPS LSSLTPRKVTKEFMVKYRRGDLNPISALYQFAQMQR MEIELKETVTTGNVFGAYFAFCAVVDGLEYKTGMGQ NKKEAKANAAKLALDELLLHEDPALIDSENQSLNVIE NPPPLPMNPRGTTETSTISRTRTDKRTFIHEKISSIIKETF TNLVSKYPEYENCGSSLAAFVIEKGGQHWEVVAIGTG EFNYGQSLQSDGRVLHDSHAMVVARRSLLRYFYRQL LLLYSGNNGMMDKSIFCTEPATNLLALKPNLNIFLYM NQLPKGAAQTNPQLCLSPHSLSAHEANDKLSLHVSVE GKNIPASYYSGEIVHNLYSMSSTDKLTRWEVLGVQGA LLSIFIQPVYINSIIIGNAACSDTRGLEIAVKQRIDDALTS RLPMFYLVNRPYMSIVSSTHLTNNDTANKTLSLNWSQ SEQ ID NO: 148 GDACVEVVDAAIGRTVEGSPFKSGSCLASRLCKAAML CRFNLVVKESKRNAIPSGLSYHEAKRLAGPYQEAKCL LNSYFKQQGFGSWIAKPPIIGEFTM Human AD ADI MASNNHWFQSSQVPSFAQMLKKNLPVQPATKTITTPT GWSSESYGLSKMASKVTQVTGNFPEPLLSKNLSSISNP VLPPKKIPKEFIMKYKRGEINPVSALHQFAQMQRVQL DLKETVTTGNVMGPYFAFCAVVDGIQYKTGLGQNKK ESRSNAAKLALDELLQLDEPEPRILETSGPPPFPAEPVV LSELAYVSKVHYEGRHIQYAKISQIVKERFNQLISNRS EYLKYSSSLAAFIIERAGQHEVVAIGTGEYNYSQDIKP DGRVLHDTHAVVTARRSLLRYFYRQLLLFYSKNPAM MEKSIFCTEPTSNLLTLKQNINICLYMNQLPKGSAQIKS QLRLNPHSISAFEANEELCLHVAVEGKIYLTVYCPKDG VNRISSMSSSDKLTRWEVLGVQGALLSHFIQPVYISSIL IGDGNCSDTRGLEIAIKQRVDDALTSKLPMFYLVNRP HISLVPSAYPLQMNLEYKFLSLNWAQGDVSLEIVDGL SGKITESSPFKSGMSMASRLCKAAMLSRFNLLAKEAK KELLEAGTYHAAKCMSASYQEAKCKLKSYLQQHGY GSWIVKSPCIEQFNM SEQ ID NO: 149 Bos taurus AD AL MMEAEEQPWKTTFYSKLPKVELHAHLNGSISSNTIRK LIAKKPDLKIHDQMTMIDKGEKRTLEECLQMFQIIHLL TTTPEDVLMVTKDVIKEFADDGVKYLELRSTPRGEDA TGMTKKTYVESILEGIKQSKEENVDIDVRYLISIDRRG GSSAAKEAVKLAEEFFLSAEDTVLGLDLSGDPSAGQA KDFLEPLLEAKKSGLKLALHLSEIPNQKTETQVLLNLF PDRIGHGTFLSSSEEGSPDLVDFVRQHQIPLELCLTSNV KSQTVPAYDQHHFGFWYSVAHPAVICTDDKGVFATR LSQEYQLVAETFHLTQSQVWDLSYESISYIFASDSTKA DLRKKWSHLKPHF SEQ ID NO: 150 Danio rerio AD AL MDTEADLFYRQLPKVELHAHLNGSVSFETMEKLIKRK PHLNIEHSMTAIRRGQRRTLDECFQVFKVIHQLVDSEE DILMVAKSVIQEFAADGVKYLELRSTPREVTETGLSK QRYIETVLEAIRQCKQEGVDIDVRFLVAVDRRHGPEV AMQTVKLAEDFLLSSDGTVVGLDLSGDPTVGHGKDL LAALQKAKNCGLKLALHLSEVPSQIDETELLLNLPPDR IGHGTFLHPDVGGSDSLVDKVCKQNIPIEICLTSNVKG QTVPSYDKHHFKYWYNRGHPCVLCTDDKGVFCTDLS QEYQLAASTFGLTKEAVWILSQQAIGYTFAPEPIKQRL EKTWAELKQQILQ SEQ ID NO: 151 Xenopus laevis AD AL MAGEGALQFYRDLPKVELHAHLNGSISTATMKKLMA RKPHLDIQHGMTMIDKGQKRTLEECFQMFKIIHQITDT AEDILLVTKDVIKEFAADGVKYLELRSTPRDTPAGLTK QAYVETVLEGIKQCKEEGVDIDVRFLLAIDRRGGPTA SEQ ID NO: 152 AKETVKLAEDFFCSSNELVLGLDLSGDPTVGHGRDFM EPLNKARQSGLKLALHLSEIPSQTEETELLLGLPPDRIG HGTFLTTSAHIVEIVKKQHIPLELCITSNIKGQTVSSYN EHHFGFWYNLHHPFVLCTDDKGVFATDLSVEYEIAA KTFNLTPHHVWDLSYQAIDYTFASADVKANLKEKWL LLKPDVFRHAL Human AD AL MIEAEEQQPCKTDFYSELPKVELHAHLNGSISSHTMK KLIAQKPDLKIHDQMTVIDKGKKRTLEECFQMFQTIH QLTSSPEDILMVTKDVIKEFADDGVKYLELRSTPRREN ATGMTKKTYVESILEGIKQSKQENLDIDVRYLIAVDRR GGPLVAKETVKLAEEFFLSTEGTVLGLDLSGDPTVGQ AKDFLEPLLEAKKAGLKLALHLSEIPNQKKETQILLDL LPDRIGHGTFLNSGEGGSLDLVDFVRQHRIPLELCLTS NVKSQTVPSYDQHHFGFWYSIAHPSVICTDDKGVFAT HLSQEYQLAAETFNLTQSQVWDLSYESINYIFASDSTR SELRKKWNHLKPRVLHI SEQ ID NO: 153 Caenorhabditi s elegans AD AL MPNNSKHKKKQQRRQQEAQKKSRAKQIETDKKNDEF LDTELDEVSPLVIDDDMTEFKNMPKVELHAHLSGSLS PETIKLIMESDETRAEEIMKKYKLEKPENMTGVFDCFP VIHAILRKPEAIRIAIRQTIKEFEEDNCVYLELRTSPKET DFMTYEDYLQVCIESFEAAKHEFPRIKTFLIVSLDRRM PFETAAHILGLIGEAQQRTNVIVGVELSGDPHLDGRRL LKLFVAARRFHGLGITIHLAEVLQNMADVEDYLNLRP DRIGHGTFLHTDPYTEYLTNKYKIPLEICLSSNVYSKTT TNYRNSHFNYWRKRGVPVFICTDDKGVIPGATLTEEY YKAAITFDLSTEELIGINQDALLNSFAYKYNVTDLTET FRKINNNVLD SEQ ID NO: 154 Mus musculus AD AL MEAGQQWPGKTDFYLQLPKVELHAHLNGSISSSTMK KLIAKKPHLNVHGHMTMIDKGKKRTLQECFQMFQVI HQLTTSAEDILMVTKDVIKEFADDGVKYLELRSTPRE ENATGMTRKTYVESVLEGIKQCKQENLDIDVRYLMAI DRRGGPTIARETVELAKEFFLSTENTVLGLDLSGDPTI GQANDFLEPLLEAKKAGLKLALHLAEIPNREKENQML LSLLPDRIGHGTFLSASEAGALDQVDFVRQHQIPLELC LTSNIKSQTVPSYDQHHFGFWYSIAHPSVICTDDKGVF ATYLSQEYQLAAETFNLTPFQVWDLSYESINYIFACDN TRSELRKRWTHLKQKVLNCNEVNYF SEQ ID NO: 155 Human ADAD2 MASASQGADDDGSRRKPRLAASLQISPQPRPWRPLPA QAQSAWGPAPAPATYRAEGGWPQVSVLRDSGPGAG AGVGELGAARAWENLGEQMGKAPRVPVPPAGLSLPL KDPPASQAVSLLTEYAASLGIFLLFREDQPPGPCFPFSV SAELDGVVCPAGTANSKTEAKQQAALSALCYIRSQLE NPESPQTSSRPPLAPLSVENILTHEQRCAALVSAGFDLL SEQ ID NO: 156 LDERSPYWACKGTVAGVILEREIPRARGHVKEIYKLV ALGTGSSCCAGWLEFSGQQLHDCHGLVIARRALLRFL FRQLLLATQGGPKGKEQSVLAPQPGPGPPFTLKPRVFL HLYISNTPKGAARDIYLPPTSEGGLPHSPPMRLQAHVL GQLKPVCYVAPSLCDTHVGCLSASDKLARWAVLGLG GALLAHLVSPLYSTSLILADSCHDPPTLSRAIHTRPCLD SVLGPCLPPPYVRTALHLFAGPPVAPSEPTPDTCRGLS LNWSLGDPGIEVVDVATGRVKANAALGPPSRLCKASF LRAFHQAARAVGKPYLLALKTYEAAKAGPYQEARRQ LSLLLDQQGLGAWPSKPLVGKFRN Mus musculus ADAD2 MASVDEGGRRRPRLAASLQISPGPWKPSGGQEPTEAG DAAPRTAEHGVAGAQEAHREACKALGGSVLSPGPAG DFPGALHGLSMLPKDPPPAQAVALLTQCMANLGVSL TFLEDQTAGPGSSFSVCADLDGLVCPAGTGSSKLEAK QQAALSALQYIQKQLERPEPLVTPRQPLLTSLSIETILT HEQRCAAVVSAGLDRLLSESSPYQACKGTVAA VILER EVQGSIGHSKETYELVALGTGSSSCAGWLEFSGRRLH DCHGLVIARRALLRFFFRQLLLVTQGGPKGQERSVLT PQPGPGPPFALKPGVFLHLYVSNTPKGAAHDIYLPLAS EDSVLHSPAFRLQAHVCGQLKPVSYVAPALRDTHVG CLSASDKLARWAILGLGGGLLAHFLPPLYATSLVLAD PCHDPSTLNRVIHSRPRLDSVLGSCLPCPYVRTTLHLF AGPLVAPSDPGPSTCHSLSLNWSLGDPDIEVVDVATG RVKTDSSVGPPSRLCKAAFLSAFRQVARALEKPQLLS LQTYEAAKAVPYREARQQLSLLLDQQGLGAWPSKPL VGKFRH SEQ ID NO: 157 Macaca fascicularis ADAD2 MASASQGADDGSRRKPRLAASLQISPEPRPWRPLPPQ AQGAWEPAPAMDHAEGGQPQVSVLRDSGPGAGAGV GELGAAQAWENLGEQMGRTPRVPVPPAGLSLPLKDP PASQAVSLLTEYAASLGIILLFREDQQPGPCFPFSVSAE LDGVVCPAGTANSKTEAKQQAALSALCYIRSQLESPE SPQTSSRPPPPPLSVDSILTHGQRCAALVSAGFDLLLDE RSPYWACKGTVAGVILEREIPGARGHVKEIYKLVALG TGSSCCAGWLEFSGQQLHDCHGLVIARRALLRFLFRQ LLLATQGGAKGKEQSVLAPQPGPGPPFTLKPRVFLHL YISNTPKGAARDIYLPPTSEGGLPHSPPMRLQAHVLGQ LKPVCYVAPSLCDTHVGCLSASDKLARWAVLGLGGA LLAHLVSPLYSTSLILADSCHDPPTLSRAIHTRPCLDSV LGPCLPPPYVRTALHLFSGPPVAPSEPTPDTCHGLSLN WSLGDPGIEVVDVATGRVKANAALGPPSRLCKASFLR AFHQVARAVGKPYLLALKTYEAAKAGPYQEARRQLS LLLDQQGLGAWPSKPLVGKFRN SEQ ID NO: 158

[00259] In some embodiments, the first fusion protein further comprises an uracil glycosylase inhibitor (UGI).

[00260] The “Uracil Glycosylase Inhibitor” (UGI), which can be prepared from Bacillus subtilis bacteriophage PBS1, is a small protein (9.5 kDa) which inhibits E. coli uracil-DNA glycosylase (UDG) as well as UDG from other species. Inhibition of UDG occurs by reversible protein binding with a 1 : 1 UDG : UGI stoichiometry. UGI is capable of dissociating UDG-DNA complexes. A non-limiting example of UGI is found in Bacillus phage AR9 (YP_009283008.1). In some embodiments, the UGI comprises the amino acid sequence of "TNLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTS DAPEYKPWALVIQDSNGENKIKML (SEQ ID NO: 209) or has at least 70%, 75%, 80%, 85%, 90% or 95% sequence identity to SEQ ID NO: 209 and retains the uracil glycosylase inhibition activity.

[00261] In some embodiments, the first fusion protein further comprises at least one nuclear localization sequence (NLS).

[00262] A “nuclear localization signal or sequence” (NLS) is an amino acid sequence that tags a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different nuclear localized proteins may share the same NLS. An NLS has the opposite function of a nuclear export signal (NES), which targets proteins out of the nucleus. A non-limiting example of NLS is the internal SV40 nuclear localization sequence (iNLS).

[00263] In some embodiments, a peptide linker is optionally provided between each of the fragments in any of the fusion proteins. In some embodiments, the peptide linker has from 1 to 100 amino acid residues (or 3-20, 4-15, without limitation). In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the amino acid residues of peptide linker are amino acid residues selected from the group consisting of alanine, glycine, cysteine, and serine.

[00264] The term “Cas protein” or “clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) protein” refers to RNA-guided DNA endonuclease enzymes associated with the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) adaptive immunity system in Streptococcus pyogenes, as well as other bacteria. In some embodiments, the Cas protein is Cas9, a dead Cas9 (dCas9), or a Cas9 nickase (nCas9) selected from the group consisting of SpCas9, FnCas9, StlCas9, St3Cas9, NmCas9, SaCas9, AsCpfl, LbCpfl, FnCpfl, VQR Cas9, EQR Cas9, VRER Cas9, Cas9-NG, xCas9, eCas9, SpCas9-HFl, HypaCas9, HiFiCas9, sniper-Cas9, SpG, SpRY, KKH SaCas9, CjCas9, Cas9-NRRH, Cas9-NRCH, Cas9-NRTH, ScCpfl, PcCpfl, BpCpfl, LiCpfl, PmCpfl, Lb2Cpfl, PbCpfl, PeCpfl, PdCpfl, MbCpfl, EeCpfl, CmtCpfl, BsCpfl, BhCasl2b, AkCasl2b, BsCasl2b, AmCasl2b, AaCasl2b, RfxCasl3d, LwaCasl3a, PspCasl3b, PguCasl3b, and 5 RanCasl3b.

[00265] In some embodiments, the Cas protein comprises an amino acid sequence selected from SEQ ID NOs: 1-52. Table 4A Exemplary Cas proteins Cas protein types Cas proteins Cas9 proteins Cas9 from Staphylococcus aureus (SaCas9) Cas9 from Neisseria meningitidis (NmeCas9) Cas9 from Streptococcus thermophilus (StCas9) Cas9 from Campylobacter jejuni (CjCas9) Casl2a (Cpfl) proteins Casl2a (Cpfl) from Acidaminococcus sp BV3L6 (AsCpfl) Casl2a (Cpfl) from Francisella novicida sp BV3L6 (FnCpfl) Casl2a (Cpfl) from Smithella sp SC K08D17 (SsCpfl) Casl2a (Cpfl) from Porphyromonas crevioricanis (PcCpfl) Casl2a (Cpfl) from Butyrivibrioproteoclasticus (BpCpfl) Casl2a (Cpfl) from Candidatus Methanoplasma termitum (CmtCpfl) Casl2a (Cpfl) from Leptospira inadai (LiCpfl) Casl2a (Cpfl) from Porphyromonas macacae (PmCpfl) Casl2a (Cpfl) from Peregrinibacteria bacterium GW2011 WA2 33 10 (Pb331OCpfl) Casl2a (Cpfl) from Parcubacteria bacterium GW2011 GWC2 44 17 (Pb4417Cpfl) Casl2a (Cpfl) from Butyrivibrio sp. NC3005 (BsCpfl) Casl2a (Cpfl) from Eubacterium eligens (EeCpfl) Cas 12b (C2cl) proteins Casl2b (C2cl) Bacillus hisashii (BhCasl2b) Casl2b (C2cl) Bacillus hisashii with a gain-of-function mutation (see, e.g., Strecker et al., Nature Communications 10 (article 212) (2019) Casl2b (C2cl) Alicyclobacillus kakegawensis (AkCasl2b) Casl2b (C2cl) Elusimicrobia bacterium (EbCasl2b) Casl2b (C2cl) Laceyella sediminis (Ls) (LsCasl2b) Cas 13 proteins Casl3d from Ruminococcus jlavefaciens XPD3002 (RfCasl3d) Casl3a from Leptotrichia wadei (LwaCasl3a) Casl3b from Prevotella sp. P5-125 (PspCasl3b) Cas 13b from Porphyromonas gulae (PguCasl3b) Cas 13b from Riemerella anatipestifer (RanCasl3b) Engineered Cas proteins Nickases (mutation in one nuclease domain) Catalytically inactive mutant (dCas9; mutations in both of the nuclease domains) Enhanced variants with improved specificity (see, e.g., Chen et al., Nature, 550, 407-410 (2017) Table 4B Exemplary sequences of Cas proteins Name Sequence SEQ ID NO: SpCas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR SEQ ID NO: 1 KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD dSpCas9 MDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN SEQ ID NO: 2 IIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD nSpCas9(D10 A) MDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD SEQ ID NO: 3 nSpCas9(H84 OA) MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD SEQ ID NO: 4 LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD FnCas9 MNFKILPIAIDLGVKNTGVFSAFYQKGTSLERLDNKN GKVYELSKDSYTLLMNNRTARRHQRRGIDRKQLVKR LFKLIWTEQLNLEWDKDTQQAISFLFNRRGFSFITDGY SPEYLNIVPEQVKAILMDIFDDYNGEDDLDSYLKLATE QESKISEIYNKLMQKILEFKLMKLCTDIKDDKVSTKTL KEITSYEFELLADYLANYSESLKTQKFSYTDKQGNLK ELSYYHHDKYNIQEFLKRHATINDRILDTLLTDDLDIW NFNFEKFDFDKNEEKLQNQEDKDHIQAHLHHFVFAV NKIKSEMASGGRHRSQYFQEITNVLDENNHQEGYLKN FCENLHNKKYSNLSVKNLVNLIGNLSNLELKPLRKYF SEQ ID NO: 5 NDKIHAKADHWDEQKFTETYCHWILGEWRVGVKDQ DKKDGAKYSYKDLCNELKQKVTKAGLVDFLLELDPC RTIPPYLDNNNRKPPKCQSLILNPKFLDNQYPNWQQY LQELKKLQSIQNYLDSFETDLKVLKSSKDQPYFVEYK SSNQQIASGQRDYKDLDARILQFIFDRVKASDELLLNE IYFQAKKLKQKASSELEKLESSKKLDEVIANSQLSQIL KSQHTNGIFEQGTFLHLVCKYYKQRQRARDSRLYIMP EYRYDKKLHKYNNTGRFDDDNQLLTYCNHKPRQKR YQLLNDLAGVLQVSPNFLKDKIGSDDDLFISKWLVEH IRGFKKACEDSLKIQKDNRGLLNHKINIARNTKGKCE KEIFNLICKIEGSEDKKGNYKHGLAYELGVLLFGEPNE ASKPEFDRKIKKFNSIYSFAQIQQIAFAERKGNANTCA VCSADNAHRMQQIKITEPVEDNKDKIILSAKAQRLPAI PTRIVDGAVKKMATILAKNIVDDNWQNIKQVLSAKH QLHIPIITESNAFEFEPALADVKGKSLKDRRKKALERIS PENIFKDKNNRIKEFAKGISAYSGANLTDGDFDGAKEE LDHIIPRSHKKYGTLNDEANLICVTRGDNKNKGNRIFC LRDLADNYKLKQFETTDDLEIEKKIADTIWDANKKDF KFGNYRSFINLTPQEQKAFRHALFLADENPIKQAVIRA INNRNRTFVNGTQRYFAEVLANNIYLRAKKENLNTDK ISFDYFGIPTIGNGRGIAEIRQLYEKVDSDIQAYAKGDK PQASYSHLIDAMLAFCIAADEHRNDGSIGLEIDKNYSL YPLDKNTGEVFTKDIFSQIKITDNEFSDKKLVRKKAIE GFNTHRQMTRDGIYAENYLPILIHKELNEVRKGYTWK NSEEIKIFKGKKYDIQQLNNLVYCLKFVDKPISIDIQIST LEELRNILTTNNIAATAEYYYINLKTQKLHEYYIENYN TALGYKKYSKEMEFLRSLAYRSERVKIKSIDDVKQVL DKDSNFIIGKITLPFKKEWQRLYREWQNTTIKDDYEFL KSFFNVKSITKLHKKVRKDFSLPISTNEGKFLVKRKTW DNNFIYQILNDSDSRADGTKPFIPAFDISKNEIVEAIIDS FTSKNIFWLPKNIELQKVDNKNIFAIDTSKWFEVETPS DLRDIGIATIQYKIDNNSRPKVRVKLDYVIDDDSKINY FMNHSLLKSRYPDKVLEILKQSTIIEFESSGFNKTIKEM LGMKLAGIYNETSNN StlCas9 MGSDLVLGLDIGIGSVGVGILNKVTGEIIHKNSRIFPAA QAENNLVRRTNRQGRRLARRKKHRRVRLNRLFEESG LITDFTKISINLNPYQLRVKGLTDELSNEELFIALKNMV KHRGISYLDDASDDGNSSVGDYAQIVKENSKQLETKT PGQIQLERYQTYGQLRGDFTVEKDGKKHRLINVFPTS AYRSEALRILQTQQEFNPQITDEFINRYLEILTGKRKYY HGPGNEKSRTDYGRYRTSGETLDNIFGILIGKCTFYPD EFRAAKASYTAQEFNLLNDLNNLTVPTETKKLSKEQK NQIINYVKNEKAMGPAKLFKYIAKLLSCDVADIKGYR SEQ ID NO: 6 IDKSGKAEIHTFEAYRKMKTLETLDIEQMDRETLDKL AYVLTLNTEREGIQEALEHEFADGSFSQKQVDELVQF RKANSSIFGKGWHNFSVKLMMELIPELYETSEEQMTIL TRLGKQKTTSSSNKTKYIDEKLLTEEIYNPVVAKSVRQ AIKIVNAAIKEYGDFDNIVIEMARETNEDDEKKAIQKI QKANKDEKDAAMLKAANQYNGKAELPHSVFHGHKQ LATKIRLWHQQGERCLYTGKTISIHDLINNSNQFEVDH ILPLSITFDDSLANKVLVYATANQEKGQRTPYQALDS MDDAWSFRELKAFVRESKTLSNKKKEYLLTEEDISKF DVRKKFIERNLVDTRYASRVVLNALQEHFRAHKIDTK VSVVRGQFTSQLRRHWGIEKTRDTYHHHAVDALIIAA SSQLNLWKKQKNTLVSYSEDQLLDIETGELISDDEYK ESVFKAPYQHFVDTLKSKEFEDSILFSYQVDSKFNRKI SDATIYATRQAKVGKDKADETYVLGKIKDIYTQDGY DAFMKIYKKDKSKFLMYRHDPQTFEKVIEPILENYPN KQINEKGKEVPCNPFLKYKEEHGYIRKYSKKGNGPEI KSLKYYDSKLGNHIDITPKDSNNKVVLQSVSPWRADV YFNKTTGKYEILGLKYADLQFEKGTGTYKISQEKYND IKKKEGVDSDSEFKFTLYKNDLLLVKDTETKEQQLFR FLSRTMPKQKHYVELKPYDKQKFEGGEALIKVLGNV ANSGQCKKGLGKSNISIYKVRTDVLGNQHIIKNEGDK PKLDF St3Cas9 MTKPYSIGLDIGTNSVGWAVTTDNYKVPSKKMKVLG NTSKKYIKKNLLGVLLFDSGITAEGRRLKRTARRRYT RRRNRILYLQEIFSTEMATLDDAFFQRLDDSFLVPDDK RDSKYPIFGNLVEEKAYHDEFPTIYHLRKYLADSTKK ADLRLVYLALAHMIKYRGHFLIEGEFNSKNNDIQKNF QDFLDTYNAIFESDLSLENSKQLEEIVKDKISKLEKKD RILKLFPGEKNSGIFSEFLKLIVGNQADFRKCFNLDEK ASLHFSKESYDEDLETLLGYIGDDYSDVFLKAKKLYD AILLSGFLTVTDNETEAPLSSAMIKRYNEHKEDLALLK EYIRNISLKTYNEVFKDDTKNGYAGYIDGKTNQEDFY VYLKKLLAEFEGADYFLEKIDREDFLRKQRTFDNGSIP YQIHLQEMRAILDKQAKFYPFLAKNKERIEKILTFRIPY YVGPLARGNSDFAWSIRKRNEKITPWNFEDVIDKESS AEAFINRMTSFDLYLPEEKVLPKHSLLYETFNVYNELT KVRFIAESMRDYQFLDSKQKKDIVRLYFKDKRKVTD KDIIEYLHAIYGYDGIELKGIEKQFNSSLSTYHDLLNIIN DKEFLDDSSNEAIIEEIIHTLTIFEDREMIKQRLSKFENIF DKSVLKKLSRRHYTGWGKLSAKLINGIRDEKSGNTIL DYLIDDGISNRNFMQLIHDDALSFKKKIQKAQIIGDED KGNIKEVVKSLPGSPAIKKGILQSIKIVDELVKVMGGR KPESIVVEMARENQYTNQGKSNSQQRLKRLEKSLKEL SEQ ID NO: 7 GSKILKENIPAKLSKIDNNALQNDRLYLYYLQNGKDM YTGDDLDIDRLSNYDIDHIIPQAFLKDNSIDNKVLVSS ASNRGKSDDVPSLEVVKKRKTFWYQLLKSKLISQRKF DNLTKAERGGLSPEDKAGFIQRQLVETRQITKHVARL LDEKFNNKKDENNRAVRTVKIITLKSTLVSQFRKDFEL YKVREINDFHHAHDAYLNAVVASALLKKYPKLEPEF VYGDYPKYNSFRERKSATEKVYFYSNIMNIFKKSISLA DGRVIERPLIEVNEETGESVWNKESDLATVRRVLSYP QVNVVKKVEEQNHGLDRGKPKGLFNANLSSKPKPNS NENLVGAKEYLDPKKYGGYAGISNSFTVLVKGTIEKG AKKKITNVLEFQGISILDRINYRKDKLNFLLEKGYKDI ELIIELPKYSLFELSDGSRRMLASILSTNNKRGEIHKGN QIFLSQKFVKLLYHAKRISNTINENHRKYVENHKKEFE ELFYYILEFNENYVGAKKNGKLLNSAFQSWQNHSIDE LCSSFIGPTGSERKGLFELTSRGSAADFEFLGVKIPRYR DYTPSSLLKDATLIHQSVTGLYETRIDLAKLGEG NmCas9 MAAFKPNSINYILGLDIGIASVGWAMVEIDEEENPIRLI DLGVRVFERAEVPKTGDSLAMARRLARSVRRLTRRR AHRLLRTRRLLKREGVLQAANFDENGLIKSLPNTPWQ LRAAALDRKLTPLEWSAVLLHLIKHRGYLSQRKNEGE TADKELGALLKGVAGNAHALQTGDFRTPAELALNKF EKESGHIRNQRSDYSHTFSRKDLQAELILLFEKQKEFG NPHVSGGLKEGIETLLMTQRPALSGDAVQKMLGHCT FEPAEPKAAKNTYTAERFIWLTKLNNLRILEQGSERPL TDTERATLMDEPYRKSKLTYAQARKLLGLEDTAFFK GLRYGKDNAEASTLMEMKAYHAISRALEKEGLKDKK SPLNLSPELQDEIGTAFSLFKTDEDITGRLKDRIQPEILE ALLKHISFDKFVQISLKALRRIVPLMEQGKRYDEACAE IYGDHYGKKNTEEKIYLPPIPADEIRNPVVLRALSQAR KVINGVVRRYGSPARIHIETAREVGKSFKDRKEIEKRQ EENRKDREKAAAKFREYFPNFVGEPKSKDILKLRLYE QQHGKCLYSGKEINLGRLNEKGYVEIDHALPFSRTWD DSFNNKVLVLGSENQNKGNQTPYEYFNGKDNSREWQ EFKARVETSRFPRSKKQRILLQKFDEDGFKERNLNDTR YVNRFLCQFVADRMRLTGKGKKRVFASNGQITNLLR GFWGLRKVRAENDRHHALDAVVVACSTVAMQQKIT RFVRYKEMNAFDGKTIDKETGEVLHQKTHFPQPWEFF AQEVMIRVFGKPDGKPEFEEADTLEKLRTLLAEKLSS RPEAVHEYVTPLFVSRAPNRKMSGQGHMETVKSAKR LDEGVSVLRVPLTQLKLKDLEKMVNREREPKLYEAL KARLEAHKDDPAKAFAEPFYKYDKAGNRTQQVKAV RVEQVQKTGVWVRNHNGIADNATMVRVDVFEKGDK YYLVPIYSWQVAKGILPDRAVVQGKDEEDWQLIDDSF SEQ ID NO: 8 NFKFSLHPNDLVEVITKKARMFGYFASCHRGTGNINIR IHDLDHKIGKNGILEGIGVKTALSFQKYQIDELGKEIRP CRLKKRPPVR SaCas9 MKRNYILGLDIGITSVGYGIIDYETRDVIDAGVRLFKE ANVENNEGRRSKRGARRLKRRRRHRIQRVKKLLFDY NLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHL AKRRGVHNVNEVEEDTGNELSTKEQISRNSKALEEKY VAELQLERLKKDGEVRGSINRFKTSDYVKEAKQLLKV QKAYHQLDQSFIDTYIDLLETRRTYYEGPGEGSPFGW KDIKEWYEMLMGHCTYFPEELRSVKYAYNADLYNAL NDLNNLVITRDENEKLEYYEKFQIIENVFKQKKKPTLK QIAKEILVNEEDIKGYRVTSTGKPEFTNLKVYHDIKDIT ARKEIIENAELLDQIAKILTIYQSSEDIQEELTNLNSELT QEEIEQISNLKGYTGTHNLSLKAINLILDELWHTNDNQ IAIFNRLKLVPKKVDLSQQKEIPTTLVDDFILSPVVKRS FIQSIKVINAIIKKYGLPNDIIIELAREKNSKDAQKMINE MQKRNRQTNERIEEIIRTTGKENAKYLIEKIKLHDMQE GKCLYSLEAIPLEDLLNNPFNYEVDHIIPRSVSFDNSFN NKVLVKQEENSKKGNRTPFQYLSSSDSKISYETFKKHI LNLAKGKGRISKTKKEYLLEERDINRFSVQKDFINRNL VDTRYATRGLMNLLRSYFRVNNLDVKVKSINGGFTSF LRRKWKFKKERNKGYKHHAEDALIIANADFIFKEWK KLDKAKKVMENQMFEEKQAESMPEIETEQEYKEIFIT PHQIKHIKDFKDYKYSHRVDKKPNRELINDTLYSTRK DDKGNTLIVNNLNGLYDKDNDKLKKLINKSPEKLLM YHHDPQTYQKLKLIMEQYGDEKNPLYKYYEETGNYL TKYSKKDNGPVIKKIKYYGNKLNAHLDITDDYPNSRN KVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVIKKEN YYEVNSKCYEEAKKLKKISNQAEFIASFYNNDLIKING ELYRVIGVNNDLLNRIEVNMIDITYREYLENMNDKRP PRIIKTIASKTQSIKKYSTDILGNLYEVKSKKHPQIIKKG SEQ ID NO: 9 AsCpfl MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIE EDKARNDHYKELKPIIDRIYKTYADQCLQLVQLDWEN LSAAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGR TDNLTDAINKRHAEIYKGLFKAELFNGKVLKQLGTVT TTEHENALLRSFDKFTTYFSGFYENRKNVFSAEDISTAI PHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKK AIGIFVSTSIEEVFSFPFYNQLLTQTQIDLYNQLLGGISR EAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLF KQILSDRNTLSFILEEFKSDEEVIQSFCKYKTLLRNENV LETAEALFNELNSIDLTHIFISHKKLETISSALCDHWDT LRNALYERRISELTGKITKSAKEKVQRSLKHEDINLQEI ISAAGKELSEAFKQKTSEILSHAHAALDQPLPTTLKKQ SEQ ID NO: 10 EEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSA RLTGIKLEMEPSLSFYNKARNYATKKPYSVEKFKLNF QMPTLASGWDVNKEKNNGAILFVKNGLYYLGIMPKQ KGRYKALSFEPTEKTSEGFDKMYYDYFPDAAKMIPKC STQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNN PEKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDF LSKYTKTTSIDLSSLRPSSQYKDLGEYYAELNPLLYHIS FQRIAEKEIMDAVETGKLYLFQIYNKDFAKGHHGKPN LHTLYWTGLFSPENLAKTSIKLNGQAELFYRPKSRMK RMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNH RLSHDLSDEARALLPNVITKEVSHEIIKDRRFTSDKFFF HVPITLNYQAANSPSKFNQRVNAYLKEHPETPIIGIDR GERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNRE KERVAARQAWSVVGTIKDLKQGYLSQVIHEIVDLMIH YQAVVVLENLNFGFKSKRTGIAEKAVYQQFEKMLID KLNCLVLKDYPAEKVGGVLNPYQLTDQFTSFAKMGT QSGFLFYVPAPYTSKIDPLTGFVDPFVWKTIKNHESRK HFLEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGF MPAWDIVFEKNETQFDAKGTPFIAGKRIVPVIENHRFT GRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDD SHAIDTMVALIRSVLQMRNSNAATGEDYINSPVRDLN GVCFDSRFQNPEWPMDADANGAYHIALKGQLLLNHL KESKDLKLQNGISNQDWLAYIQELRN LbCpfl MAASKLEKFTNCYSLSKTLRFKAIPVGKTQENIDNKR LLVEDEKRAEDYKGVKKLLDRYYLSFINDVLHSIKLK NLNNYISLFRKKTRTEKENKELENLEINLRKEIAKAFK GAAGYKSLFKKDIIETILPEAADDKDEIALVNSFNGFT TAFTGFFDNRENMFSEEAKSTSIAFRCINENLTRYISN MDIFEKVDAIFDKHEVQEIKEKILNSDYDVEDFFEGEF FNFVLTQEGIDVYNAIIGGFVTESGEKIKGLNEYINLYN AKTKQALPKFKPLYKQVLSDRESLSFYGEGYTSDEEV LEVFRNTLNKNSEIFSSIKKLEKLFKNFDEYSSAGIFVK NGPAISTISKDIFGEWNLIRDKWNAEYDDIHLKKKAV VTEKYEDDRRKSFKKIGSFSLEQLQEYADADLSVVEK LKEIIIQKVDEIYKVYGSSEKLFDADFVLEKSLKKNDA VVAIMKDLLDSVKSFENYIKAFFGEGKETNRDESFYG DFVLAYDILLKVDHIYDAIRNYVTQKPYSKDKFKLYF QNPQFMGGWDKDKETDYRATILRYGSKYYLAIMDK KYAKCLQKIDKDDVNGNYEKINYKLLPGPNKMLPKV FFSKKWMAYYNPSEDIQKIYKNGTFKKGDMFNLNDC HKLIDFFKDSISRYPKWSNAYDFNFSETEKYKDIAGFY REVEEQGYKVSFESASKKEVDKLVEEGKLYMFQIYN KDFSDKSHGTPNLHTMYFKLLFDENNHGQIRLSGGAE SEQ ID NO: 11 LFMRRASLKKEELVVHPANSPIANKNPDNPKKTTTLS YDVYKDKRFSEDQYELHIPIAINKCPKNIFKINTEVRVL LKHDDNPYVIGIDRGERNLLYIVVVDGKGNIVEQYSL NEIINNFNGIRIKTDYHSLLDKKEKERFEARQNWTSIE NIKELKAGYISQVVHKICELVEKYDAVIALEDLNSGFK NSRVKVEKQVYQKFEKMLIDKLNYMVDKKSNPCAT GGALKGYQITNKFESFKSMSTQNGFIFYIPAWLTSKID PSTGFVNLLKTKYTSIADSKKFISSFDRIMYVPEEDLFE FALDYKNFSRTDADYIKKWKLYSYGNRIRIFAAAKKN NVFAWEEVCLTSAYKELFNKYGINYQQGDIRALLCEQ SDKAFYSSFMALMSLMLQMRNSITGRTDVDFLISPVK NSDGIFYDSRNYEAQENAILPKNADANGAYNIARKVL WAIGQFKKAEDEKLDKVKIAISNKEWLEYAQTSVK FnCpfl MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILD DEKRAKDYKKAKQIIDKYHQFFIEEILSSVCISEDLLQN YSDVYFKLKKSDDDNLQKDFKSAKDTIKKQISEYIKD SEKFKNLFNQNLIDAKKGQESDLILWLKQSKDNGIELF KANSDITDIDEALEIIKSFKGWTTYFKGFHENRKNVYS SNDIPTSIIYRIVDDNLPKFLENKAKYESLKDKAPEAIN YEQIKKDLAEELTFDIDYKTSEVNQRVFSLDEVFEIAN FNNYLNQSGITKFNTIIGGKFVNGENTKRKGINEYINL YSQQINDKTLKKYKMSVLFKQILSDTESKSFVIDKLED DSDVVTTMQSFYEQIAAFKTVEEKSIKETLSLLFDDLK AQKLDLSKIYFKNDKSLTDLSQQVFDDYSVIGTAVLE YITQQIAPKNLDNPSKKEQELIAKKTEKAKYLSLETIK LALEEFNKHRDIDKQCRFEEILANFAAIPMIFDEIAQNK DNLAQISIKYQNQGKKDLLQASAEDDVKAIKDLLDQT NNLLHKLKIFHISQSEDKANILDKDEHFYLVFEECYFE LANIVPLYNKIRNYITQKPYSDEKFKLNFENSTLANGW DKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAI KENKGEGYKKIVYKLLPGANKMLPKVFFSAKSIKFYN PSEDILRIRNHSTHTKNGSPQKGYEKFEFNIEDCRKFID FYKQSISKHPEWKDFGFRFSDTQRYNSIDEFYREVENQ GYKLTFENISESYIDSVVNQGKLYLFQIYNKDFSAYSK GRPNLHTLYWKALFDERNLQDVVYKLNGEAELFYRK QSIPKKITHPAKEAIANKNKDNPKKESVFEYDLIKDKR FTEDKFFFHCPITINFKSSGANKFNDEINLLLKEKANDV HILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRM KTNYHDKLAAIEKDRDSARKDWKKINNIKEMKEGYL SQVVHEIAKLVIEYNAIVVFEDLNFGFKRGRFKVEKQ VYQKLEKMLIEKLNYLVFKDNEFDKTGGVLRAYQLT APFETFKKMGKQTGIIYYVPAGFTSKICPVTGFVNQLY PKYESVSKSQEFFSKFDKICYNLDKGYFEFSFDYKNFG SEQ ID NO: 12 DKAAKGKWTIASFGSRLINFRNSDKNHNWDTREVYP TKELEKLLKDYSIEYGHGECIKAAICGESDKKFFAKLT SVLNTILQMRNSKTGTELDYLISPVADVNGNFFDSRQ APKNMPQDADANGAYHIGLKGLMLLGRIKNNQEGK KLNLVIKNEEYFEFVQNRNN VQRCas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFVSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKQYRSTKEVLDAT LIHQSITGLYETRIDLSQLGGD SEQ ID NO: 13 EQRCas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFESPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKQYRSTKEVLDAT LIHQSITGLYETRIDLSQLGGD SEQ ID NO: 14 VRERCas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI SEQ ID NO: 15 AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFVSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASARELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKEYRSTKEVLDAT LIHQSITGLYETRIDLSQLGGD Cas9-NG MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG SEQ ID NO: 16 PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESIRPKRNSDKLIAR KKDWDPKKYGGFVSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASARFLQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPRAFKYFDTTIDRKVYRSTKEVLDAT LIHQSITGLYETRIDLSQLGGD xCas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDTKL QLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAIL LSDILRVNTEITKAPLSASMIKLYDEHHQDLTLLKALV RQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIK PILEKMDGTEELLVKLNREDLLRKQRTFDNGIIPHQIH LGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGP LARGNSRFAWMTRKSEETITPWNFEKVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGDQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG SEQ ID NO: 17 KTILDFLKSDGFANRNFIQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGVLQKGNELALPSKY VNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEI IEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAE NIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDA TLIHQSITGLYETRIDLSQLGGD eCas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLADDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD SEQ ID NO: 18 NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPALESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKAPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD SpCas9-HFl MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTAFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGALSRKLINGIRDKQSG KTILDFLKSDGFANRNFMALIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRAITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR SEQ ID NO: 19 KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD HypaCas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRAFAALIADDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN SEQ ID NO: 20 IIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD HiFiCas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANANFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAGELQKGNELALPSKYV NFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEII EQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAEN IIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD SEQ ID NO: 21 sniper-Cas9 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD SEQ ID NO: 22 LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPASLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEIARENQTTQKGQKNSRERMKRIEEGIK ELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVD QELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKN RGKSDNVPSEEVVKKMKNYWRQLLNANLITQRKFDN LTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDS RMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYK VREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVY GDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFK TEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRK VLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARK KDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLK SVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIK LPKYSLFELENGRKRMLASAGELQKGNELALPSKYVN FLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIE QISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENII HLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLI HQSITGLYETRIDLSQLGGD spG MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI SEQ ID NO: 23 KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIAR KKDWDPKKYGGFLWPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAKQLQKGNELALPSKY VNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEI IEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAE NIIHLFTLTNLGAPAAFKYFDTTIDRKQYRSTKEVLDA TLIHQSITGLYETRIDLSQLGGD SpRY MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAERTRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKAL VRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFI KPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQI HLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVG PLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQS FIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKV KYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQ LKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIK SEQ ID NO: 24 DKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSG KTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVM GRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGI KELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYV DQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDK NRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFD NLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILD SRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFY KVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFV YGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVR KVLSMPQVNIVKKTEVQTGGFSKESIRPKRNSDKLIAR KKDWDPKKYGGFLWPTVAYSVLVVAKVEKGKSKKL KSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLII KLPKYSLFELENGRKRMLASAKQLQKGNELALPSKY VNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEI IEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAE NIIHLFTLTRLGAPRAFKYFDTTIDPKQYRSTKEVLDA TLIHQSITGLYETRIDLSQLGGD KKH SaCas9 MGKRNYILGLDIGITSVGYGIIDYETRDVIDAGVRLFK EANVENNEGRRSKRGARRLKRRRRHRIQRVKKLLFD YNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLH LAKRRGVHNVNEVEEDTGNELSTKEQISRNSKALEEK YVAELQLERLKKDGEVRGSINRFKTSDYVKEAKQLLK VQKAYHQLDQSFIDTYIDLLETRRTYYEGPGEGSPFG WKDIKEWYEMLMGHCTYFPEELRSVKYAYNADLYN ALNDLNNLVITRDENEKLEYYEKFQIIENVFKQKKKPT LKQIAKEILVNEEDIKGYRVTSTGKPEFTNLKVYHDIK DITARKEIIENAELLDQIAKILTIYQSSEDIQEELTNLNS ELTQEEIEQISNLKGYTGTHNLSLKAINLILDELWHTN DNQIAIFNRLKLVPKKVDLSQQKEIPTTLVDDFILSPVV KRSFIQSIKVINAIIKKYGLPNDIIIELAREKNSKDAQKM INEMQKRNRQTNERIEEIIRTTGKENAKYLIEKIKLHD MQEGKCLYSLEAIPLEDLLNNPFNYEVDHIIPRSVSFD NSFNNKVLVKQEENSKKGNRTPFQYLSSSDSKISYETF KKHILNLAKGKGRISKTKKEYLLEERDINRFSVQKDFI NRNLVDTRYATRGLMNLLRSYFRVNNLDVKVKSING GFTSFLRRKWKFKKERNKGYKHHAEDALIIANADFIF KEWKKLDKAKKVMENQMFEEKQAESMPEIETEQEY KEIFITPHQIKHIKDFKDYKYSHRVDKKPNRKLINDTL YSTRKDDKGNTLIVNNLNGLYDKDNDKLKKLINKSPE SEQ ID NO: 25 KLLMYHHDPQTYQKLKLIMEQYGDEKNPLYKYYEET GNYLTKYSKKDNGPVIKKIKYYGNKLNAHLDITDDYP NSRNKVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVI KKENYYEVNSKCYEEAKKLKKISNQAEFIASFYKNDL IKINGELYRVIGVNNDLLNRIEVNMIDITYREYLENMN DKRPPHIIKTIASKTQSIKKYSTDILGNLYEVKSKKHPQ IIKKG CjCas9 MARILAFDIGISSIGWAFSENDELKDCGVRIFTKVENP KTGESLALPRRLARSARKRLARRKARLNHLKHLIANE FKLNYEDYQSFDESLAKAYKGSLISPYELRFRALNELL SKQDFARVILHIAKRRGYDDIKNSDDKEKGAILKAIKQ NEEKLANYQSVGEYLYKEYFQKFKENSKEFTNVRNK KESYERCIAQSFLKDELKLIFKKQREFGFSFSKKFEEEV LSVAFYKRALKDFSHLVGNCSFFTDEKRAPKNSPLAF MFVALTRIINLLNNLKNTEGILYTKDDLNALLNEVLK NGTLTYKQTKKLLGLSDDYEFKGEKGTYFIEFKKYKE FIKALGEHNLSQDDLNEIAKDITLIKDEIKLKKALAKY DLNQNQIDSLSKLEFKDHLNISFKALKLVTPLMLEGK KYDEACNELNLKVAINEDKKDFLPAFNETYYKDEVT NPVVLRAIKEYRKVLNALLKKYGKVHKINIELAREVG KNHSQRAKIEKEQNENYKAKKDAELECEKLGLKINSK NILKLRLFKEQKEFCAYSGEKIKISDLQDEKMLEIDHIY PYSRSFDDSYMNKVLVFTKQNQEKLNQTPFEAFGNDS AKWQKIEVLAKNLPTKKQKRILDKNYKDKEQKNFKD RNLNDTRYIARLVLNYTKDYLDFLPLSDDENTKLNDT QKGSKVHVEAKSGMLTSALRHTWGFSAKDRNNHLH HAIDA VIIAYANNSIVKAFSDFKKEQESNSAELYAKKI SELDYKNKRKFFEPFSGFRQKVLDKIDEIFVSKPERKK PSGALHEETFRKEEEFYQSYGGKEGVLKALELGKIRK VNGKIVKNGDMFRVDIFKHKKTNKFYAVPIYTMDFA LKVLPNKAVARSKKGEIKDWILMDENYEFCFSLYKDS LILIQTKDMQEPEFVYYNAFTSSTVSLIVSKHDNKFET LSKNQKILFKNANEKEVIAKSIGIQNLKVFEKYIVSAL GEVTKAEFRQREDFKK SEQ ID NO: 26 Cas9-NRRH MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMVKRYDEHHQDLTLLKA SEQ ID NO: 27 LVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYK FIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGIIPH QIHLGELHAILRRQGDFYPFLKDNREKIEKILTFRIPYY VGPLARGNSRFAWMTRKSEETrrPWNFEEVVDKGAS AQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNEL TKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVT VKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLL KIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLK TYAHLFDDKVMKQLKRLRYTGWGRLSRKLINGIRDK QSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKA QVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELV KVMGGHKPENIVIEMARENQTTQKGQKNSRERMKRI EEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRD MYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLT RSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQ RKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRK DFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKL ESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSN IMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDF ATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKGNSD KLIARKKDWDPKKYGGFNSPTAAYSVLVVAKVEKGK SKKLKSVKELLGITIMERSSFEKNPIGFLEAKGYKEVK KDLIIKLPKYSLFELENGRKRMLASAGVLHKGNELAL PSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKH YLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGVPAAFKYFDTTIDKKRYTSTKE VLDATLIHQSITGLYETRIDLSQLGGD Cas9-NRCH MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMVKRYDEHHQDLTLLKA LVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYK FIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGIIPH QIHLGELHAILRRQGDFYPFLKDNREKIEKILTFRIPYY VGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGAS AQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNEL TKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVT SEQ ID NO: 28 VKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLL KIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLK TYAHLFDDKVMKQLKRLRYTGWGRLSRKLINGIRDK QSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKA QVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELV KVMGGHKPENIVIEMARENQTTQKGQKNSRERMKRI EEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRD MYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLT RSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQ RKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRK DFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKL ESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSN IMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDF ATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKGNSD KLIARKKDWDPKKYGGFNSPTVAYSVLVVAKVEKGK SKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVK KDLIIKLPKYSLFELENGRKRMLASAGVLQKGNELAL PSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKH YLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTINRKQYNTTKE VLDATLIRQSITGLYETRIDLSQLGGD Cas9-NRTH MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGN TDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRR KNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKH ERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQL VQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLI AQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAK LQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI LLSDILRVNTEITKAPLSASMVKRYDEHHQDLTLLKA LVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYK FIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGIIPH QIHLGELHAILRRQGDFYPFLKDNREKIEKILTFRIPYY VGPLARGNSRFAWMTRKSEETrrPWNFEEVVDKGAS AQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNEL TKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVT VKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLL KIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLK TYAHLFDDKVMKQLKRLRYTGWGRLSRKLINGIRDK QSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKA QVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELV KVMGGHKPENIVIEMARENQTTQKGQKNSRERMKRI SEQ ID NO: 29 EEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRD MYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLT RSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQ RKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRK DFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKL ESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSN IMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDF ATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKGNSD KLIARKKDWDPKKYGGFNSPTVAYSVLVVAKVEKGK SKKLKSVKELLGITIMERSSFEKNPIGFLEAKGYKEVK KDLIIKLPKYSLFELENGRKRMLASASVLHKGNELALP SKYVNFLYLASHYEKLKGSSEDNKQKQLFVEQHKHY LDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIRE QAENIIHLFTLTNLGASAAFKYFDTTIGRKLYTSTKEV LDATLIHQSITGLYETRIDLSQLGGD ScCpfl MQTLFENFTNQYPVSKTLRFELIPQGKTKDFIEQKGLL KKDEDRAEKYKKVKNIIDEYHKDFIEKSLNGLKLDGL EKYKTLYLKQEKDDKDKKAFDKEKENLRKQIANAFR NNEKFKTLFAKELIKNDLMSFACEEDKKNVKEFEAFT TYFTGFHQNRANMYVADEKRTAIASRLIHENLPKFID NIKIFEKMKKEAPELLSPFNQTLKDMKDVIKGTTLEEI FSLDYFNKTLTQSGIDIYNSVIGGRTPEEGKTKIKGLNE YINTDFNQKQTDKKKRQPKFKQLYKQILSDRQSLSFIA EAFKNDTEILEAIEKFYVNELLHFSNEGKSTNVLDAIK NAVSNLESFNLTKMYFRSGASLTDVSRKVFGEWSIIN RALDNYYATTYPIKPREKSEKYEERKEKWLKQDFNVS LIQTAIDEYDNETVKGKNSGKVIADYFAKFCDDKETD LIQKVNEGYIAVKDLLNTPCPENEKLGSNKDQVKQIK AFMDSIMDIMHFVRPLSLKDTDKEKDETFYSLFTPLY DHLTQTIALYNKVRNYLTQKPYSTEKIKLNFENSTLLG GWDLNKETDNTAIILRKDNLYYLGIMDKRHNRIFRNV PKADKKDFCYEKMVYKLLPGANKMLPKVFFSQSRIQ EFTPSAKLLENYANETHKKGDNFNLNHCHKLIDFFKD SINKHEDWKNFDFRFSATSTYADLSGFYHEVEHQGYK ISFQSVADSFIDDLVNEGKLYLFQIYNKDFSPFSKGKPN LHTLYWKMLFDENNLKDVVYKLNGEAEVFYRKKSIA EKNTTIHKANESIINKNPDNPKATSTFNYDIVKDKRYTI DKFQFHIPITMNFKAEGIFNMNQRVNQFLKANPDINII GIDRGERHLLYYALINQKGKILKQDTLNVIANEKQKV DYHNLLDKKEGDRATARQEWGVIETIKELKEGYLSQ VIHKLTDLMIENNAIIVMEDLNFGFKRGRQKVEKQVY QKFEKMLIDKLNYLVDKNKKANELGGLLNAFQLANK SEQ ID NO: 30 FESFQKMGKQNGFIFYVPAWNTSKTDPATGFIDFLKP RYENLNQAKDFFEKFDSIRLNSKADYFEFAFDFKNFTE KADGGRTKWTVCTTNEDRYAWNRALNNNRGSQEKY DITAELKSLFDGKVDYKSGKDLKQQIASQESADFFKA LMKNLSITLSLRHNNGEKGDNEQDYILSPVADSKGRF FDSRKADDDMPKNADANGAYHIALKGLWCLEQISKT DDLKKVKLAISNKEWLEFVQTLKG PcCpfl MDSLKDFTNLYPVSKTLRFELKPVGKTLENIEKAGILK EDEHRAESYRRVKKIIDTYHKVFIDSSLENMAKMGIE NEIKAMLQSFCELYKKDHRTEGEDKALDKIRAVLRGL IVGAFTGVCGRRENTVQNEKYESLFKEKLIKEILPDFV LSTEAESLPFSVEEATRSLKEFDSFTSYFAGFYENRKNI YSTKPQSTAIAYRLIHENLPKFIDNILVFQKIKEPIAKEL EHIRADFSAGGYIKKDERLEDIFSLNYYIHVLSQAGIEK YNALIGKIVTEGDGEMKGLNEHINLYNQQRGREDRLP LFRPLYKQILSDREQLSYLPESFEKDEELLRALKEFYD HIAEDILGRTQQLMTSISEYDLSRIYVRNDSQLTDISKK MLGDWNAIYMARERAYDHEQAPKRITAKYERDRIKA LKGEESISLANLNSCIAFLDNVRDCRVDTYLSTLGQKE GPHGLSNLVENVFASYHEAEQLLSFPYPEENNLIQDK DNVVLIKNLLDNISDLQRFLKPLWGMGDEPDKDERFY GEYNYIRGALDQVIPLYNKVRNYLTRKPYSTRKVKLN FGNSQLLSGWDRNKEKDNSCVILRKGQNFYLAIMNN RHKRSFENKMLPEYKEGEPYFEKMDYKFLPDPNKML PKVFLSKKGIEIYKPSPKLLEQYGHGTHKKGDTFSMD DLHELIDFFKHSIEAHEDWKQFGFKFSDTATYENVSSF YREVEDQGYKLSFRKVSESYVYSLIDQGKLYLFQIYN KDFSPCSKGTPNLHTLYWRMLFDERNLADVIYKLDG KAEIFFREKSLKNDHPTHPAGKPIKKKSRQKKGEESLF EYDLVKDRRYTMDKFQFHVPITMNFKCSAGSKVNDM VNAHIREAKDMHVIGIDRGERNLLYICVIDSRGTILDQI SLNTINDIDYHDLLESRDKDRQQEHRNWQTIEGIKELK QGYLSQAVHRIAELMVAYKAVVALEDLNMGFKRGR QKVESSVYQQFEKQLIDKLNYLVDKKKRPEDIGGLLR AYQFTAPFKSFKEMGKQNGFLFYIPAWNTSNIDPTTGF VNLFHVQYENVDKAKSFFQKFDSISYNPKKDWFEFAF DYKNFTKKAEGSRSMWILCTHGSRIKNFRNSQKNGQ WDSEEFALTEAFKSLFVRYEIDYTADLKTAIVDEKQK DFFVDLLKLFKLTVQMRNSWKEKDLDYLISPVAGAD GRFFDTREGNKSLPKDADANGAYNIALKGLWALRQI RQTSEGGKLKLAISNKEWLQFVQERSYEKD SEQ ID NO: 31 BpCpfl MLLYENYTKRNQITKSLRLELRPQGKTLRNIKELNLLE QDKAIYALLERLKPVIDEGIKDIARDTLKNCELSFEKL SEQ ID NO: 32 YEHFLSGDKKAYAKESERLKKEIVKTLIKNLPEGIGKI SEINSAKYLNGVLYDFIDKTHKDSEEKQNILSDILETK GYLALFSKFLTSRITTLEQSMPKRVIENFEIYAANIPKM QDALERGAVSFAIEYESICSVDYYNQILSQEDIDSYNR LISGIMDEDGAKEKGINQTISEKNIKIKSEHLEEKPFRIL KQLHKQILEEREKAFTIDHIDSDEEVVQVTKEAFEQTK EQWENIKKINGFYAKDPGDITLFIVVGPNQTHVLSQLI YGEHDRIRLLLEEYEKNTLEVLPRRTKSEKARYDKFV NAVPKKVAKESHTFDGLQKMTGDDRLFILYRDELAR NYMRIKEAYGTFERDILKSRRGIKGNRDVQESLVSFY DELTKFRSALRIINSGNDEKADPIFYNTFDGIFEKANRT YKAENLCRNYVTKSPADDARIMASCLGTPARLRTHW WNGEENFAINDVAMIRRGDEYYYFVLTPDVKPVDLK TKDETDAQIFVQRKGAKSFLGLPKALFKCILEPYFESP EHKNDKNCVIEEYVSKPLTIDRRAYDIFKNGTFKKTNI GIDGLTEEKFKDDCRYLIDVYKEFIAVYTRYSCFNMS GLKRADEYNDIGEFFSDVDTRLCTMEWIPVSFERIND MVDKKEGLLFLVRSMFLYNRPRKPYERTFIQLFSDSN MEHTSMLLNSRAMIQYRAASLPRRVTHKKGSILVALR DSNGEHIPMHIREAIYKMKNNFDISSEDFIMAKAYLAE HDVAIKKANEDIIRNRRYTEDKFFLSLSYTKNADISAR TLDYINDKVEEDTQDSRMAVIVTRNLKDLTYVAVVD EKNNVLEEKSLNEIDGVNYRELLKERTKIKYHDKTRL WQYDVSSKGLKEAYVELAVTQISKLATKYNAVVVVE SMSSTFKDKFSFLDEQIFKAFEARLCARMSDLSFNTIK EGEAGSISNPIQVSNNNGNSYQDGVIYFLNNAYTRTLC PDTGFVDVFDKTRLITMQSKRQFFAKMKDIRIDDGEM LFTFNLEEYPTKRLLDRKEWTVKIAGDGSYFDKDKGE YVYVNDIVREQIIPALLEDKAVFDGNMAEKFLDKTAIS GKSVELIYKWFANALYGIITKKDGEKIYRSPITGTEIDV SKNTTYNFGKKFMFKQEYRGDGDFLDAFLNYMQAQ DIAV LiCpfl MEDYSGFVNIYSIQKTLRFELKPVGKTLEHIEKKGFLK KDKIRAEDYKAVKKIIDKYHRAYIEEVFDSVLHQKKK KDKTRFSTQFIKEIKEFSELYYKTEKNIPDKERLEALSE KLRKMLVGAFKGEFSEEVAEKYKNLFSKELIRNEIEKF CETDEERKQVSNFKSFTTYFTGFHSNRQNIYSDEKKST AIGYRIIHQNLPKFLDNLKIIESIQRRFKDFPWSDLKKN LKKIDKNIKLTEYFSIDGFVNVLNQKGIDAYNTILGGK SEESGEKIQGLNEYINLYRQKNNIDRKNLPNVKILFKQI LGDRETKSFIPEAFPDDQSVLNSITEFAKYLKLDKKKK SIIAELKKFLSSFNRYELDGIYLANDNSLASISTFLFDD WSFIKKSVSFKYDESVGDPKKKIKSPLKYEKEKEKWL SEQ ID NO: 33 KQKYYTISFLNDAIESYSKSQDEKRVKIRLEAYFAEFK SKDDAKKQFDLLERIEEAYAIVEPLLGAEYPRDRNLK ADKKEVGKIKDFLDSIKSLQFFLKPLLSAEIFDEKDLGF YNQLEGYYEEIDSIGHLYNKVRNYLTGKIYSKEKFKL NFENSTLLKGWDENREVANLCVIFREDQKYYLGVMD KENNTILSDIPKVKPNELFYEKMVYKLIPTPHMQLPRII FSSDNLSIYNPSKSILKIREAKSFKEGKNFKLKDCHKFI DFYKESISKNEDWSRFDFKFSKTSSYENISEFYREVER QGYNLDFKKVSKFYIDSLVEDGKLYLFQIYNKDFSIFS KGKPNLHTIYFRSLFSKENLKDVCLKLNGEAEMFFRK KSINYDEKKKREGHHPELFEKLKYPILKDKRYSEDKF QFHLPISLNFKSKERLNFNLKVNEFLKRNKDINIIGIDR GERNLLYLVMINQKGEILKQTLLDSMQSGKGRPEINY KEKLQEKEIERDKARKSWGTVENIKELKEGYLSIVIHQ ISKLMVENNAIVVLEDLNIGFKRGRQKVERQVYQKFE KMLIDKLNFLVFKENKPTEPGGVLKAYQLTDEFQSFE KLSKQTGFLFYVPSWNTSKIDPRTGFIDFLHPAYENIE KAKQWINKFDSIRFNSKMDWFEFTADTRKFSENLML GKNRVWVICTTNVERYFTSKTANSSIQYNSIQITEKLK ELFVDIPFSNGQDLKPEILRKNDAVFFKSLLFYIKTTLS LRQNNGKKGEEEKDFILSPVVDSKGRFFNSLEASDDEP KDADANGAYHIALKGLMNLLVLNETKEENLSRPKWK IKNKDWLEFVWERNR PmCpfl MKTQHFFEDFTSLYSLSKTIRFELKPIGKTLENIKKNGL IRRDEQRLDDYEKLKKVIDEYHEDFIANILSSFSFSEEIL QSYIQNLSESEARAKIEKTMRDTLAKAFSEDERYKSIF KKELVKKDIPVWCPAYKSLCKKFDNFTTSLVPFHENR KNLYTSNEITASIPYRIVHVNLPKFIQNIEALCELQKKM GADLYLEMMENLRNVWPSFVKTPDDLCNLKTYNHL MVQSSISEYNRFVGGYSTEDGTKHQGINEWINIYRQR NKEMRLPGLVFLHKQILAKVDSSSFISDTLENDDQVFC VLRQFRKLFWNTVSSKEDDAASLKDLFCGLSGYDPEA IYVSDAHLATISKNIFDRWNYISDAIRRKTEVLMPRKK ESVERYAEKISKQIKKRQSYSLAELDDLLAHYSEESLP AGFSLLSYFTSLGGQKYLVSDGEVILYEEGSNIWDEVL IAFRDLQVILDKDFTEKKLGKDEEAVSVIKKALDSALR LRKFFDLLSGTGAEIRRDSSFYALYTDRMDKLKGLLK MYDKVRNYLTKKPYSIEKFKLHFDNPSLLSGWDKNK ELNNLSVIFRQNGYYYLGIMTPKGKNLFKTLPKLGAE EMFYEKMEYKQIAEPMLMLPKVFFPKKTKPAFAPDQS VVDIYNKKTFKTGQKGFNKKDLYRLIDFYKEALTVHE WKLFNFSFSPTEQYRNIGEFFDEVREQAYKVSMVNVP ASYIDEAVENGKLYLFQIYNKDFSPYSKGIPNLHTLYW SEQ ID NO: 34 KALFSEQNQSRVYKLCGGGELFYRKASLHMQDTTVH PKGISIHKKNLNKKGETSLFNYDLVKDKRFTEDKFFFH VPISINYKNKKITNVNQMVRDYIAQNDDLQIIGIDRGE RNLLYISRIDTRGNLLEQFSLNVIESDKGDLRTDYQKIL GDREQERLRRRQEWKSIESIKDLKDGYMSQVVHKICN MVVEHKAIVVLENLNLSFMKGRKKVEKSVYEKFERM LVDKLNYLVVDKKNLSNEPGGLYAAYQLTNPLFSFEE LHRYPQSGILFFVDPWNTSLTDPSTGFVNLLGRINYTN VGDARKFFDRFNAIRYDGKGNILFDLDLSRFDVRVET QRKLWTLTTFGSRIAKSKKSGKWMVERIENLSLCFLE LFEQFNIGYRVEKDLKKAILSQDRKEFYVRLIYLFNLM MQIRNSDGEEDYILSPALNEKNLQFDSRLIEAKDLPVD ADANGAYNVARKGLMVVQRIKRGDHESIHRIGRAQW LRYVQEGIVE Lb2Cpfl MYYESLTKQYPVSKTIRNELIPIGKTLDNIRQNNILESD VKRKQNYEHVKGILDEYHKQLINEALDNCTLPSLKIA AEIYLKNQKEVSDREDFNKTQDLLRKEVVEKLKAHE NFTKIGKKDILDLLEKLPSISEDDYNALESFRNFYTYFT SYNKVRENLYSDKEKSSTVAYRLINENFPKFLDNVKS YRFVKTAGILADGLGEEEQDSLFIVETFNKTLTQDGID TYNSQVGKINSSINLYNQKNQKANGFRKIPKMKMLY KQILSDREESFIDEFQSDEVLIDNVESYGSVLIESLKSSK VSAFFDALRESKGKNVYVKNDLAKTAMSNIVFENWR TFDDLLNQEYDLANENKKKDDKYFEKRQKELKKNKS YSLEHLCNLSEDSCNLIENYIHQISDDIENIIINNETFLRI VINEHDRSRKLAKNRKAVKAIKDFLDSIKVLERELKLI NSSGQELEKDLIVYSAHEELLVELKQVDSLYNMTRNY LTKKPFSTEKVKLNFNRSTLLNGWDRNKETDNLGVLL LKDGKYYLGIMNTSANKAFVNPPVAKTEKVFKKVDY KLLPVPNQMLPKVFFAKSNIDFYNPSSEIYSNYKKGTH KKGNMFSLEDCHNLIDFFKESISKHEDWSKFGFKFSDT ASYNDISEFYREVEKQGYKLTYTDIDETYINDLIERNE LYLFQIYNKDFSMYSKGKLNLHTLYFMMLFDQRNID DVVYKLNGEAEVFYRPASISEDELIIHKAGEEIKNKNP NRARTKETSTFSYDIVKDKRYSKDKFTLHIPITMNFGV DEVKRFNDAVNSAIRIDENVNVIGIDRGERNLLYVVVI DSKGNILEQISLNSIINKEYDIETDYHALLDEREGGRDK ARKDWNTVENIRDLKAGYLSQVVNVVAKLVLKYNAI ICLEDLNFGFKRGRQKVEKQVYQKFEKMLIDKLNYLV IDKSREQTSPKELGGALNALQLTSKFKSFKELGKQSGV IYYVPAYLTSKIDPTTGFANLFYMKCENVEKSKRFFD GFDFIRFNALENVFEFGFDYRSFTQRACGINSKWTVCT NGERIIKYRNPDKNNMFDEKVVVVTDEMKNLFEQYK SEQ ID NO: 35 IPYEDGRNVKDMIISNEEAEFYRRLYRLLQQTLQMRN STSDGTRDYIISPVKNKREAYFNSELSDGSVPKDADAN GAYNIARKGLWVLEQIRQKSEGEKINLAMTNAEWLE YAQTHLL PbCpfl MENIFDQFIGKYSLSKTLRFELKPVGKTEDFLKINKVF EKDQTIDDSYNQAKFYFDSLHQKFIDAALASDKTSELS FQNFADVLEKQNKIILDKKREMGALRKRDKNAVGID RLQKEINDAEDIIQKEKEKIYKDVRTLFDNEAESWKTY YQEREVDGKKITFSKADLKQKGADFLTAAGILKVLKY EFPEEKEKEFQAKNQPSLFVEEKENPGQKRYIFDSFDK FAGYLTKFQQTKKNLYAADGTSTAVATRIADNFIIFH QNTKVFRDKYKNNHTDLGFDEENIFEIERYKNCLLQR EIEHIKNENSYNKIIGRINKKIKEYRDQKAKDTKLTKS DFPFFKNLDKQILGEVEKEKQLIEKTREKTEEDVLIERF KEFIENNEERFTAAKKLMNAFCNGEFESEYEGIYLKN KAINTISRRWFVSDRDFELKLPQQKSKNKSEKNEPKV KKFISIAEIKNAVEELDGDIFKAVFYDKKIIAQGGSKLE QFLVIWKYEFEYLFRDIERENGEKLLGYDSCLKIAKQL GIFPQEKEAREKATAVIKNYADAGLGIFQMMKYFSLD DKDRKNTPGQLSTNFYAEYDGYYKDFEFIKYYNEFRN FITKKPFDEDKIKLNFENGALLKGWDENKEYDFMGVI LKKEGRLYLGIMHKNHRKLFQSMGNAKGDNANRYQ KMIYKQIADASKDVPRLLLTSKKAMEKFKPSQEILRIK KEKTFKRESKNFSLRDLHALIEYYRNCIPQYSNWSFYD FQFQDTGKYQNIKEFTDDVQKYGYKISFRDIDDEYINQ ALNEGKMYLFEVVNKDIYNTKNGSKNLHTLYFEHILS AENLNDPVFKLSGMAEIFQRQPSVNEREKITTQKNQCI LDKGDRAYKYRRYTEKKIMFHMSLVLNTGKGEIKQV QFNKIINQRISSSDNEMRVNVIGIDRGEKNLLYYSVVK QNGEIIEQASLNEINGVNYRDKLIEREKERLKNRQSWK PVVKIKDLKKGYISHVIHKICQLIEKYSAIVVLEDLNM RFKQIRGGIERSVYQQFEKALIDKLGYLVFKDNRDLR APGGVLNGYQLSAPFVSFEKMRKQTGILFYTQAEYTS KTDPITGFRKNVYISNSASLDKIKEAVKKFDAIGWDG KEQSYFFKYNPYNLADEKYKNSTVSKEWAIFASAPRI RRQKGEDGYWKYDRVKVNEEFEKLLKVWNFVNPKA TDIKQEIIKKEKAGDLQGEKELDGRLRNFWHSFIYLFN LVLELRNSFSLQIKIKAGEVIAVDEGVDFIASPVKPFFT TPNPYIPSNLCWLAVENADANGAYNIARKGVMILKKI REHAKKDPEFKKLPNLFISNAEWDEAARDWGKYAGT TALNLDH SEQ ID NO: 36 PeCpfl MSNFFKNFTNLYELSKTLRFELKPVGDTLTNMKDHLE YDEKLQTFLKDQNIDDAYQALKPQFDEIHEEFITDSLE SEQ ID NO: 37 SKKAKEIDFSEYLDLFQEKKELNDSEKKLRNKIGETFN KAGEKWKKEKYPQYEWKKGSKIANGADILSCQDML QFIKYKNPEDEKIKNYIDDTLKGFFTYFGGFNQNRAN YYETKKEASTAVATRIVHENLPKFCDNVIQFKHIIKRK KDGTVEKTERKTEYLNAYQYLKNNNKITQIKDAETEK MIESTPIAEKIFDVYYFSSCLSQKQIEEYNRIIGHYNLLI NLYNQAKRSEGKHLSANEKKYKDLPKFKTLYKQIGC GKKKDLFYTIKCDTEEEANKSRNEGKESHSVEEIINKA QEAINKYFKSNNDCENINTVPDFINYILTKENYEGVY WSKAAMNTISDKYFANYHDLQDRLKEAKVFQKADK KSEDDIKIPEAIELSGLFGVLDSLADWQTTLFKSSILSN EDKLKIITDSQTPSEALLKMIFNDIEKNMESFLKETNDII TLKKYKGNKEGTEKIKQWFDYTLAINRMLKYFLVKE NKIKGNSLDTNISEALKTLIYSDDAEWFKWYDALRNY LTQKPQDEAKENKLKLNFDNPSLAGGWDVNKECSNF CVILKDKNEKKYLAIMKKGENTLFQKEWTEGRGKNL TKKSNPLFEINNCEILSKMEYDFWADVSKMIPKCSTQL KAVVNHFKQSDNEFIFPIGYKVTSGEKFREECKISKQD FELNNKVFNKNELSVTAMRYDLSSTQEKQYIKAFQKE YWELLFKQEKRDTKLTNNEIFNEWINFCNKKYSELLS WERKYKDALTNWINFCKYFLSKYPKTTLFNYSFKESE NYNSLDEFYRDVDICSYKLNINTTINKSILDRLVEEGK LYLFEIKNQDSNDGKSIGHKNNLHTIYWNAIFENFDNR PKLNGEAEIFYRKAISKDKLGIVKGKKTKNGTEIIKNY RFSKEKFILHVPITLNFCSNNEYVNDIVNTKFYNFSNL HFLGIDRGEKHLAYYSLVNKNGEIVDQGTLNLPFTDK DGNQRSIKKEKYFYNKQEDKWEAKEVDCWNYNDLL DAMASNRDMARKNWQRIGTIKEAKNGYVSLVIRKIA DLAVNNERPAFIVLEDLNTGFKRSRQKIDKSVYQKFE LALAKKLNFLVDKNAKRDEIGSPTKALQLTPPVNNYG DIENKKQAGIMLYTRANYTSQTDPATGWRKTIYLKA GPEETTYKKDGKIKNKSVKDQIIETFTDIGFDGKDYYF EYDKGEFVDEKTGEIKPKKWRLYSGENGKSLDRFRGE REKDKYEWKIDKIDIVKILDDLFVNFDKNISLLKQLKE GVELTRNNEHGTGESLRFAINLIQQIRNTGNNERDNDF ILSPVRDENGKHFDSREYWDKETKGEKISMPSSGDAN GAFNIARKGIIMNAHILANSDSKDLSLFVSDEEWDLHL NNKTEWKKQLNIFSSRKAMAKRKK PdCpfl MENYQEFTNLFQLNKTLRFELKPIGKTCELLEEGKIFA SGSFLEKDKVRADNVSYVKKEIDKKHKIFIEETLSSFSI SNDLLKQYFDCYNELKAFKKDCKSDEEEVKKTALRN KCTSIQRAMREAISQAFLKSPQKKLLAIKNLIENVFKA DENVQHFSEFTSYFSGFETNRENFYSDEEKSTSIAYRL SEQ ID NO: 38 VHDNLPIFIKNIYIFEKLKEQFDAKTLSEIFENYKLYVA GSSLDEVFSLEYFNNTLTQKGIDNYNAVIGKIVKEDKQ EIQGLNEHINLYNQKHKDRRLPFFISLKKQILSDREALS WLPDMFKNDSEVIKALKGFYIEDGFENNVLTPLATLL SSLDKYNLNGIFIRNNEALSSLSQNVYRNFSIDEAIDAN AELQTFNNYELIANALRAKIKKETKQGRKSFEKYEEYI DKKVKAIDSLSIQEINELVENYVSEFNSNSGNMPRKVE DYFSLMRKGDFGSNDLIENIKTKLSAAEKLLGTKYQE TAKDIFKKDENSKLIKELLDATKQFQHFIKPLLGTGEE ADRDLVFYGDFLPLYEKFEELTLLYNKVRNRLTQKPY SKDKIRLCFNKPKLMTGWVDSKTEKSDNGTQYGGYL FRKKNEIGEYDYFLGISSKAQLFRKNEAVIGDYERLDY YQPKANTIYGSAYEGENSYKEDKKRLNKVIIAYIEQIK QTNIKKSIIESISKYPNISDDDKVTPSSLLEKIKKVSIDSY NGILSFKSFQSVNKEVIDNLLKTISPLKNKAEFLDLINK DYQIFTEVQAVIDEICKQKTFIYFPISNVELEKEMGDK DKPLCLFQISNKDLSFAKTFSANLRKKRGAENLHTML FKALMEGNQDNLDLGSGAIFYRAKSLDGNKPTHPAN EAIKCRNVANKDKVSLFTYDIYKNRRYMENKFLFHLS IVQNYKAANDSAQLNSSATEYIRKADDLHIIGIDRGER NLLYYSVIDMKGNIVEQDSLNIIRNNDLETDYHDLLD KREKERKANRQNWEAVEGIKDLKKGYLSQAVHQIAQ LMLKYNAIIALEDLGQMFVTRGQKIEKAVYQQFEKSL VDKLSYLVDKKRPYNELGGILKAYQLASSITKNNSDK QNGFLFYVPAWNTSKIDPVTGFTDLLRPKAMTIKEAQ DFFGAFDNISYNDKGYFEFETNYDKFKIRMKSAQTRW TICTFGNRIKRKKDKNYWNYEEVELTEEFKKLFKDSNI DYENCNLKEEIQNKDNRKFFDDLIKLLQLTLQMRNSD DKGNDYIISPVANAEGQFFDSRNGDKKLPLDADANGA YNIARKGLWNIRQIKQTKNDKKLNLSISSTEWLDFVR EKPYLK MbCpfl MLFQDFTHLYPLSKTVRFELKPIDRTLEHIHAKNFLSQ DETMADMHQKVKVILDDYHRDFIADMMGEVKLTKL AEFYDVYLKFRKNPKDDELQKQLKDLQAVLRKEIVK PIGNGGKYKAGYDRLFGAKLFKDGKELGDLAKFVIA QEGESSPKLAHLAHFEKFSTYFTGFHDNRKNMYSDED KHTAIAYRLIHENLPRFIDNLQILTTIKQKHSALYDQIIN ELTASGLDVSLASHLDGYHKLLTQEGITAYNTLLGGIS GEAGSPKIQGINELINSHHNQHCHKSERIAKLRPLHKQI LSDGMSVSFLPSKFADDSEMCQAVNEFYRHYADVFA KVQSLFDGFDDHQKDGIYVEHKNLNELSKQAFGDFA LLGRVLDGYYVDVVNPEFNERFAKAKTDNAKAKLTK EKDKFIKGVHSLASLEQAIEHYTARHDDESVQAGKLG SEQ ID NO: 39 QYFKHGLAGVDNPIQKIHNNHSTIKGFLERERPAGER ALPKIKSGKNPEMTQLRQLKELLDNALNVAHFAKLLT TKTTLDNQDGNFYGEFGVLYDELAKIPTLYNKVRDYL SQKPFSTEKYKLNFGNPTLLNGWDLNKEKDNFGVILQ KDGCYYLALLDKAHKKVFDNAPNTGKSIYQKMIYKY LEVRKQFPKVFFSKEAIAINYHPSKELVEIKDKGRQRS DDERLKLYRFILECLKIHPKYDKKFEGAIGDIQLFKKD KKGREVPISEKDLFDKINGIFSSKPKLEMEDFFIGEFKR YNPSQDLVDQYNIYKKIDSNDNRKKENFYNNHPKFK KDLVRYYYESMCKHEEWEESFEFSKKLQDIGCYVDV NELFTEIETRRLNYKISFCNINADYIDELVEQGQLYLFQ IYNKDFSPKAHGKPNLHTLYFKALFSEDNLADPIYKLN GEAQIFYRKASLDMNETTIHRAGEVLENKNPDNPKKR QFVYDIIKDKRYTQDKFMLHVPITMNFGVQGMTIKEF NKKVNQSIQQYDEVNVIGIDRGERHLLYLTVINSKGEI LEQCSLNDITTASANGTQMTTPYHKILDKREIERLNAR VGWGEIETIKELKSGYLSHVVHQISQLMLKYNAIVVL EDLNFGFKRGRFKVEKQIYQNFENALIKKLNHLVLKD KADDEIGSYKNALQLTNNFTDLKSIGKQTGFLFYVPA WNTSKIDPETGFVDLLKPRYENIAQSQAFFGKFDKICY NADKDYFEFHIDYAKFTDKAKNSRQIWTICSHGDKRY VYDKTANQNKGAAKGINVNDELKSLFARHHINEKQP NLVMDICQNNDKEFHKSLMYLLKTLLALRYSNASSD EDFILSPVANDEGVFFNSALADDTQPQNADANGAYHI ALKGLWLLNELKNSDDLNKVKLAIDNQTWLNFAQNR EeCpfl MNGNRSIVYREFVGVIPVAKTLRNELRPVGHTQEHIIQ NGLIQEDELRQEKSTELKNIMDDYYREYIDKSLSGVT DLDFTLLFELMNLVQSSPSKDNKKALEKEQSKMREQI CTHLQSDSNYKNIFNAKLLKEILPDFIKNYNQYDVKD KAGKLETLALFNGFSTYFTDFFEKRKNVFTKEAVSTSI AYRIVHENSLIFLANMTSYKKISEKALDEIEVIEKNNQ DKMGDWELNQIFNPDFYNMVLIQSGIDFYNEICGVVN AHMNLYCQQTKNNYNLFKMRKLHKQILAYTSTSFEV PKMFEDDMSVYNAVNAFIDETEKGNIIGKLKDIVNKY DELDEKRIYISKDFYETLSCFMSGNWNLITGCVENFYD ENIHAKGKSKEEKVKKAVKEDKYKSINDVNDLVEKYI DEKERNEFKNSNAKQYIREISNIITDTETAHLEYDDHIS LIESEEKADEMKKRLDMYMNMYHWAKAFIVDEVLD RDEMFYSDIDDIYNILENIVPLYNRVRNYVTQKPYNSK KIKLNFQSPTLANGWSQSKEFDNNAIILIRDNKYYLAIF NAKNKPDKKIIQGNSDKKNDNDYKKMVYNLLPGAN KMLPKVFLSKKGIETFKPSDYIISGYNAHKHIKTSENF DISFCRDLIDYFKNSIEKHAEWRKYEFKFSATDSYSDIS SEQ ID NO: 40 EFYREVEMQGYRIDWTYISEADINKLDEEGKIYLFQIY NKDFAENSTGKENLHTMYFKNIFSEENLKDIIIKLNGQ AELFYRRASVKNPVKHKKDSVLVNKTYKNQLDNGD VVRIPIPDDIYNEIYKMYNGYIKESDLSEAAKEYLDKV EVRTAQKDIVKDYRYTVDKYFIHTPITINYKVTARNN VNDMVVKYIAQNDDIHVIGIDRGERNLIYISVIDSHGNI VKQKSYNILNNYDYKKKLVEKEKTREYARKNWKSIG NIKELKEGYISGVVHEIAMLIVEYNAIIAMEDLNYGFK RGRFKVERQVYQKFESMLINKLNYFASKEKSVDEPGG LLKGYQLTYVPDNIKNLGKQCGVIFYVPAAFTSKIDPS TGFISAFNFKSISTNASRKQFFMQFDEIRYCAEKDMFSF GFDYNNFDTYNITMGKTQWTVYTNGERLQSEFNNAR RTGKTKSINLTETIKLLLEDNEINYADGHDIRIDMEKM DEDKKSEFFAQLLSLYKLTVQMRNSYTEAEEQENGIS YDKIISPVINDEGEFFDSDNYKESDDKECKMPKDADA NGAYCIALKGLYEVLKIKSEWTEDGFDRNCLKLPHAE WLDFIQNKRYE CmtCpfl MNNYDEFTKLYPIQKTIRFELKPQGRTMEHLETFNFFE EDRDRAEKYKILKEAIDEYHKKFIDEHLTNMSLDWNS LKQISEKYYKSREEKDKKVFLSEQKRMRQEIVSEFKK DDRFKDLFSKKLFSELLKEEIYKKGNHQEIDALKSFDK FSGYFIGLHENRKNMYSDGDEITAISNRIVNENFPKFL DNLQKYQEARKKYPEWIIKAESALVAHNIKMDEVFSL EYFNKVLNQEGIQRYNLALGGYVTKSGEKMMGLND ALNLAHQSEKSSKGRIHMTPLFKQILSEKESFSYIPDVF TEDSQLLPSIGGFFAQIENDKDGNIFDRALELISSYAEY DTERIYIRQADINRVSNVIFGEWGTLGGLMREYKADSI NDINLERTCKKVDKWLDSKEFALSDVLEAIKRTGNND AFNEYISKMRTAREKIDAARKEMKFISEKISGDEESIHII KTLLDSVQQFLHFFNLFKARQDIPLDGAFYAEFDEVH SKLFAIVPLYNKVRNYLTKNNLNTKKIKLNFKNPTLA NGWDQNKVYDYASLIFLRDGNYYLGIINPKRKKNIKF EQGSGNGPFYRKMVYKQIPGPNKNLPRVFLTSTKGKK EYKPSKEIIEGYEADKHIRGDKFDLDFCHKLIDFFKESI EKHKDWSKFNFYFSPTESYGDISEFYLDVEKQGYRMH FENISAETIDEYVEKGDLFLFQIYNKDFVKAATGKKD MHTIYWNAAFSPENLQDVVVKLNGEAELFYRDKSDI KEIVHREGEILVNRTYNGRTPVPDKIHKKLTDYHNGR TKDLGEAKEYLDKVRYFKAHYDITKDRRYLNDKIYF HVPLTLNFKANGKKNLNKMVIEKFLSDEKAHIIGIDRG ERNLLYYSIIDRSGKIIDQQSLNVIDGFDYREKLNQREI EMKDARQSWNAIGKIKDLKEGYLSKAVHEITKMAIQ YNAIVVMEELNYGFKRGRFKVEKQIYQKFENMLIDK SEQ ID NO: 41 MNYLVFKDAPDESPGGVLNAYQLTNPLESFAKLGKQ TGILFYVPAAYTSKIDPTTGFVNLFNTSSKTNAQERKE FLQKFESISYSAKDGGIFAFAFDYRKFGTSKTDHKNV WTAYTNGERMRYIKEKKRNELFDPSKEIKEALTSSGIK YDGGQNILPDILRSNNNGLIYTMYSSFIAAIQMRVYDG KEDYIISPIKNSKGEFFRTDPKRRELPIDADANGAYNIA LRGELTMRAIAEKFDPDSEKMAKLELKHKDWFEFMQ TRGD BsCpfl MYYQNLTKKYPVSKTIRNELIPIGKTLENIRKNNILESD VKRKQDYEHVKGIMDEYHKQLINEALDNYMLPSLNQ AAEIYLKKHVDVEDREEFKKTQDLLRREVTGRLKEHE NYTKIGKKDILDLLEKLPSISEEDYNALESFRNFYTYFT SYNKVRENLYSDEEKSSTVAYRLINENLPKFLDNIKSY AFVKAAGVLADCIEEEEQDALFMVETFNMTLTQEGID MYNYQIGKVNSAINLYNQKNHKVEEFKKIPKMKVLY KQILSDREEVFIGEFKDDETLLSSIGAYGNVLMTYLKS EKINIFFDALRESEGKNVYVKNDLSKTTMSNIVFGSWS AFDELLNQEYDLANENKKKDDKYFEKRQKELKKNKS YTLEQMSNLSKEDISPIENYIERISEDIEKICIYNGEFEKI VVNEHDSSRKLSKNIKAVKVIKDYLDSIKELEHDIKLI NGSGQELEKNLVVYVGQEEALEQLRPVDSLYNLTRN YLTKKPFSTEKVKLNFNKSTLLNGWDKNKETDNLGIL FFKDGKYYLGIMNTTANKAFVNPPAAKTENVFKKVD YKLLPGSNKMLPKVFFAKSNIGYYNPSTELYSNYKKG THKKGPSFSIDDCHNLIDFFKESIKKHEDWSKFGFEFS DTADYRDISEFYREVEKQGYKLTFTDIDESYINDLIEK NELYLFQIYNKDFSEYSKGKLNLHTLYFMMLFDQRNL DNVVYKLNGEAEVFYRPASIAENELVIHKAGEGIKNK NPNRAKVKETSTFSYDIVKDKRYSKYKFTLHIPITMNF GVDEVRRFNDVINNALRTDDNVNVIGIDRGERNLLYV VVINSEGKILEQISLNSIINKEYDIETNYHALLDEREDD RNKARKDWNTIENIKELKTGYLSQVVNVVAKLVLKY NAIICLEDLNFGFKRGRQKVEKQVYQKFEKMLIEKLN YLVIDKSREQVSPEKMGGALNALQLTSKFKSFAELGK QSGIIYYVPAYLTSKIDPTTGFVNLFYIKYENIEKAKQF FDGFDFIRFNKKDDMFEFSFDYKSFTQKACGIRSKWIV YTNGERIIKYPNPEKNNLFDEKVINVTDEIKGLFKQYRI PYENGEDIKEIIISKAEADFYKRLFRLLHQTLQMRNSTS DGTRDYIISPVKNDRGEFFCSEFSEGTMPKDADANGA YNIARKGLWVLEQIRQKDEGEKVNLSMTNAEWLKYA QLHLL SEQ ID NO: 42 BhCasl2b MGIHGVPAAATRSFILKIEPNEEVKKGLWKTHEVLNH GIAYYMNILKLIRQEAIYEHHEQDPKNPKKVSKAEIQA SEQ ID NO: 43 ELWDFVLKMQKCNSFTHEVDKDEVFNILRELYEELVP SSVEKKGEANQLSNKFLYPLVDPNSQSGKGTASSGRK PRWYNLKIAGDPSWEEEKKKWEEDKKKDPLAKILGK LAEYGLIPLFIPYTDSNEPIVKEIKWMEKSRNQSVRRL DKDMFIQALERFLSWESWNLKVKEEYEKVEKEYKTL EERIKEDIQALKALEQYEKERQEQLLRDTLNTNEYRLS KRGLRGWREIIQKWLKMDENEPSEKYLEVFKDYQRK HPREAGDYSVYEFLSKKENHFIWRNHPEYPYLYATFC EIDKKKKDAKQQATFTLADPINHPLWVRFEERSGSNL NKYRILTEQLHTEKLKKKLTVQLDRLIYPTESGGWEE KGKVDIVLLPSRQFYNQIFLDIEEKGKHAFTYKDESIK FPLKGTLGGARVQFDRDHLRRYPHKVESGNVGRIYFN MTVNIEPTESPVSKSLKIHRDDFPKVVNFKPKELTEWI KDSKGKKLKSGIESLEIGLRVMSIDLGQRQAAAASIFE VVDQKPDIEGKLFFPIKGTELYAVHRASFNIKLPGETL VKSREVLRKAREDNLKLMNQKLNFLRNVLHFQQFED ITEREKRVTKWISRQENSDVPLVYQDELIQIRELMYKP YKDWVAFLKQLHKRLEVEIGKEVKHWRKSLSDGRK GLYGISLKNIDEIDRTRKFLLRWSLRPTEPGEVRRLEPG QRFAIDQLNHLNALKEDRLKKMANTIIMHALGYCYD VRKKKWQAKNPACQIILFEDLSNYNPYGERSRFENSR LMKWSRREIPRQVALQGEIYGLQVGEVGAQFSSRFHA KTGSPGIRCRVVTKEKLQDNRFFKNLQREGRLTLDKI AVLKEGDLYPDKGGEKFISLSKDRKCVTTHADINAAQ NLQKRFWTRTHGFYKVYCKAYQVDGQTVYIPESKDQ KQKIIEEFGEGYFILKDGVYEWVNAGKLKIKKGSSKQ SSSELVDSDILKDSFDLASELKGEKLMLYRDPSGNVFP SDKWMAAGVFFGKLERILISKLTNQYSISTIEDDSSKQ S AkCasl2b MAVKSIKVKLRLSECPDILAGMWQLHRATNAGVRYY TEWVSLMRQEILYSRGPDGGQQCYMTAEDCQRELLR RLRNRQLHNGRQDQPGTDADLLAISRRLYEILVLQSIG KRGDAQQIASSFLSPLVDPNSKGGRGEAKSGRKPAWQ KMRDQGDPRWVAAREKYEQRKAVDPSKEILNSLDAL GLRPLFAVFTETYRSGVDWKPLGKSQGVRTWDRDMF QQALERLMSWESWNRRVGEEYARLFQQKMKFEQEH FAEQSHLVKLARALEADMRAASQGFEAKRGTAHQIT RRALRGADRVFEIWKSIPEEALFSQYDEVIRQVQAEKR RDFGSHDLFAKLAEPKYQPLWRADETFLTRYALYNG VLRDLEKARQFATFTLPDACVNPIWTRFESSQGSNLH KYEFLFDHLGPGRHAVRFQRLLVVESEGAKERDSVV VPVAPSGQLDKLVLREEEKSSVALHLHDTARPDGFM AEWAGAKLQYERSTLARKARRDKQGMRSWRRQPSM SEQ ID NO: 44 LMSAAQMLEDAKQAGDVYLNISVRVKSPSEVRGQRR PPYAALFRIDDKQRRVTVNYNKLSAYLEEHPDKQIPG APGLLSGLRVMSVDLGLRTSASISVFRVAKKEEVEAL GDGRPPHYYPIHGTDDLVAVHERSHLIQMPGETETKQ LRKLREERQAVLRPLFAQLALLRLLVRCGAADERIRT RSWQRLTKQGREFTKRLTPSWREALELELTRLEAYCG RVPDDEWSRIVDRTVIALWRRMGKQVRDWRKQVKS GAKVKVKGYQLDVVGGNSLAQIDYLEQQYKFLRRW SFFARASGLVVRADRESHFAVALRQHIENAKRDRLKK LADRILMEALGYVYEASGPREGQWTAQHPPCQLIILE ELSAYRFSDDRPPSENSKLMAWGHRGILEELVNQAQV HDVLVGTVYAAFSSRFDARTGAPGVRCRRVPARFVG ATVDDSLPLWLTEFLDKHRLDKNLLRPDDVIPTGEGE FLVSPCGEEAARVRQVHADINAAQNLQRRLWQNFDIT ELRLRCDVKMGGEGTVLVPRVNNARAKQLFGKKVL VSQDGVTFFERSQTGGKPHSEKQTDLTDKELELIAEA DEARAKS VVLFRDPSGHIGKGHWIRQREFWSLVKQRI ESHTAERIRVRGVGSSLD BsCasl2b MAIRSIKLKLKTHTGPEAQNLRKGIWRTHRLLNEGVA YYMKMLLLFRQESTGERPKEELQEELICHIREQQQRN QADKNTQALPLDKALEALRQLYELLVPSSVGQSGDA QIISRKFLSPLVDPNSEGGKGTSKAGAKPTWQKKKEA NDPTWEQDYEKWKKRREEDPTASVITTLEEYGIRPIFP LYTNTVTDIAWLPLQSNQFVRTWDRDMLQQAIERLLS WESWNKRVQEEYAKLKEKMAQLNEQLEGGQEWISL LEQYEENRERELRENMTAANDKYRITKRQMKGWNEL YELWSTFPASASHEQYKEALKRVQQRLRGRFGDAHF FQYLMEEKNRLIWKGNPQRIHYFVARNELTKRLEEAK QSATMTLPNARKHPLWVRFDARGGNLQDYYLTAEA DKPRSRRFVTFSQLIWPSESGWMEKKDVEVELALSRQ FYQQVKLLKNDKGKQKIEFKDKGSGSTFNGHLGGAK LQLERGDLEKEEKNFEDGEIGSVYLNVVIDFEPLQEVK NGRVQAPYGQVLQLIRRPNEFPKVTTYKSEQLVEWIK ASPQHSAGVESLASGFRVMSIDLGLRAAAATSIFSVEE SSDKNAADFSYWIEGTPLVAVHQRSYMLRLPGEQVE KQVMEKRDERFQLHQRVKFQIRVLAQIMRMANKQY GDRWDELDSLKQAVEQKKSPLDQTDRTFWEGIVCDL TKVLPRNEADWEQAVVQIHRKAEEYVGKAVQAWRK RFAADERKGIAGLSMWNIEELEGLRKLLISWSRRTRN PQEVNRFERGHTSHQRLLTHIQNVKEDRLKQLSHAIV MTALGYVYDERKQEWCAEYPACQVILFENLSQYRSN LDRSTKENSTLMKWAHRSIPKYVHMQAEPYGIQIGDV RAEYSSRFYAKTGTPGIRCKKVRGQDLQGRRFENLQK SEQ ID NO: 45 RLVNEQFLTEEQVKQLRPGDIVPDDSGELFMTLTDGS GSKEVVFLQADINAAHNLQKRFWQRYNELFKVSCRVI VRDEEEYLVPKTKSVQAKLGKGLFVKKSDTAWKDV YVWDSQAKLKGKTTFTEESESPEQLEDFQEIIEEAEEA KGTYRTLFRDPSGVFFPESVWYPQKDFWGEVKRKLY GKLRERFLTKAR AmCasl2b MNVAVKSIKVKLMLGHLPEIREGLWHLHEAVNLGVR YYTEWLALLRQGNLYRRGKDGAQECYMTAEQCRQE LLVRLRDRQKRNGHTGDPGTDEELLGVARRLYELLV PQSVGKKGQAQMLASGFLSPLADPKSEGGKGTSKSG RKPAWMGMKEAGDSRWVEAKARYEANKAKDPTKQ VIASLEMYGLRPLFDVFTETYKTIRWMPLGKHQGVRA WDRDMFQQSLERLMSWESWNERVGAEFARLVDRRD RFREKHFTGQEHLVALAQRLEQEMKEASPGFESKSSQ AHRITKRALRGADGIIDDWLKLSEGEPVDRFDEILRKR QAQNPRRFGSHDLFLKLAEPVFQPLWREDPSFLSRWA SYNEVLNKLEDAKQFATFTLPSPCSNPVWARFENAEG TNIFKYDFLFDHFGKGRHGVRFQRMIVMRDGVPTEVE GIVVPIAPSRQLDALAPNDAASPIDVFVGDPAAPGAFR GQFGGAKIQYRRSALVRKGRREEKAYLCGFRLPSQRR TGTPADDAGEVFLNLSLRVESQSEQAGRRNPPYAAVF HISDQTRRVIVRYGEIERYLAEHPDTGIPGSRGLTSGLR VMSVDLGLRTSAAISVFRVAHRDELTPDAHGRQPFFF PIHGMDHLVALHERSHLIRLPGETESKKVRSIREQRLD RLNRLRSQMASLRLLVRTGVLDEQKRDRNWERLQSS MERGGERMPSDWWDLFQAQVRYLAQHRDASGEAW GRMVQAAVRTLWRQLAKQVRDWRKEVRRNADKVK IRGIARDVPGGHSLAQLDYLERQYRFLRSWSAFSVQA GQVVRAERDSRFAVALREHIDNGKKDRLKKLADRIL MEALGYVYVTDGRRAGQWQAVYPPCQLVLLEELSE YRFSNDRPPSENSQLMVWSHRGVLEELIHQAQVHDV LVGTIPAAFSSRFDARTGAPGIRCRRVPSIPLKDAPSIPI WLSHYLKQTERDAAALRPGELIPTGDGEFLVTPAGRG ASGVRVVHADINAAHNLQRRLWENFDLSDIRVRCDR REGKDGTVVLIPRLTNQRVKERYSGVIFTSEDGVSFTV GDAKTRRRSSASQGEGDDLSDEEQELLAEADDARERS VVLFRDPSGFVNGGRWTAQRAFWGMVHNRIETLLAE RFSVSGAAEKVRG SEQ ID NO: 46 AaCasl2b MAVKSMKVKLRLDNMPEIRAGLWKLHTEVNAGVRY YTEWLSLLRQENLYRRSPNGDGEQECYKTAEECKAE LLERLRARQVENGHCGPAGSDDELLQLARQLYELLVP QAIGAKGDAQQIARKFLSPLADKDAVGGLGIAKAGN KPRWVRMREAGEPGWEEEKAKAEARKSTDRTADVL SEQ ID NO: 47 RALADFGLKPLMRVYTDSDMSSVQWKPLRKGQAVR TWDRDMFQQAIERMMSWESWNQRVGEAYAKLVEQ KSRFEQKNFVGQEHLVQLVNQLQQDMKEASHGLESK EQTAHYLTGRALRGSDKVFEKWEKLDPDAPFDLYDT EIKNVQRRNTRRFGSHDLFAKLAEPKYQALWREDASF LTRYAVYNSIVRKLNHAKMFATFTLPDATAHPIWTRF DKLGGNLHQYTFLFNEFGEGRHAIRFQKLLTVEDGVA KEVDDVTVPISMSAQLDDLLPRDPHELVALYFQDYGA EQHLAGEFGGAKIQYRRDQLNHLHARRGARDVYLNL SVRVQSQSEARGERRPPYAAVFRLVGDNHRAFVHFD KLSDYLAEHPDDGKLGSEGLLSGLRVMSVDLGLRTSA SISVFRVARKDELKPNSEGRVPFCFPIEGNENLVAVHE RSQLLKLPGETESKDLRAIREERQRTLRQLRTQLAYLR LLVRCGSEDVGRRERSWAKLIEQPMDANQMTPDWRE AFEDELQKLKSLYGICGDREWTEAVYESVRRVWRHM GKQVRDWRKDVRSGERPKIRGYQKDVVGGNSIEQIE YLERQYKFLKSWSFFGKVSGQVIRAEKGSRFAITLREH IDHAKEDRLKKLADRIIMEALGYVYALDDERGKGKW VAKYPPCQLILLEELSEYQFNNDRPPSENNQLMQWSH RGVFQELLNQAQVHDLLVGTMYAAFSSRFD ARTGAP GIRCRRVPARCAREQNPEPFPWWLNKFVAEHKLDGC PLRADDLIPTGEGEFFVSPFSAEEGDFHQIHADLNAAQ NLQRRLWSDFDISQIRLRCDWGEVDGEPVLIPRTTGK RTADSYGNKVFYTKTGVTYYERERGKKRRKVFAQEE LSEEEAELLVEADEAREKSVVLMRDPSGIINRGDWTR QKEFWSMVNQRIEGYLVKQIRSRVRLQESACENTGDI RfxCasl3d MIEKKKSFAKGMGVKSTLVSGSKVYMTTFAEGSDAR LEKIVEGDSIRSVNEGEAFSAEMADKNAGYKIGNAKF SHPKGYAVVANNPLYTGPVQQDMLGLKETLEKRYFG ESADGNDNICIQVIHNILDIEKILAEYITNAAYAVNNIS GLDKDIIGFGKFSTVYTYDEFKDPEHHRAAFNNNDKLI NAIKAQYDEFDNFLDNPRLGYFGQAFFSKEGRNYIINY GNECYDILALLSGLRHWVVHNNEEESRISRTWLYNLD KNLDNEYISTLNYLYDRITNELTNSFSKNSAANVNYIA ETLGINPAEFAEQYFRFSIMKEQKNLGFNITKLREVML DRKDMSEIRKNHKVFDSIRTKVYTMMDFVIYRYYIEE DAKVAAANKSLPDNEKSLSEKDIFVINLRGSFNDDQK DALYYDEANRIWRKLENIMHNIKEFRGNKTREYKKK DAPRLPRILPAGRDVSAFSKLMYALTMFLDGKEINDL LTTLINKFDNIQSFLKVMPLIGVNAKFVEEYAFFKDSA KIADELRLIKSFARMGEPIADARRAMYIDAIRILGTNLS YDELKALADTFSLDENGNKLKKGKHGMRNFIINNVIS NKRFHYLIRYGDPAHLHEIAKNEAVVKFVLGRIADIQ SEQ ID NO: 48 KKQGQNGKNQIDRYYETCIGKDKGKSVSEKVDALTKI ITGMNYDQFDKKRSVIEDTGRENAEREKFKKIISLYLT VIYHILKNIVNINARYVIGFHCVERDAQLYKEKGYDIN LKKLEEKGFSSVTKLCAGIDETAPDKRKDVEKEMAER AKESIDSLESANPKLYANYIKYSDEKKAEEFTRQINRE KAKTALNAYLRNTKWNVIIREDLLRIDNKTCTLFRNK AVHLEVARYVHAYINDIAEVNSYFQLYHYIMQRIIMN ERYEKSSGKVSEYFDAVNDEKKYNDRLLKLLCVPFG YCIPRFKNLSIEALFDRNEAAKFDKEKKKVSGN LwaCasl3a MKVTKVDGISHKKYIEEGKLVKSTSEENRTSERLSELL SIRLDIYIKNPDNASEEENRIRRENLKKFFSNKVLHLKD SVLYLKNRKEKNAVQDKNYSEEDISEYDLKNKNSFSV LKKILLNEDVNSEELEIFRKDVEAKLNKINSLKYSFEE NKANYQKINENNVEKVGGKSKRNIIYDYYRESAKRN DYINNVQEAFDKLYKKEDIEKLFFLIENSKKHEKYKIR EYYHKIIGRKNDKENFAKIIYEEIQNVNNIKELIEKIPD MSELKKSQVFYKYYLDKEELNDKNIKYAFCHFVEIEM SQLLKNYVYKRLSNISNDKIKRIFEYQNLKKLIENKLL NKLDTYVRNCGKYNYYLQVGEIATSDFIARNRQNEAF LRNIIGVSSVAYFSLRNILETENENGITGRMRGKTVKN NKGEEKYVSGEVDKIYNENKQNEVKENLKMFYSYDF NMDNKNEIEDFFANIDEAISSIRHGIVHFNLELEGKDIF AFKNIAPSEISKKMFQNEINEKKLKLKIFKQLNSANVF NYYEKDVIIKYLKNTKFNFVNKNIPFVPSFTKLYNKIE DLRNTLKFFWSVPKDKEEKDAQIYLLKNIYYGEFLNK FVKNSKVFFKITNEVIKINKQRNQKTGHYKYQKFENIE KTVPVEYLAIIQSREMINNQDKEEKNTYIDFIQQIFLKG FIDYLNKNNLKYIESNNNNDNNDIFSKIKIKKDNKEKY DKILKNYEKHNRNKEIPHEINEFVREIKLGKILKYTENL NMFYLILKLLNHKELTNLKGSLEKYQSANKEETFSDE LELINLLNLDNNRVTEDFELEANEIGKFLDFNENKIKD RKELKKFDTNKIYFDGENIIKHRAFYNIKKYGMLNLLE KIADKAKYKISLKELKEYSNKKNEIEKNYTMQQNLHR KYARPKKDEKFNDEDYKEYEKAIGNIQKYTHLKNKV EFNELNLLQGLLLKILHRLVGYTSIWERDLRFRLKGEF PENHYIEEIFNFDNSKNVKYKSGQIVEKYINFYKELYK DNVEKRSIYSDKKVKKLKQEKKDLYIRNYIAHFNYIP HAEISLLEVLENLRKLLSYDRKLKNAIMKSIVDILKEY GFVATFKIGADKKIEIQTLESEKIVHLKNLKKKKLMTD RNSEELCELVKVMFEYKALE SEQ ID NO: 49 PspCasl3b MNIPALVENQKKYFGTYSVMAMLNAQTVLDHIQKVA DIEGEQNENNENLWFHPVMSHLYNAKNGYDKQPEKT MFIIERLQSYFPFLKIMAENQREYSNGKYKQNRVEVN SEQ ID NO: 50 SNDIFEVLKRAFGVLKMYRDLTNHYKTYEEKLNDGC EFLTSTEQPLSGMINNYYTVALRNMNERYGYKTEDLA FIQDKRFKFVKDAYGKKKSQVNTGFFLSLQDYNGDT QKKLHLSGVGIALLICLFLDKQYINIFLSRLPIFSSYNA QSEERRIIIRSFGINSIKLPKDRIHSEKSNKSVAMDMLN EVKRCPDELFTTLSAEKQSRFRIISDDHNEVLMKRSSD RFVPLLLQYIDYGKLFDHIRFHVNMGKLRYLLKADKT CIDGQTRVRVIEQPLNGFGRLEEAETMRKQENGTFGN SGIRIRDFENMKRDDANPANYPYIVDTYTHYILENNK VEMFINDKEDSAPLLPVIEDDRYVVKTIPSCRMSTLEIP AMAFHMFLFGSKKTEKLIVDVHNRYKRLFQAMQKEE VTAENIASFGIAESDLPQKILDLISGNAHGKDVDAFIRL TVDDMLTDTERRIKRFKDDRKSIRSADNKMGKRGFK QISTGKLADFLAKDIVLFQPSVNDGENKITGLNYRIMQ SAIAVYDSGDDYEAKQQFKLMFEKARLIGKGTTEPHP FLYKVFARSIPANAVEFYERYLIERKFYLTGLSNEIKK GNRVDVPFIRRDQNKWKTPAMKTLGRIYSEDLPVELP RQMFDNEIKSHLKSLPQMEGIDFNNANVTYLIAEYMK RVLDDDFQTFYQWNRNYRYMDMLKGEYDRKGSLQH CFTSVEEREGLWKERASRTERYRKQASNKIRSNRQMR NASSEEIETILDKRLSNSRNEYQKSEKVIRRYRVQDAL LFLLAKKTLTELADFDGERFKLKEIMPDAEKGILSEIM PMSFTFEKGGKKYTITSEGMKLKNYGDFFVLASDKRI GNLLELVGSDIVSKEDIMEEFNKYDQCRPEISSIVFNLE KWAFDTYPELSARVDREEKVDFKSILKILLNNKNINKE QSDILRKIRNAFDHNNYPDKGVVEIKALPEIAMSIKKA FGEYAIMKGSLQ PguCasl3b MTEQSERPYNGTYYTLEDKHFWAAFLNLARHNAYIT LTHIDRQLAYSKADITNDQDVLSFKALWKNFDNDLER KSRLRSLILKHFSFLEGAAYGKKLFESKSSGNKSSKNK ELTKKEKEELQANALSLDNLKSILFDFLQKLKDFRNY YSHYRHSGSSELPLFDGNMLQRLYNVFDVSVQRVKID HEHNDEVDPHYHFNHLVRKGKKDRYGHNDNPSFKH HFVDGEGMVTEAGLLFFVSLFLEKRDAIWMQKKIRGF KGGTETYQQMTNEVFCRSRISLPKLKLESLRMDDWM LLDMLNELVRCPKPLYDRLREDDRACFRVPVDILPDE DDTDGGGEDPFKNTLVRHQDRFPYFALRYFDLKKVF TSLRFHIDLGTYHFAIYKKMIGEQPEDRHLTRNLYGFG RIQDFAEEHRPEEWKRLVRDLDYFETGDKPYISQTSPH YHIEKGKIGLRFMPEGQHLWPSPEVGTTRTGRSKYAQ DKRLTAEAFLSVHELMPMMFYYFLLREKYSEEVSAER VQGRIKRVIEDVYAVYDAFARDEINTRDELDACLADK GIRRGHLPRQMIAILSQEHKDMEEKIRKKLQEMMADT SEQ ID NO: 51 DHRLDMLDRQTDRKIRIGRKNAGLPKSGVIADWLVR DMMRFQPVAKDASGKPLNNSKANSTEYRMLQRALA LFGGEKERLTPYFRQMNLTGGNNPHPFLHETRWESHT NILSFYRSYLRARKAFLERIGRSDRVENRPFLLLKEPKT DRQTLVAGWKGEFHLPRGIFTEAVRDCLIEMGHDEV ASYKEVGFMAKAVPLYFERACEDRVQPFYDSPFNVG NSLKPKKGRFLSKEERAEEWERGKERFRDLEAWSYS AARRIEDAFAGIEYASPGNKKKIEQLLRDLSLWEAFES KLKVRADRINLAKLKKEILEAQEHPYHDFKSWQKFER ELRLVKNQDIITWMMCRDLMEENKVEGLDTGTLYLK DIRPNVQEQGSLNVLNRVKPMRLPVVVYRADSRGHV HKEEAPLATVYIEERDTKLLKQGNFKSFVKDRRLNGL FSFVDTGGLAMEQYPISKLRVEYELAKYQTARVCVFE LTLRLEESLLTRYPHLPDESFREMLESWSDPLLAKWPE LHGKVRLLIAVRNAFSHNQYPMYDEAVFSSIRKYDPS SPDAIEERMGLNIAHRLSEEVKQAKETVERIIQAGSLQ RanCasl3b MEKPLLPNVYTLKHKFFWGAFLNIARHNAFITICHINE QLGLKTPSNDDKIVDVVCETWNNILNNDHDLLKKSQ LTELILKHFPFLTAMCYHPPKKEGKKKGHQKEQQKEK ESEAQSQAEALNPSKLIEALEILVNQLHSLRNYYSHYK HKKPDAEKDIFKHLYKAFDASLRMVKEDYKAHFTVN LTRDFAHLNRKGKNKQDNPDFNRYRFEKDGFFTESGL LFFTNLFLDKRDAYWMLKKVSGFKASHKQREKMTTE VFCRSRILLPKLRLESRYDHNQMLLDMLSELSRCPKLL YEKLSEENKKHFQVEADGFLDEIEEEQNPFKDTLIRHQ DRFPYFALRYLDLNESFKSIRFQVDLGTYHYCIYDKKI GDEQEKRHLTRTLLSFGRLQDFTEINRPQEWKALTKD LDYKETSNQPFISKTTPHYHITDNKIGFRLGTSKELYPS LEIKDGANRIAKYPYNSGFVAHAFISVHELLPLMFYQH LTGKSEDLLKETVRHIQRIYKDFEEERINTIEDLEKANQ GRLPLGAFPKQMLGLLQNKQPDLSEKAKIKIEKLIAET KLLSHRLNTKLKSSPKLGKRREKLIKTGVLADWLVKD FMRFQPVAYDAQNQPIKSSKANSTEFWFIRRALALYG GEKNRLEGYFKQTNLIGNTNPHPFLNKFNWKACRNL VDFYQQYLEQREKFLEAIKNQPWEPYQYCLLLKIPKE NRKNLVKGWEQGGISLPRGLFTEAIRETLSEDLMLSKP IRKEIKKHGRVGFISRAITLYFKEKYQDKHQSFYNLSY KLEAKAPLLKREEHYEYWQQNKPQSPTESQRLELHTS DRWKDYLLYKRWQHLEKKLRLYRNQDVMLWLMTL ELTKNHFKELNLNYHQLKLENLAVNVQEADAKLNPL NQTLPMVLPVKVYPATAFGEVQYHKTPIRTVYIREEH TKALKMGNFKALVKDRRLNGLFSFIKEENDTQKHPIS QLRLRRELEIYQSLRVDAFKETLSLEEKLLNKHTSLSS SEQ ID NO: 52 LENEFRALLEEWKKEYAASSMVTDEHIAFIASVRNAF CHNQYPFYKEALHAPIPLFTVAQPTTEEKDGLGIAEAL LKVLREYCEIVKSQIGSSLQKKLEELELGSS

[00266] In some embodiments, the Cas protein is a nCas9. In some embodiments, the nCas9 protein is a nSpCas9-D10A protein or nSpCas9-H840A, comprising an amino acid sequence of SEQ ID NO: 3 or 4, respectively.

[00267] In some embodiments, the first protein-binding RNA motif and the first RNA 5 binding domain, the second protein-binding RNA motif and the second RNA binding domain, and the third protein-binding RNA motif and the third RNA binding domain, are each independently selected from the group consisting of a MS2 phage operator stem-loop and MS2 coat protein (MCP) or an RNA-binding section thereof; a BoxB and N22P or an RNA-binding section thereof; a telomerase Ku binding motif and Ku protein or an RNA- 10 binding section thereof; a telomerase Sm7 binding motif and Sm7 protein or an RNA-binding section thereof; a PP7 phage operator stem - loop and PP7 coat protein (PCP) or an RNA-binding section thereof; a SfMu phage Com stem-loop and Com RNA binding protein or an RNA-binding section thereof; and a non-natural RNA aptamer and corresponding aptamer ligand or an RNA-binding section thereof. 15 Table 5 Exemplary sequences of protein-binding RNA motifs and RNA binding domains Name Sequence SEQ ID NO: MS2 coat protein (MCP) MASNFTQFVLVDNGGTGDVTVAPSNFANGIAEWISSN SRSQAYKVTCSVRQSSAQNRKYTIKVEVPKGAWRSY LNMELTIPIFATNSDCELIVKAMQGLLKDGNPIPSAIAA NSGIY SEQ ID NO: 53 PP7 coat protein (PCP) MGSKTIVLSVGEATRTLTEIQSTADRQIFEEKVGPLVGRLRL TASLRQNGAKTAYRVNLKLDQADVVDSGLPKVRYTQVWS HDVTIVANSTEASRKSLYDLTKSLVATSQVEDLVVNLVPL GR SEQ ID NO: 54 boxB coat protein (N22p) MGNARTRRRERRAEKQAQWKAAN SEQ ID NO: 55 MS2 ACATGAGGATCACCCATGT SEQ ID NO: 56 PP7 GGAGCAGACGATATGGCGTCGCTCC SEQ ID NO: 57 boxB GCCCTGAAGAAGGGC SEQ ID NO: 58 Telomerase Ku binding motif TTGTGTTTCTACTTATAGATGGCTAAAATCTGAGTT TAGAAAATGCAA SEQ ID NO: 59 Telomerase Sm7 binding motif AATTTTTGGA SEQ ID NO: 60 SfMu CTGAATGCCTGCGAGCATC SEQ ID NO: 61 YKU70 MELDPDDVFRDEDEDPENDFFQEKEASKEFVVYLIDA SPKMFCSTCPSEEEDKQESHFHIAVSCIAQSLKAHIINR SNDEIAICFFNTREKKNLQDLNGVYVFNVPERDSIDRP TARLIKEFDLIEESFDKEIGSQTGIVSDSRENSLYSALW VAQALLRKGSLKTADKRMFLFTNEDDPFGSMRISVKE DMTRTTLQRAKDAQDLGISIELLPLSQPDKQFNITLFY KDLIGLNSDELTEFMPSVGQKLEDMKDQLKKRVLAK RIAKRITFVICDGLSIELNGYALLRPAIPGSITWLDSTTN LPVKVERSYICTDTGAIMQDPIQRIQPYKNQNIMFTVE ELSQVKRISTGHLRLLGFKPLSCLKDYHNLKPSTFLYP SDKEVIGSTRAFIALHRSMIQLERFAVAFYGGTTPPRL VALVAQDEIESDGGQVEPPGINMIYLPYANDIRDIDEL HSKPGVAAPRASDDQLKKASALMRRLELKDFSVCQF ANPALQRHYAILQAIALDENELRETRDETLPDEEGMN RPAVVKAIEQFKQSIYGDDPDEESDSGAKEKSKKRKA GDADDGKYDYIELAKTGKLKDLTVVELKTYLTANNL LVSGKKEVLINRILTHIGK SEQ ID NO: 62 YKU80 MSSESTTFIVDVSPSMMKNNNVSKSMAYLEYTLLNKS KKSRKTDWISCYLANCPVSENSQEIPNVFQIQSFLAPV TTTATIGFIKRLKQYCDQHSHDSSNEGLQSMIQCLLVV SLDIKQQFQARKILKQIVVFTDNLDDLDITDEEIDLLTE ELSTRIILIDCGKDTQEERKKSNWLKLVEAIPNSRIYN MNELLVEITSPATSVVKPVRVFSGELRLGADILSTQTS NPSGSMQDENCLCIKVEAFPATKAVSGLNRKTAVEVE DSQKKERYVGVKSIIEYEIHNEGNKKNVSEDDQSGSS YIPVTISKDSVTKAYRYGADYVVLPSVLVDQTVYESF PGLDLRGFLNREALPRYFLTSESSFITADTRLGCQSDL MAFSALVDVMLENRKIAVARYVSKKDSEVNMCALCP VLIEHSNINSEKKFVKSLTLCRLPFAEDERVTDFPKLLD SEQ ID NO: 63 RTTTSGVPLKKETDGHQIDELMEQFVDSMDTDELPEIP LGNYYQPIGEVTTDTTLPLPSLNKDQEENKKDPLRIPT VFVYRQQQVLLEWIHQLMINDSREFEIPELPDSLKNKI SPYTHKKFDSTKLVEVLGIKKVDKLKLDSELKTELER EKIPDLETLLKRGEQHSRGSPNNSNN Sm7-like protein GSVIDVSSQRVNVQRPLDALGNSLNSPVIIKLKGDREF RGVLKSFDLHMNLVLNDAEELEDGEVTRRLGT SEQ ID NO: 64 SfMu Com binding protein MKSIRCKNCNKLLFKADSFDHIEIRCPRCKRHIIMLNA CEHPTEKHCGKREKITHSDETVRY SEQ ID NO: 65

[00268] In some embodiments of the gene editing system described herein, the mgRNA and / or the hgRNA comprises a dual-RNA structure.

[00269] In some embodiments, the dual-RNA structure is formed by a CRISPR RNA (crRNA) and a trans-activating crRNA (tracrRNA), wherein the crRNA comprises the spacer.

[00270] In some embodiments of the gene editing system described herein, the mgRNA comprises a mcrRNA and a first tracrRNA, and the mcrRNA comprises the mgRNA spacer, wherein the hgRNA comprises a hcrRNA and a second tracrRNA, and the hcrRNA comprises the hgRNA spacer, and wherein the first tracrRNA and the second tracrRNA are same or different.

[00271] In some embodiments, the mcrRNA and / or the hcrRNA is capable of binding to the PCSK9 gene. In some embodiments, the mcrRNA and the hcrRNA are SEQ ID NO: 1112 and SEQ ID NO: 1111, respectively; or SEQ ID NO: 1114 and SEQ ID NO: 1113, respectively; or SEQ ID NO: 1116 and SEQ ID NO: 1115, respectively.

[00272] In some embodiments, the mcrRNA and / or the hcrRNA is capable of binding to the ANGPTL3 gene. In some embodiments, the mcrRNA and the hcrRNA are SEQ ID NO: 1138 and SEQ ID NO: 1137, respectively; or SEQ ID NO: 1140 and SEQ ID NO: 1139, respectively; or SEQ ID NO: 1142 and SEQ ID NO: 1141, respectively.

[00273] In some embodiments, the tracrRNA is SEQ ID NO: 1117 and 1242.

[00274] In another aspect, the present disclosure provides a polynucleotide encoding the hgRNA and / or the mgRNA disclosed herein.

[00275] In another aspect, the present disclosure provides a polynucleotide encoding all components except the first and the second Cas protein in the gene editing system disclosed herein.

[00276] In another aspect, the present disclosure provides a polynucleotide encoding all components except the mgRNA and hgRNA in the gene editing system described herein.

[00277] In another aspect, the present disclosure provides a polynucleotide encoding all components except the mgRNA, hgRNA, and the first and second Cas proteins in the gene editing system described herein.

[00278] In another aspect, the present disclosure provides a kit comprising a polynucleotide encoding all components except the first and the second Cas protein in the gene editing system disclosed herein, and a polynucleotide encoding the first and / or second Cas protein in the gene editing system disclosed herein. In some embodiments, the first and the second Cas proteins are the same Cas protein.

[00279] In an aspect, the present disclosure provides a vector comprising the polynucleotide described herein. In another aspect, the present disclosure provides a vector comprising the polynucleotide encoding the hgRNA and / or the mgRNA disclosed herein.

[00280] In another aspect, the present disclosure provides a vector comprising the polynucleotide encoding all components except the first and the second Cas protein in the gene editing system disclosed herein.

[00281] In some embodiments, the vector is a plasmid, a viral vector, a non-viral vector or a lipid nanoparticle (LNP) vector.

[00282] In some embodiments, the vector is a polycistronic vector.

[00283] In some embodiments, the vector is an AAV vector.

[00284] In another aspect, the present disclosure provides a kit comprising the vector disclosed above, and a vector comprising the polynucleotide encoding the first and / or second Cas protein in the gene editing system disclosed herein.

[00285] In another aspect, the present disclosure provides a cell comprising the gene editing system disclosed herein.

[00286] In another aspect, the present disclosure provides a cell comprising the polynucleotide disclosed herein. In some embodiments, the cell further comprises a polynucleotide encoding the first and / or second Cas protein in the gene editing system disclosed herein.

[00287] In another aspect, the present disclosure provides a cell comprising the vector disclosed herein. In some embodiments, the cell further comprises a vector comprising a polynucleotide encoding the first and / or second Cas protein in the gene editing system disclosed herein.

[00288] In another aspect, the present disclosure provides a cell comprising the kit disclosed herein.

[00289] In another aspect, the present disclosure provides a composition comprising the gene editing system disclosed herein.

[00290] In another aspect, the present disclosure provides a composition comprising the cell disclosed herein.

[00291] In another aspect, the present disclosure provides a method for disrupting or regulating the expression of a gene selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT and APOC3 gene in a cell, comprising introducing into the cell the gene editing system disclosed herein.

[00292] In some embodiments, the present disclosure provides a method for disrupting or regulating the expression of PCSK9 gene in a cell, comprising introducing into the cell the gene editing system disclosed herein.

[00293] In some embodiments, the present disclosure provides a method for disrupting or regulating the expression of ANGPTL3 gene in a cell, comprising introducing into the cell the gene editing system disclosed herein.

[00294] In some embodiments, the present disclosure provides a method for disrupting or regulating the expression of ASGR1 gene in a cell, comprising introducing into the cell the gene editing system disclosed herein.

[00295] In some embodiments, the present disclosure provides a method for disrupting or regulating the expression of LPA gene in a cell, comprising introducing into the cell the gene editing system disclosed herein.

[00296] In some embodiments, the present disclosure provides a method for disrupting or regulating the expression of AGT gene in a cell, comprising introducing into the cell the gene editing system disclosed herein.

[00297] In some embodiments, the present disclosure provides a method for disrupting or regulating the expression of APOC3 gene in a cell, comprising introducing into the cell the gene editing system disclosed herein.

[00298] In another aspect, the present disclosure provides a method for regulating Low-Density Lipoprotein cholesterol (LDL-C) metabolism in a subject, comprising introducing into a cell of the subject the gene editing system disclosed herein.

[00299] In another aspect, the present disclosure provides a method for treating hypercholesterolemia in a subject, comprising introducing into a cell of the subject a therapeutically effective amount of the gene editing system disclosed herein.

[00300] In another aspect, the present disclosure provides a method for lowering LDL-C level in a subject, comprising introducing into a cell of the subject the gene editing system disclosed herein.

[00301] In another aspect, the present disclosure provides a method for regulating triglyceride-rich remnant particles and / or lipoprotein(a) (Lp(a)) metabolism in a subject, comprising introducing into a cell of the subject the gene editing system disclosed herein.

[00302] In another aspect, the present disclosure provides a method for regulating blood pressure in a subject, comprising introducing into a cell of the subject the gene editing system disclosed herein.

[00303] In another aspect, the present disclosure provides a method for reducing the expression of angiotensinogen in a subject, comprising introducing into a cell of the subject the gene editing system disclosed herein.

[00304] In another aspect, the present disclosure provides a method for treating hypertension in a subject, comprising introducing into a cell of the subject a therapeutically effective amount of the gene editing system disclosed herein.

[00305] In another aspect, the present disclosure provides a method for treating cardiovascular disease (CVD) in a subject, comprising introducing into the subject a therapeutically effective amount of the gene editing system disclosed herein. In some embodiments, the present disclosure provides a method for treating CVD, comprising lowering blood lipid level with a method as disclosed herein, and / or lowering the level of circulating lipoprotein particles with a method disclosed herein, and / or lowering blood pressure with a method disclosed herein.

[00306] In some embodiments, the cardiovascular disease is associated with the expression of genes selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT and APOC3 gene.

[00307] In some embodiments, the cardiovascular disease is selected from atherosclerosis, congestive heart failure, peripheral vascular disease, cerebrovascular disease, rheumatic heart disease, arrhythmia, hypertension, and coronary artery disease.

[00308] In some embodiments, the cell as disclosed herein is a stem cell.

[00309] In some embodiments, the cell as disclosed herein is a pluripotent stem cell.

[00310] In some embodiments, the cell as disclosed herein is an embryonic stem cell (ESC).

[00311] In some embodiments, the cell as disclosed herein is an induced pluripotent stem cell (iPSC).

[00312] In some embodiments, the cell as disclosed herein is the cell is a somatic cell.

[00313] In some embodiments, the cell as disclosed herein is the cell is a hepatocyte.

[00314] In some embodiments, the cell as disclosed herein is a primary cell.

[00315] In some embodiments, the cell as disclosed herein is a differentiated cell. BRIEF DESCRIPTION OF THE FIGURES

[00316] Figure 1 illustrates exemplary base editors that can be used in the gene editing systems disclosed herein. The various versions of base editors are denoted as VI, V2, V3, V4, and V5, with constructs denoted as tBE-Vl-rAl, tBE-V2-rAl, tBE-V3-rAl, tBE-V4-rAl, tBE-V5-rAl, and tBE-V5-mA3. Figure 1A shows schematic diagrams illustrating the construction and development of various versions of base editors. Figure IB shows interactions of molecular components in different versions of the base editors. Base editors of V2 to V5 illustrate different strategies to cleave mA3dCDI off. The dCDI domain could be cleaved off from APOBEC through a two-component interaction of the TEV site and a free TEV protease (V2), a N22p-fused TEV protease (V3), or a TEV protease reconstituted by an mgRNA-boxB (V4). In the version 5 (V5) of the base editor, the dCDI is cleaved off from APOBEC through a three-component interaction of TEV site, TEVn, and N22p-TEVc.

[00317] Figure 2 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human PCSK9 gene. Figure 2A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 2B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 2C shows editing frequency at each target site calculated by EditR analysis.

[00318] Figure 3 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human PCSK9 gene. Figure 3A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 3B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 3C shows editing frequency at each target site calculated by EditR analysis.

[00319] Figure 4 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human PCSK9 gene. Figure 4A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 4B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 4C shows editing frequency at each target site calculated by EditR analysis.

[00320] Figure 5 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human PCSK9 gene. Figure 5A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 5B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 5C shows editing frequency at each target site calculated by EditR analysis.

[00321] Figure 6 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human PCSK9 gene. Figure 6A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 6B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 6C shows editing frequency at each target site calculated by EditR analysis.

[00322] Figure 7 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human PCSK9 gene. Figure 7A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 7B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 7C shows editing frequency at each target site calculated by EditR analysis.

[00323] Figure 8 illustrates relative human PCSK9 protein expression induced by a tBE gene editing system with pairs of mgRNA and hgRNA targeting human PCSK9 gene in human cells. Figure 8A shows protein expression level examined with western blot using GAPDH as the loading control. Figure 8B shows protein expression level examined with ELISA and corresponding editing frequency at indicated sites.

[00324] Figure 9 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting mouse PCSK9 gene. Figure 9A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 9B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 9C shows editing frequency at each target site calculated by EditR analysis.

[00325] Figure 10 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting mouse PCSK9 gene. Figure 10A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 10B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites.

[00326] Figure 11 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting mouse PCSK9 gene. Figure 11A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding with tBE-V5-mA3 and nCas9. Figure 11B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 11C shows editing frequency at each target site in Figure 10B calculated by EditR analysis. Figure 11D shows editing frequency at each target sites in Figure 11B calculated by EditR analysis.

[00327] Figure 12 illustrates relative mouse PCSK9 protein expression induced by a tBE gene editing system with pairs of mgRNA and hgRNA targeting mouse PCSK9 gene in mouse cells. Figure 12A shows protein expression level examined with western blot using GAPDH as the loading control in Hepal-6 cells. Figure 12B shows protein expression level examined with ELISA and corresponding editing frequency at indicated sites in Hepal-6 cells. Figure 12C shows protein expression level examined with ELISA and corresponding editing frequency at indicated sites in COS-1 cells. Figure 12D shows editing efficiency induced by tBE-V5-mA3 with different pairs of mgRNA / hgRNA at indicated sites in Hepal-6 cells.

[00328] Figure 13 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ANGPTL3 gene. Figure 13A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 13B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 13C shows editing frequency at each target site calculated by EditR analysis.

[00329] Figure 14 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ANGPTL3 gene. Figure 14A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 14B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 14C shows editing frequency at each target site calculated by EditR analysis.

[00330] Figure 15 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ANGPTL3. Figure 15A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 15B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 15C shows editing frequency at each target site calculated by EditR analysis.

[00331] Figure 16 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ANGPTL3 gene. Figure 16A is a schematic diagram illustrating the co-transfection of 123 mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 16B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites.

[00332] Figure 17 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ANGPTL3 gene. Figure 17A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 17B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 17C shows editing frequency at each target sites in figure 16B calculated by EditR analysis. Figure 17D shows editing frequency at each target site in figure 17B calculated by EditR analysis.

[00333] Figure 18 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ANGPTL3 gene. Figure 18A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 18B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 18C shows editing frequency at each target site calculated by EditR analysis.

[00334] Figure 19 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ANGPTL3 gene. Figure 19A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 19B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 19C shows editing frequency at each target site calculated by EditR analysis.

[00335] Figure 20 illustrates relative human ANGPTL3 protein expression induced by a tBE gene editing system with pairs of mgRNA and hgRNA targeting human ANGPTL3 gene in human cells. Figure 20A shows protein expression level examined with ELISA and corresponding editing frequency at indicated sites.

[00336] Figure 21 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting mouse ANGPTL3 gene. Figure 21A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 21B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 2IC shows editing frequency at each target site calculated by EditR analysis.

[00337] Figure 22 illustrates relative mouse ANGPTL3 protein expression induced by a tBE gene editing system with pairs of mgRNA and hgRNA targeting mouse ANGPTL3 gene in mouse cells. Figure 22A shows protein expression level examined with western blot using GAPDH as the loading control and corresponding editing frequency at indicated sites.

[00338] Figure 23 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ASGR1 gene. Figure 23 A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 23B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 23C shows editing frequency at each target site calculated by EditR analysis.

[00339] Figure 24 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ASGR1 gene. Figure 24A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 24B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 24C shows editing frequency at each target site calculated by EditR analysis.

[00340] Figure 25 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ASGR1 gene. Figure 25A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 25B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 25C shows editing frequency at each target site calculated by EditR analysis.

[00341] Figure 26 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ASGR1 gene. Figure 26A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 26B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 26C shows editing frequency at each target site calculated by EditR analysis.

[00342] Figure 27 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ASGR1 gene. Figure 27A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 27B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 27C shows editing frequency at each target site calculated by EditR analysis.

[00343] Figure 28 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human ASGR1 gene. Figure 28A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 28B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 28C shows editing frequency at each target site calculated by EditR analysis.

[00344] Figure 29 illustrates relative human ASGR1 protein expression induced by a tBE gene editing system with pairs of mgRNA and hgRNA targeting human ASGR1 gene in human cells. Figure 29A shows protein expression level examined with western blot using GAPDH as the loading control and corresponding editing frequency at indicated sites.

[00345] Figure 30 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting mouse ASGR1 gene. Figure 30A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 30B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 30C shows editing frequency at each target site calculated by EditR analysis.

[00346] Figure 31 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting mouse ASGR1 gene. Figure 31A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 3 IB shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 3 IC shows editing frequency at each target site calculated by EditR analysis.

[00347] Figure 32 illustrates relative mouse ASGR1 protein expression induced by a tBE gene editing system with pairs of mgRNA and hgRNA targeting mouse ASGR1 gene in mouse cells. Figure 32A shows protein expression level examined with western blot using GAPDH as the loading control and corresponding editing frequency at indicated sites.

[00348] Figure 33 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 33A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 33B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 33C shows editing frequency at each target site calculated by EditR analysis.

[00349] Figure 34 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 34A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 34B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 34C shows editing frequency at each target site calculated by EditR analysis.

[00350] Figure 35 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 35A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 35B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 35C shows editing frequency at each target site calculated by EditR analysis.

[00351] Figure 36 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 36A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 36B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 36C shows editing frequency at each target site calculated by EditR analysis.

[00352] Figure 37 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 37A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 37B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 37C shows editing frequency at each target site calculated by EditR analysis.

[00353] Figure 38 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 38A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 38B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 38C shows editing frequency at each target site calculated by EditR analysis.

[00354] Figure 39 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 39A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 39B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 39C shows editing frequency at each target site calculated by EditR analysis.

[00355] Figure 40 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 40A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 40B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 40C shows editing frequency at each target site calculated by EditR analysis.

[00356] Figure 41 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 41A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 41B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 41C shows editing frequency at each target site calculated by EditR analysis.

[00357] Figure 42 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human LPA gene. Figure 42A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 42B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 42C shows editing frequency at each target site calculated by EditR analysis.

[00358] Figure 43 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 43 A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 43B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 43C shows editing frequency at each target site calculated by EditR analysis.

[00359] Figure 44 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 44A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 44B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 44C shows editing frequency at each target site calculated by EditR analysis.

[00360] Figure 45 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 45A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 45B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 45C shows editing frequency at each target site calculated by EditR analysis.

[00361] Figure 46 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 46A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 46B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 46C shows editing frequency at each target site calculated by EditR analysis.

[00362] Figure 47 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 47A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 47B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 47C shows editing frequency at each target site calculated by EditR analysis.

[00363] Figure 48 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 48A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 48B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 48C shows editing frequency at each target site calculated by EditR analysis.

[00364] Figure 49 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 49A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 49B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 49C shows editing frequency at each target site calculated by EditR analysis.

[00365] Figure 50 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 50A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 50B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 50C shows editing frequency at each target site calculated by EditR analysis.

[00366] Figure 51 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 51A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 5 IB shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 5IC shows editing frequency at each target site calculated by EditR analysis.

[00367] Figure 52 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human AGT gene. Figure 52A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 52B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 52C shows editing frequency at each target site calculated by EditR analysis.

[00368] Figure 53 illustrates relative human AGT protein expression induced by a tBE gene editing system with pairs of mgRNA and hgRNA targeting human AGT gene in human cells. Figure 53A shows protein expression level examined with western blot using GAPDH as the loading control. Figure 53B shows protein expression level examined with ELISA and corresponding editing frequency at indicated sites.

[00369] Figure 54 illustrates LNP delivery of a tBE gene editing system targeting the PCSK9 gene for in vivo base editing. Figure 54A is a schematic of an LNP system for tBE-V5-mA3 and key experimental steps. Figure 54B-54D shows in vivo editing frequencies (B) induced by LNP containing a tBE system with different detection time periods and the levels of plasma PCSK9 protein (C) and cholesterol levels (D) in the mice injected with LNP expressing tBE system. Figure 54E-54G shows in vivo editing frequencies (E) induced by LNP containing a tBE system and the corresponding chemically modified guide RNA and the levels of plasma PCSK9 protein (F) and cholesterol levels (G) in the mice injected with LNP expressing tBE system.

[00370] Figure 55 illustrates several versions of a LigoRNA-based gene editing systems. Figure 55A shows polynucleotide constructs encoding components of six versions of the LigoRNA-based gene editing system that comprises two LigoRNA structures (denoted as VI, V2, V3, V4, V5, and V6). Figure 55B&C are the illustrations of the six versions of the LigoRNA-based gene editing system (denoted as VI, V2, V3, V4, V5, and V6).

[00371] Figure 56 illustrates LNP delivery of LigoRNA-tCBE-V5 targeting the PCSK9 gene for in vivo base editing. Figure 56A-56C shows in vivo editing frequencies (A) induced by LNP containing tBE system with end modified guide RNA or a LigoRNA-tCBE-V5 system and the levels of plasma PCSK9 protein (B) and cholesterol levels (C) in the mice injected with LNP expressing tBE or LigoRNA-tCBE-V5.

[00372] Figure 57 illustrates a dual editing strategy by LigoRNA-tCBE-V5 in different cells. Figure 57A shows co-editing by guide RNA (including two pairs of mgRNA and hgRNA) targeting PCSK9 and ANGPTL3, showing comparable editing efficiency with their respective single editing control. Figure 57B shows the dual editing strategy produced comparable protein level reduction compared to single editing as evidenced by an ELISA assay.

[00373] Figure 58 illustrates LNP delivery of a tBE gene editing system targeting the PCSK9 and ANGPTL3 gene for in vivo base editing. Figure 58A is a schematic of an LNP system for tBE-V5-mA3 and key experimental steps. Figure 58B shows in vivo editing efficiencies in mouse liver and mouse hepatocytes induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs (including two pairs of mgRNA and hgRNA). Figure 58C-D shows the levels of plasma PCSK9 protein (C) and ANGPTL3 protein (D) in the mice injected with LNP expressing tBE system.

[00374] Figure 59 illustrates editing efficiencies induced by a tBE gene editing system with the indicated pairs of mgRNA and the corresponding hgRNAs targeting human APOC3 gene. Figure 59A is a schematic diagram illustrating the co-transfection of mgRNA and the corresponding hgRNA with tBE-V5-mA3 and nCas9. Figure 59B shows editing efficiency induced by tBE-V5-mA3 with indicated pairs of mgRNA / hgRNA at indicated sites. Figure 59C shows editing frequency at each target site calculated by EditR analysis.

[00375] Figure 60 illustrates LNP delivery of a tBE gene editing system targeting the APOC3 gene for in vivo base editing. Figure 60A is a schematic of an LNP system for tBE-V5-mA3 and key experimental steps. Figure 60B-60D shows in vivo editing frequencies (B) induced by LNP containing a tBE system with different sgRNA pairs, plasma level of hApoC3 protein (C) detected in ELISA assay, and plasma triglyceride (TG) levels (D) in the mice injected with LNP expressing tBE system. Figure 60E-60G shows the levels of plasma low-density lipoprotein cholesterol (LDL-C) (E), high-density lipoprotein cholesterol (HDL-C) (F) and cholesterol (CHOL) (G).

[00376] Figure 61 illustrates LNP delivery of a tBE gene editing system targeting the PCSK9 gene for in vivo base editing. Figure 61A is a schematic of an LNP system for tBE-Vl-mA3 or tBE-V5-mA3 and key experimental steps. Figure 61B shows in vivo editing frequencies induced by LNP containing different tBE versions and different doses (mpk, mg of RNA per kg of body weight). DETAILED DESCRIPTION

[00377] All publications, patents, and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[00378] In the present disclosure, unless otherwise specified, the scientific and technical terms used herein have the meanings generally understood by a person skilled in the art. Although any methods and materials similar or equivalent to those described herein find use in the practice of the present disclosure, the preferred methods and materials are described herein. Accordingly, the terms defined herein are more fully described by reference to the Specification as a whole.

[00379] As used herein, the singular terms “a,” “an,” and “the” include the plural reference unless the context clearly indicates otherwise.

[00380] As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.

[00381] Unless the context requires otherwise, the terms “comprise,” “comprises,” and “comprising,” or similar terms are intended to mean a non-exclusive inclusion, such that a recited list of elements or features does not include those stated or listed elements solely, but may include other elements or features that are not listed or stated.

[00382] Unless otherwise indicated, nucleic acids are written left to right in the 5' to 3' orientation, and amino acid sequences are written left to right in amino to carboxy orientation, respectively. A number “n”, when used in the context of an amino acid sequence, refers to the n* amino acid in the amino acid sequence counting from the amino end. For example, “amino acid 15” refers to the 15th amino acid in a certain amino acid sequence. For example, “RI 5” refers to the 15th amino acid, which is an arginine (R), in a certain amino acid sequence.

[00383] It is to be understood that this disclosure is not limited to the particular methodology, protocols, and reagents described, as these may vary, depending upon the context in which they are used by those skilled in the art.

[00384] As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending on the context in which it is used. In some embodiments, the term “about” when referring to a value is meant to encompass art-accepted variations. In some embodiments, the term “about” when referring to such values, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate in the context in which the term “about” is used.

[00385] As used herein, the terms “percent identity” and “% identity,” as applied to nucleic acid or polynucleotide sequences, refer to the percentage of residue matches between at least two nucleic acid or polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.

[00386] Percent identity between nucleic acid or polynucleotide sequences may be determined using a suite of commonly used and freely available sequence comparison algorithms provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403410), which is available from several sources, including the NCBI, Bethesda, Md., and on the Internet at http: / / www.ncbi.nlm.nih.gov / BLAST / .

[00387] Nucleic acid or polynucleotide sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al. (1991) Nucleic Acid Res 19:5081; Ohtsuka et al. (1985) J Biol Chern 260:2605-2608; Cassol et al. (1992); Rossolini et al. (1994) Mol Cell Probes 8:91-98). The term “nucleic acid” refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides which have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. The term nucleic acid is used interchangeably with polynucleotide, and (in appropriate contexts) gene, cDNA, and mRNA encoded by a gene.

[00388] As used herein, “percent (%) amino acid sequence identity” with respect to a peptide, polypeptide or protein sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in another peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Percent amino acid sequence identity in the current disclosure is measured using BLAST software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[00389] An amino acid substitution refers to the replacement of one amino acid in a polypeptide with another amino acid. Amino acid substitutions can be conservative or nonconservative substitutions. Exemplary substitutions are shown in Table 6. Amino acid substitutions may be introduced into a protein of interest and the products screened for a desired activity, for example, retained / improved biological activity. Table 6 Original Residue Exemplary Substitutions Ala (A) Vai; Leu; He Arg (R) Lys; Gin; Asn Asn (N) Gin; His; Asp, Lys; Arg Asp (D) Glu; Asn Cys (C) Ser; Ala Gin (Q) Asn; Glu Glu (E) Asp; Gin Gly (G) Ala His (H) Asn; Gin; Lys; Arg He (I) Leu; Vai; Met; Ala; Phe; Norleucine Leu (L) Norleucine; He; Vai; Met; Ala; Phe Lys (K) Arg; Gin; Asn Met (M) Leu; Phe; He Phe (F) Trp; Leu; Vai; He; Ala; Tyr Pro (P) Ala Ser (S) Thr Thr (T) Vai; Ser Trp(W) Tyr; Phe Tyr(Y) Trp; Phe; Thr; Ser Vai (V) He; Leu; Met; Phe; Ala; Norleucine

[00390] Amino acids may be grouped according to common side-chain properties:

[00391] (1) hydrophobic: Norleucine, Met, Ala, Vai, Leu, He;

[00392] (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; 5

[00393] (3) acidic: Asp, Glu;

[00394] (4) basic: His, Lys, Arg;

[00395] (5) residues that influence chain orientation: Gly, Pro;

[00396] (6) aromatic: Trp, Tyr, Phe.

[00397] The term “nucleic acid” or “polynucleotide” refers to deoxyribonucleic acids 10 (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chern. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).

[00398] The term “polypeptide” is intended to encompass a singular “polypeptide” as well as plural “polypeptides,” and refers to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as peptide bonds). The term “polypeptide” refers to any chain or chains of two or more amino acids, and does not refer to a specific length of the product. Thus, “peptides,” “protein”, or any other term used to refer to a chain or chains of two or more amino acids, are included within the definition of “polypeptide,” and the term “polypeptide” may be used instead of, or interchangeably with any of these terms. The term “polypeptide” is also intended to refer to the products of post-expression modifications of the polypeptide, including without limitation glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, or modification by non- naturally occurring amino acids. A polypeptide may be derived from a natural biological source or produced by recombinant technology, but is not necessarily translated from a designated nucleic acid sequence. It may be generated in any manner, including by chemical synthesis.

[00399] The term “promoter” refers to a nucleic acid sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence.

[00400] As used herein, the term “encode” or “encoding” as it is applied to polynucleotides refers to a polynucleotide which is said to “encode” a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, it can be transcribed and / or translated to produce the mRNA for the polypeptide and / or a fragment thereof. The antisense strand is the complement of such a nucleic acid, and the encoding sequence can be deduced therefrom.

[00401] A “guide RNA” (gRNA) refers to a synthetic or expressed RNA sequence that comprises a CRISPR binding motif and a spacer. In some embodiments, the guide RNA is a single guide RNA. In some embodiments, the guide RNA is a dual-RNA structure. In some embodiments, the guide RNA is a dual-RNA structure formed by a ligand-bound CRISPR RNA (crRNA) and a trans-activating crRNA (tracrRNA). In some embodiments, the guide RNA is a LigoRNA. A “spacer” is a DNA-targeting motif, which is a sequence that is complementary to a target specific DNA region. In some embodiments, the guide RNA is a crRNA-tracrRNA dual RNA structure, and the crRNA comprises the spacer. The CRISPR binding motif of a guide RNA can bind to a Cas enzyme and DNA-targeting motif of the gRNA can guide the complex to a specific target location on a DNA. In some embodiments, the guide RNA is a crRNA-tracrRNA dual RNA structure, and the base-pair structure formed by the crRNA and the tracrRNA comprises the CRISPR binding motif. A guide RNA may further comprise one or more other motifs, such as one or more protein-binding motifs, or the like.

[00402] As used herein, a “fusion protein” is a protein comprising at least two polypeptides that have been joined as a single polypeptide. For example, a fusion protein can comprise two domains that are encoded by separate genes that have been joined so that they are transcribed and translated as a single unit, producing a single polypeptide. In some embodiments, the at least two domains are fused together directly. In some embodiments, the domains are connected by one or more linkers.

[00403] The term “genetic modification” and its grammatical equivalents, as used herein can refer to one or more alterations of a nucleic acid, e.g., the nucleic acid within an organism’s genome. For example, genetic modification can refer to alterations, additions, and / or deletion of genes or portions of genes or other nucleic acid sequences. A genetically modified cell can also refer to a cell with an added, deleted, and / or altered gene or portion of a gene. A genetically modified cell can also refer to a cell with an added nucleic acid sequence that is not a gene or gene portion. Genetic modifications include, for example, both transient knock-in or knock-down mechanisms, and mechanisms that result in permanent knock-in, knock-down, or knock-out of target genes or portions of genes or nucleic acid sequences. Genetic modifications include, for example, both transient knock-in and mechanisms that result in permanent knock-in of nucleic acids sequences. Genetic modifications also include, for example, reduced or increased transcription, reduced or increased mRNA stability, reduced or increased translation, and reduced or increased protein stability.

[00404] “Cleavage” or “cleavable” refers to the breakage of a covalent bond, e.g., of a covalent bond on the backbone of a DNA molecule, or the capability thereof. Cleavage can be initiated by a variety of methods including, but not limited to, enzymatic or chemical hydrolysis of a phosphodiester bond. Both single-stranded cleavage and double-stranded cleavage are possible, and double-stranded cleavage can occur as a result of two distinct single-stranded cleavage events. DNA cleavage can result in the production of either blunt ends or staggered ends.

[00405] Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).

[00406] The term “expression” refers to the transcription and / or translation of a particular nucleotide sequence driven by its promoter.

[00407] The term “effective amount” or “therapeutically effective amount” is used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result. The term “endogenous” refers to any material from or produced inside an organism, cell, tissue or system.

[00408] As used herein, a composition refers to any mixture of two or more products, substances, or compounds, including cells.

[00409] The term “subject” means any animal such as a mammal, e.g., a human.

[00410] The term “transfer vector” or “vector” refers to a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “transfer vector” includes an autonomously replicating plasmid or a virus. The term should also be construed to further include non-plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, a polylysine compound, liposome, and the like. Examples of viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, and the like.

[00411] As used herein, the term “treat,” “treating,” or “treatment” refers to ameliorating a disease or disorder, e.g., slowing or arresting or reducing the development of the disease or disorder or reducing at least one of the clinical symptoms thereof. For example, in some embodiments, ameliorating a disease or disorder can include obtaining a beneficial or desired clinical result that includes, but is not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting or eliminating the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total). As used herein, "regulation " or "regulate " in relation to sene expression refers to any process that increases, decreases, or alters gene expression. For example, regulation of gene expression may be achieved through the modulation or control of transcription or translation of a genetic material.Cardiovascular disease (CVD)

[00412] Cardiovascular disease (CVD) represents a broad category of disorders that affect the heart and blood vessels, encompassing conditions such as coronary artery disease, heart failure, stroke, and peripheral vascular disease. As a leading cause of morbidity and mortality globally, CVD poses significant public health challenges. The intricate interplay of risk factors, including hypertension, dyslipidemia, diabetes, and genetic predispositions, contributes to the multifactorial nature of CVD. The clinical manifestations of CVD range from atherosclerosis-related events, such as myocardial infarction and stroke, to chronic conditions affecting cardiac function and overall cardiovascular health. Since CVD encompasses a broad spectrum of conditions, ongoing research continues to uncover new facets of its complex etiology.

[00413] Proprotein convertase subtilisin / kexin type 9 (PCSK9) is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al., 100(3) Proc. Nat'l Acad. Sci. 928-33 (2003)). PCSK9 is a key regulator of LDL metabolism and a popular LLT target; that the expression or upregulation of PCSK9 is associated with increased plasma levels of LDL cholesterol, that the corresponding inhibition or lack of expression of PCSK9 is associated with reduced LDL cholesterol plasma levels; and that decreased levels of LDL cholesterol are associated with sequence variations in PCSK9 have been found to confer protection against coronary heart disease; Cohen, 2006 N. Engl. J. Med. 354:1264-1272. Loss of function mutations in PCSK9 are associated with reduced LDL-C and risk of coronary heart disease and no apparent adverse health consequences. Till now, treatments with monoclonal antibodies, small interfering RNAs, and antisense oligonucleotides targeting PCSK9 mRNA or protein are already approved. Notably, introducing nonsense mutations in PCSK9 through a lipid nanoparticle (LNP) delivery system resulted in reduction of PCSK9 protein and LDL-C levels in mice, showing the potential of this approach for therapeutic interventions.

[00414] Angiopoietin-like protein 3 (ANGPTL3) is another attractive target for lipid lowering. In vitro analysis of recombinant protein showed that ANGPTL3 directly inhibits lipoprotein lipase (LPL) activity, indicating that it is a lipid metabolism modulator that regulates very low density lipoprotein (VLDL) triglyceride levels through the inhibition of LPL activity (Shimizugawa et al., 2002, J Biol Chern 277(37):33742-33748). By mainly affecting triglyceride-rich lipoproteins, ANGPTL3 reduction might prove complementary to LDL cholesterol lowering with PCSK9 blockade. Targeting ANGPTL3 protein is already approved for the treatment of homozygous familial hypercholesterolemia, which reducing LDL-C in these patients in an LDLR-independent mechanism.

[00415] ASGR1 is the predominant isoform of the asialoglycoprotein receptor, a liverspecific receptor mediating the endocytosis and lysosomal degradation of a variety of desialylated glycoproteins. A large-scale genetic study identified that the loss-of-function ASGR1 variants were associated with low cholesterol and a reduced risk of CVD.

[00416] Lipoprotein(a) (Lp(a)) represents a unique subclass of circulating lipoprotein particles. The metabolism of Lp(a) particles is distinct from that of LDL-C, and currently approved lipid-lowering drugs do not provide substantial reductions in Lp(a), a causal risk factor for CVD. The clinical phase III outcomes study with Pelacarsen targeting the LPA gene indicating its strong candidacy as a CVD treatment target.

[00417] AGT, the upstream precursor in the renin-angiotensin-aldosterone system (RAAS) pathway, plays a pivotal role in blood pressure regulation. Inhibiting AGT synthesis in the liver could lead to durable reductions in AGT protein and, consequently, in the vasoconstrictor angiotensin II. Recognizing the importance of AGT as a therapeutic target, especially for hypertension, demonstrates its potential impact on reducing the leading cause of cardiovascular diseases, including valvular heart disease and atrial fibrillation.

[00418] Aside from the PCSK9 and ANGPTL3 genes associated with lowering LDL-C, the importance of APOC3 in the prevention and treatment of cardiovascular diseases is also gradually gaining attention. APOC3 encodes a protein component of triglyceride (TG)-rich lipoproteins (TRLs) including very low density lipoproteins (VLDL), high density lipoproteins (HDL) and chylomicrons. The encoded protein plays a role in role in the metabolism of these TRLs through multiple modes. This protein has been shown to promote the secretion of VLDL1, inhibit lipoprotein lipase enzyme activity, and delay catabolism of TRL remnants. Mutations in this gene are associated with low plasma triglyceride levels and reduced risk of ischemic cardiovascular disease, and hyperalphalipoproteinemia, which is characterized by elevated levels of high density lipoprotein (HDL) and HDL cholesterol in human patients.

[00419] Gene Editing Systems

[00420] Gene editing systems are known in the art, and include but are not limited to, zinc finger nucleases, transcription activator-like effector nucleases (TALENs); clustered regularly interspaced short palindromic repeats (CRISPR) / Cas systems, and meganuclease systems. Gene editing tools offer a versatile approach for targeting specific genes, enabling precise repair or disruption to address conditions such as familial hypercholesterolemia, dyslipidemia or established CVD. Somatic genome editing has the potential to be a one-time therapy for individuals.

[00421] “CRISPR” or “CRISPR / Cas” as used herein refers to a set of clustered regularly interspaced short palindromic repeats, or a system comprising such a set of repeats. “Cas”, as used herein, refers to a CRISPR-associated protein. The CRISPR / Cas gene editing system, denoting clustered regularly interspaced short palindromic repeats and associated proteins, comprises a prokaryotic immune system prevalent in approximately 40% of eubacteria genomes and 90% of archaea genomes. Initially identified as a defense mechanism against foreign genetic elements, this system has been repurposed for gene editing in eukaryotes like mice and primates. In this modified application, a designed CRISPR and suitable Cas proteins are introduced into the target cells. The CRISPR locus, characterized by alternating repeats and spacers, plays a pivotal role. In the natural prokaryotic setting, these spacers typically contain sequences from foreign genetic elements. However, in eukaryotic gene editing, spacers are derived from the target gene sequence. Constitutively expressed CRISPR locus RNA is processed into small RNAs by Cas proteins, guiding other Cas proteins to silence specific genes at the RNA or DNA level. While the arrangement and structure of CRISPR and Cas genes vary across bacterial species, the CRISPR / Cas9 system, involving a nuclease with dual cutting sites, has gained prominence in eukaryotic gene editing. Utilizing this system enables precise modifications such as addition, replacement, or deletion of base pairs in the target gene, or reversible gene silencing through RNA interference mechanisms. Notably, the Cas9 protein, often derived from Streptococcus pyogenes, is a central player in this versatile and powerful gene editing tool.

[00422] The combination of CRISPR-Cas9 and cytidine deaminases leads to the development of cytosine base editors (CBEs), allowing programmable cytosine to thymine (C-to-T) substitution. This technology has demonstrated successful and efficient editing across various species, holding great potentials in clinical applications. Notably, the base editing process circumvents reliance on DNA double-strand breaks (DSB), thereby minimizing unwanted nucleotide insertions / deletions (indels) and avoiding DNA damage responses (DDRs). The importance of safety and efficiency in gene editing tools for clinical applications is underscored by previous studies revealing that Cas9 nuclease-induced DSBs can activate a p53-mediated DDR pathway, leading to cell death. It is also noted that APOBEC / AID family members can trigger C-to-T base substitutions in single-stranded DNA (ssDNA) regions, which are formed randomly during various cellular processes including DNA replication, repair and transcription. Thus, the specificity of previous base editing systems is compromised, limiting the applications of base editors for therapeutic purposes. In the present disclosure, inventors use a new base editing system, transformer base editor (tBE), which can specifically edit cytosine in target regions with no observable off-target mutations. Transformer base editor (tBE} system

[00423] The term “base editor (BE),” or “nucleobase editor (NBE)” refers to an agent comprising a polypeptide that is capable of making a modification to a base (e.g., A, T, C, G, or U) within a nucleic acid sequence (e.g., DNA or RNA).

[00424] In some embodiments, a base editor as used herein is a cytosine base editor (CBE), which comprises a combination of a CRISPR system and cytidine deaminase. A CBE effectuates a programmable cytosine to thymine (C-to-T) substitution. Because the base editing process does not depend on the generation of DNA double strand break (DSB), unwanted nucleotide insertions / deletions (indels) or DNA damage responses (DDRs) can be largely avoided.

[00425] In some embodiments, a highly specific base editing system, transformer base editor (tBE), is used, which can edit cytosine in target regions with no observable off-target mutations. In some embodiments, the tBE is any one of the base editors described in WO2020156575A1, incorporated herein by reference in its entirety. For instance, the tBE can be any base editor as illustrated in Figure 1.

[00426] In some embodiments, the transformer base editor (tBE) system may contain a cytidine deaminase inhibitor (dCDI) domain and a split-TEV protease(e.g., as illustrated in Figure 1A, V5). Thus, tBE remains inactive at off-target sites with a cleavable fusion of dCDI domain and eliminates unintended off-target mutations. Only when binding at on-target sites, tBE is transformed to cleave off the dCDI domain and catalyzes targeted deamination for precise editing. Specifically, tBE uses one main guide RNA (mgRNA, normally 20 nt) to bind at the target genomic site and one helper guide RNA (hgRNA, normally 10 to 20 nt) to bind at a nearby region (ideally upstream to the target genomic site). The binding of two gRNAs can guide the components of tBE system to correctly assemble at the target genomic site for base editing (Figure IB). tBE can specifically edit cytosine in target regions with no observable off-target mutations, e.g., inducing a premature stop codon to repress, such as PCSK9 protein expression, or breaking the GU-AG rule to disrupt splicing site.

[00427] In some embodiments, the tBE system is used to disrupt PCSK9, ANGPTL3, ASGR1, LPA, AGT or APOC3 gene. In some embodiments, the tBE system is used to disrupt one or more genes selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT, and APOC3 genes. In some embodiments, the tBE system is used to disrupt PCSK9 gene, which leads to reduced level of Low-Density Lipoprotein cholesterol and thereby leads to therapeutic effects against CVD. In some embodiments, the tBE system is used to disrupt ANGPTL3 gene, which leads to reduced level of Low-Density Lipoprotein cholesterol, reduced level of triglyceride-rich remnant particles, and / or reduced level of lipoprotein(a) (Lp(a)), and thereby leads to therapeutic effects against CVD. In some embodiments, the tBE system is used to disrupt ASGR1 gene, which leads to reduced level of Low-Density Lipoprotein cholesterol and 141 thereby leads to therapeutic effects against CVD. In some embodiments, the tBE system is used to disrupt LPA gene, which leads to reduced level of triglyceride-rich remnant particles, and / or reduced level of lipoprotein(a) (Lp(a)), and thereby leads to therapeutic effects against CVD. In some embodiments, the tBE system is used to disrupt AGT gene, which leads to reduced vasoconstrictor angiotensin (Ang) II, and thereby leads to therapeutic effects against CVD. In some embodiments, the tBE system is used to disrupt APOC3 gene, which leads to reduced triglyceride-rich lipoproteins and reduced level of LDL-C, and thereby leads to therapeutic effects against CVD.

[00428] In some embodiments, the base editors and base editing methods described herein can be applied to perform high-specificity and high-efficiency base editing in the genome of various eukaryotes. In some embodiments, the tBE comprises a Cas9 nickase (D10A), which is less toxic to cells than Cas9 nuclease, because Cas9 nickase activates a lower level of p53-mediated DDR. Besides, tBE achieves highly specific and efficient base editing at most sites.

[00429] In an aspect, the present disclosure provides a gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA, wherein the mgRNA comprises an mgRNA spacer of about 20 nucleotides (about 20 nt) that binds to a target site on a target gene and the hgRNA comprises an hgRNA spacer of about 10 to about 20 nt that binds to a site that is close to the target site that the mgRNA spacer binds to.

[00430] In some embodiments, the target gene as described herein includes one or more genes selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT and APOC3 genes.

[00431] In some embodiments, the gene editing system comprises an mgRNA comprising an mgRNA spacer selected from SEQ ID NOs: 213-236, 317-328, and 1128, and an hgRNA comprising an hgRNA spacer of about 10 to about 20 nt, e.g., 7 nt to 23 nt, 8 nt to 22 nt, 9 nt to 21 nt, and 10 nt to 20 nt, that binds to a site close to the target site that the mgRNA spacer binds to. In some embodiments, the gene editing system comprises an hgRNA comprising an hgRNA spacer selected from SEQ ID NOs: 237-316, 329-402, 1129, and 1130. In some embodiments, the gene editing system comprises an mgRNA targeting PCSK9 gene.

[00432] In some embodiments, the gene editing system comprises an mgRNA comprising an mgRNA spacer selected from SEQ ID NOs: 403-429, and 550-552, and an hgRNA comprising an hgRNA spacer of about 10 to about 20 nt, e.g., 7 nt to 23 nt, 8 nt to 22 nt, 9 nt to 21 nt, and 10 nt to 20 nt, that binds to a site close to the target site that the mgRNA spacer binds to. In some embodiments, the gene editing system comprises an hgRNA comprising an hgRNA spacer selected from SEQ ID NOs: 430-549, and 553-562. In some embodiments, the gene editing system comprises an mgRNA targeting ANGPTL3 gene.

[00433] In some embodiments, the gene editing system comprises an mgRNA comprising an mgRNA spacer selected from SEQ ID NOs: 563-584, and 677-684, and an hgRNA comprising an hgRNA spacer of about 10 to about 20 nt, e.g., 7 nt to 23 nt, 8 nt to 22 nt, 9 nt to 21 nt, and 10 nt to 20 nt, that binds to a site close to the target site that the mgRNA spacer binds to. In some embodiments, the gene editing system comprises an hgRNA comprising an hgRNA spacer selected from SEQ ID NOs: 585-676, and 685-716. In some embodiments, the gene editing system comprises an mgRNA targeting ASGR1 gene.

[00434] In some embodiments, the gene editing system comprises an mgRNA comprising an mgRNA spacer selected from SEQ ID NOs: 717-750, and an hgRNA comprising an hgRNA spacer of about 10 to about 20 nt, e.g., 7 nt to 23 nt, 8 nt to 22 nt, 9 nt to 21 nt, and 10 nt to 20 nt, that binds to a site close to the target site that the mgRNA spacer binds to. In some embodiments, the gene editing system comprises an hgRNA comprising an hgRNA spacer selected from SEQ ID NOs: 751-924. In some embodiments, the gene editing system comprises an mgRNA targeting LPA gene.

[00435] In some embodiments, the gene editing system comprises an mgRNA comprising an mgRNA spacer selected from SEQ ID NOs: 925-961, and an hgRNA comprising an hgRNA spacer of about 10 to about 20 nt, e.g., 7 nt to 23 nt, 8 nt to 22 nt, 9 nt to 21 nt, and 10 nt to 20 nt, that binds to a site close to the target site that the mgRNA spacer binds to. In some embodiments, the gene editing system comprises an hgRNA comprising an hgRNA spacer selected from SEQ ID NOs: 962-1105. In some embodiments, the gene editing system comprises an mgRNA targeting AGT gene.

[00436] In some embodiments, the gene editing system comprises an mgRNA comprising an mgRNA spacer selected from SEQ ID NOs: 1249-1251, and an hgRNA comprising an hgRNA spacer of about 10 to about 20 nt, e.g., 7 nt to 23 nt, 8 nt to 22 nt, 9 nt to 21 nt, and 10 nt to 20 nt, that binds to a site close to the target site that the mgRNA spacer binds to. In some embodiments, the gene editing system comprises an hgRNA comprising an hgRNA spacer selected from SEQ ID NOs: 1252-1265. In some embodiments, the gene editing system comprises an mgRNA targeting APOC3 gene.

[00437] In some embodiments, the present disclosure provides a gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA, wherein the mgRNA comprises an mgRNA spacer and the hgRNA comprises an hgRNA spacer, wherein the nucleic acid sequences of the mgRNA spacer and the hgRNA spacer comprise the sequences respectively as set forth in Table 7A-7F. In some embodiments, the present disclosure provides a gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA, wherein the nucleic acid sequences of the mgRNA and the hgRNA comprise the sequences respectively as set forth in Table 8A-8C.

[00438] Table 7A the mgRNA spacer and the hgRNA spacer binding to PCSK9 gene mgRNA Sequence hgRNA mg-hPCSK9- GU1 CCCGCACCUUGGCGCAGCGG (SEQ ID NO: 213) hg-hPCSK9-GUl-Ul UCCCGGCUGCGGGUUCGCCC (SEQ ID NO: 237) hg-hPCSK9-GUl-U2 CACCGCACCGUCCCGGCUGC (SEQ ID NO: 238) hg-hPCSK9-GUl-U3 GAAACAGCACCGCACCGUCC (SEQ ID NO: 239) hg-hPCSK9-GUl-Ul GGGUUCGCCC (SEQ ID NO: 277) hg-hPCSK9-GUl-U2 UCCCGGCUGC (SEQ ID NO: 278) hg-hPCSK9-GUl-U3 CGCACCGUCC (SEQ ID NO: 279) mg-hPCSK9- TGG-1 CAGCGGCCACCAGGACCGCC (SEQ ID NO: 214) hg-hPCSK9-TGGl-Ul UCCUGCGCACGGGCGCCCGC (SEQ ID NO: 240) hg-hPCSK9-TGGl-Ul GGGCGCCCGC (SEQ ID NO: 280) mg-hPCSK9- AG6 ACGGAUCCUGGCCCCAUGCA (SEQ ID NO: 215) hg-hPCSK9-AG6-Ul AGCACCACCACGUAGGUGCC (SEQ ID NO: 241) hg-hPCSK9-AG6-U2 CUCCUUCAGCACCACCACGU (SEQ ID NO: 242) hg-hPCSK9-AG6-Ul CGUAGGUGCC (SEQ ID NO: 281) hg-hPCSK9-AG6-U2 ACCACCACGU (SEQ ID NO: 282) UAGGUGCCAGGCAACCUCCA hg-hPCSK9-M5-Ul mg-hPCSK9-M5 (SEQ ID NO: 216) GCGCUCUGACUGCGAGAGGU (SEQ ID NO: 243) hg-hPCSK9-M5-U2 UGCGCUCUGACUGCGAGAGG (SEQ ID NO: 244) hg-hPCSK9-M5-U3 CAGUGCGCUCUGACUGCGAG (SEQ ID NO: 245) hg-hPCSK9-M5-Ul UGCGAGAGGU (SEQ ID NO: 283) hg-hPCSK9-M5-U2 CUGCGAGAGG (SEQ ID NO: 284) hg-hPCSK9-M5-U3 UGACUGCGAG (SEQ ID NO: 285) mg-hPCSK9- AG7 GAUCCUGGCCCCAUGCAAGG (SEQ ID NO: 217) hg-hPCSK9-AG7-Ul AGCACCACCACGUAGGUGCC (SEQ ID NO: 246) hg-hPCSK9-AG7-U2 CUCCUUCAGCACCACCACGU (SEQ ID NO: 247) hg-hPCSK9-AG7-Ul CGUAGGUGCC (SEQ ID NO: 286) hg-hPCSK9-AG7-U2 CGUAGGUGCC (SEQ ID NO: 287) mg-hPCSK9-M6 CAGGUUCCACGGGAUGCUCU (SEQ ID NO: 218) hg-hPCSK9-M6-Ul CAUCCGCCCGGUACCGUGGA (SEQ ID NO: 248) hg-hPCSK9-M6-U2 GGGGCUGGUAUUCAUCCGCC (SEQ ID NO: 249) hg-hPCSK9-M6-U3 UGGGGGUCUUACCGGGGGGC (SEQ ID NO: 250) hg-hPCSK9-M6-Ul GUACCGUGGA (SEQ ID NO: 288) hg-hPCSK9-M6-U2 UUCAUCCGCC (SEQ ID NO: 289) hg-hPCSK9-M6-U3 ACCGGGGGGC (SEQ ID NO: 290) mg-hPCSK9- M7 CCAGGUUCCACGGGAUGCUC (SEQ ID NO: 219) hg-hPCSK9-M7-Ul CAUCCGCCCGGUACCGUGGA (SEQ ID NO: 251) hg-hPCSK9-M7-U2 GGGGCUGGUAUUCAUCCGCC (SEQ ID NO: 252) hg-hPCSK9-M7-U3 UGGGGGUCUUACCGGGGGGC (SEQ ID NO: 253) hg-hPCSK9-M7-Ul GUACCGUGGA (SEQ ID NO: 291) hg-hPCSK9-M7-U2 UUCAUCCGCC (SEQ ID NO: 292) hg-hPCSK9-M7-U3 ACCGGGGGGC (SEQ ID NO: 293) mg-hPCSK9- AG12 AAGGCCUGCAGAAGCCAGAG (SEQ ID NO: 220) hg-hPCSK9-AG12-Ul GAUGCUCUGGGCAAAGACAG (SEQ ID NO: 254) hg-hPCSK9-AG12-Ul GCAAAGACAG (SEQ ID NO: 294) mg-hPCSK9- GU22 GCUUACCUGUCUGUGGAAGC (SEQ ID NO: 221) hg-hPCSK9-GU22-U 1 CACCUCCAGGAUGGGGAUAU (SEQ ID NO: 255) hg-hPCSK9-GU22-U2 CCACCUCCAGGAUGGGGAUA (SEQ ID NO: 256) hg-hPCSK9-GU22-U 1 AUGGGGAUAU (SEQ ID NO: 295) hg-hPCSK9-GU22-U2 GAUGGGGAUA (SEQ ID NO: 296) mg-hPCSK9- GU23 UGCUUACCUGUCUGUGGAAG (SEQ ID NO: 222) hg-hPCSK9-GU23-Ul CACCUCCAGGAUGGGGAUAU (SEQ ID NO: 257) hg-hPCSK9-GU23-Ul AUGGGGAUAU (SEQ ID NO: 297) mg-hPCSK9- AG26 UGGCCUGCUCGACGAACACA (SEQ ID NO: 223) hg-hPCSK9-AG26-U 1 CGCUGACCACCCCUGCCAGG (SEQ ID NO: 258) hg-hPCSK9-AG26-U2 GGCCGCUGACCACCCCUGCC (SEQ ID NO: 259) hg-hPCSK9-AG26-U 1 CCCUGCCAGG (SEQ ID NO: 298) hg-hPCSK9-AG26-U2 CACCCCUGCC (SEQ ID NO: 299) mg-hPCSK9- AG39 GAUGACCUGGAAAGGUGAGG (SEQ ID NO: 224) hg-hPCSK9-AG39-U 1 AAGUCCCCAGGGUCACCGGC (SEQ ID NO: 260) hg-hPCSK9-AG39-U 1 GGUCACCGGC (SEQ ID NO: 300) mg-hPCSK9- GU47 UACCUGCCCCAUGGGUGCUG (SEQ ID NO: 225) hg-hPCSK9-GU47-Ul AGACCUCCCAAGCCCCAGCC (SEQ ID NO: 261) hg-hPCSK9-GU47-Ul AGCCCCAGCC (SEQ ID NO: 301) mg-hPCSK9- GU48 UUACCUGCCCCAUGGGUGCU (SEQ ID NO: 226) hg-hPCSK9-GU48-Ul AGACCUCCCAAGCCCCAGCC (SEQ ID NO: 262) hg-hPCSK9-GU48-Ul AGCCCCAGCC (SEQ ID NO: 302) mg-hPCSK9- GU49 CUUACCUGCCCCAUGGGUGC (SEQ ID NO: 227) hg-hPCSK9-GU49-U 1 AGACCUCCCAAGCCCCAGCC (SEQ ID NO: 263) hg-hPCSK9-GU49-U 1 AGCCCCAGCC (SEQ ID NO: 303) mg-hPCSK9-M13 CAGCUGCCAACCUGCAAAAA (SEQ ID NO: 228) hg-hPCSK9-M13-Ul ACGGCUGUGGCCAUCCGUGU (SEQ ID NO: 264) hg-hPCSK9-M13-Ul CCAUCCGUGU (SEQ ID NO: 304) mg-hPCSK9- M14 ACAGCUGCCAACCUGCAAAA (SEQ ID NO: 229) hg-hPCSK9-M14-Ul ACGGCUGUGGCCAUCCGUGU (SEQ ID NO: 265) hg-hPCSK9-M14-Ul CCAUCCGUGU (SEQ ID NO: 305) mg-hPCSK9- AG51 CCAACCUGCAAAAAGGGCCU (SEQ ID NO: 230) hg-hPCSK9-AG51-Ul ACGGCUGUGGCCAUCCGUGU (SEQ ID NO: 266) hg-hPCSK9-AG51-Ul CCAUCCGUGU (SEQ ID NO: 306) mg-hPCSK9- AG52 GCCAACCUGCAAAAAGGGCC (SEQ ID NO: 231) hg-hPCSK9-AG52-U 1 ACGGCUGUGGCCAUCCGUGU (SEQ ID NO: 267) hg-hPCSK9-AG52-U 1 CCAUCCGUGU (SEQ ID NO: 307) mg-hPCSK9-AG54 UUGGGCCUUAGAGUCAAAGA (SEQ ID NO: 232) hg-hPCSK9-AG54-U 1 CUCACCCCCAAAAGCGUUGU (SEQ ID NO: 268) hg-hPCSK9-AG54-U 1 AAAGCGUUGU (SEQ ID NO: 308) UCCCAGUGGGAGCUGCAGCC hg-hPCSK9-M17-Ul mg-hPCSK9- M17 (SEQ ID NO: 233) CCUCGUGGCCUCAGCACAGG (SEQ ID NO: 269) hg-hPCSK9-M17-Ul UCAGCACAGG (SEQ ID NO: 309) mg-hPCSK9- GU65 CCUCUUCACCUGCUCCUGAG (SEQ ID NO: 234) hg-hPCSK9-GU65-Ul CUGACACAGAAAAGCUGUGC (SEQ ID NO: 270) hg-hPCSK9-GU65-Ul AAAGCUGUGC (SEQ ID NO: 310) mg-hPCSK9- M19 CAGGGUCCAGCCCUCCUCGC (SEQ ID NO: 235) hg-hPCSK9-M19-Ul GACGUGGGAGGUCCCAGGGA (SEQ ID NO: 271) hg-hPCSK9-M19-U2 CCAGGACGUGGGAGGUCCCA (SEQ ID NO: 272) hg-hPCSK9-M19-U3 GUAGGCCCCCAGGACGUGGG (SEQ ID NO: 273) hg-hPCSK9-M19-U4 UGUCUACGGCGUAGGCCCCC (SEQ ID NO: 274) hg-hPCSK9-M19-Ul GUCCCAGGGA (SEQ ID NO: 311) hg-hPCSK9-M19-U2 GGAGGUCCCA (SEQ ID NO: 312) hg-hPCSK9-M19-U3 AGGACGUGGG (SEQ ID NO: 313) hg-hPCSK9-M19-U4 GUAGGCCCCC (SEQ ID NO: 314) mg-hPCSK9-AG68 CGGUCACCUGCCAGAGCCCG (SEQ ID NO: 236) hg-hPCSK9-AG68-Ul GAGGGCACUGCAGCCAGUCA (SEQ ID NO: 275) hg-hPCSK9-AG68-U2 GACGUGGGAGGUCCCAGGGA (SEQ ID NO: 276) hg-hPCSK9-AG68-Ul CAGCCAGUCA (SEQ ID NO: 315) hg-hPCSK9-AG68-U2 GUCCCAGGGA (SEQ ID NO: 316) mg-mPCSK9- TGG-1 CCGCAGCCACGCAGAGCAGU (SEQ ID NO: 317) hg-mPCSK9-TGG-l-Ul AGCAGCAGCGGCGGCAACAG (SEQ ID NO: 329) hg-mPCSK9-TGG-l-U2 AGCAACAGCAGCAGCAGCGG (SEQ ID NO: 330) hg-mPCSK9-TGG-l-U3 AGCAGCAACAGCAGCAGCAG (SEQ ID NO: 331) hg-mPCSK9-TGG-l-Ul GCGGCAACAG (SEQ ID NO: 366) hg-mPCSK9-TGG-l-U2 GCAGCAGCGG (SEQ ID NO: 367) hg-mPCSK9-TGG-l-U3 GCAGCAGCAG (SEQ ID NO: 368) mg-mPCSK9- AG-3 AGGCCUCCUGAUCCCCAAGA (SEQ ID NO: 318) hg-mPCSK9-AG-3-Ul CUCCAUCAGCACCACAAUGU (SEQ ID NO: 332) hg-mPCSK9-AG-3-U2 UUGUUCAAUCUGUAGCCUCU (SEQ ID NO: 333) hg-mPCSK9-AG-3-Ul ACCACAAUGU (SEQ ID NO: 369) hg-mPCSK9-AG-3-U2 UGUAGCCUCU (SEQ ID NO: 370) mg-mPCSK9-TGG-6 CAGGUUCCAUGGGAUGCUCU (SEQ ID NO: 319) hg-mPCSK9-TGG-6-Ul GGGAGCGGUCUUCCUCUGUC (SEQ ID NO: 334) hg-mPCSK9-TGG-6-U2 UGGGGACCUUACCAGGGGAG (SEQ ID NO: 335) hg-mPCSK9-TGG-6-Ul UUCCUCUGUC (SEQ ID NO: 371) hg-mPCSK9-TGG-6-U2 ACCAGGGGAG (SEQ ID NO: 372) mg-mPCSK9- CAG-20 UCUUCGCCCAGAGCAUCCCA (SEQ ID NO: 320) hg-mPCSK9-C AG-20-U1 GGCCCUGAAGUUGCCCCAUG (SEQ ID NO: 336) hg-mPCSK9-CAG-20-U2 GCCCCAUGUGGAGUACAUUG (SEQ ID NO: 337) hg-mPCSK9-C AG-20-U1 UUGCCCCAUG (SEQ ID NO: 373) hg-mPCSK9-CAG-20-U2 GAGUACAUUG (SEQ ID NO: 374) mg-mPCSK9-AG-7 UCGCCUGAUCAAUCAACACG (SEQ ID NO: 321) hg-mPCSK9-AG-7-Ul GCUGACCACACCUGCCAGGU (SEQ ID NO: 338) hg-mPCSK9-AG-7-U2 CGCUGACCACACCUGCCAGG (SEQ ID NO: 339) hg-mPCSK9-AG-7-U3 GGCCGCUGACCACACCUGCC (SEQ ID NO: 340) hg-mPCSK9-AG-7-Ul CCUGCCAGGU (SEQ ID NO: 375) hg-mPCSK9-AG-7-U2 ACCUGCCAGG (SEQ ID NO: 376) hg-mPCSK9-AG-7-U3 CACACCUGCC (SEQ ID NO: 377) mg-mPCSK9- GU-10 CCUACCUCUGGAGCAGAAGC (SEQ ID NO: 322) hg-mPCSK9-GU-10-Ul AGGCAGCUCGGUCAGCAAGG (SEQ ID NO: 341) hg-mPCSK9-GU-10-U2 CAGGCAGCUCGGUCAGCAAG (SEQ ID NO: 342) hg-mPCSK9-GU-10-U3 CCAGGCAGCUCGGUCAGCAA (SEQ ID NO: 343) hg-mPCSK9-GU-10-U4 CCCAGGCAGCUCGGUCAGCA (SEQ ID NO: 344) hg-mPCSK9-GU-10-Ul GUCAGCAAGG (SEQ ID NO: 378) hg-mPCSK9-GU-10-U2 GGUCAGCAAG (SEQ ID NO: 379) hg-mPCSK9-GU-10-U3 CGGUCAGCAA (SEQ ID NO: 380) hg-mPCSK9-GU-10-U4 UCGGUCAGCA (SEQ ID NO: 381) mg-mPCSK9- AG-22 GACCUGGCAUGGUAAAGGAG (SEQ ID NO: 323) hg-mPCSK9-AG-22-Ul CAAGGUAACUGGCUGGUCCU (SEQ ID NO: 345) hg-mPCSK9-AG-22-U2 CCAAGGUAACUGGCUGGUCC (SEQ ID NO: 346) hg-mPCSK9-AG-22-U3 AAGUCCCCAAGGUAACUGGC (SEQ ID NO: 347) hg-mPCSK9-AG-22-U4 CCCAAAGUCCCCAAGGUAAC (SEQ ID NO: 348) hg-mPCSK9-AG-22-U5 AUUAGUCCCCAAAGUCCCCA (SEQ ID NO: 349) hg-mPCSK9-AG-22-Ul GGCUGGUCCU (SEQ ID NO: 382) hg-mPCSK9-AG-22-U2 UGGCUGGUCC (SEQ ID NO: 383) hg-mPCSK9-AG-22-U3 GGUAACUGGC (SEQ ID NO: 384) hg-mPCSK9-AG-22-U4 CCAAGGUAAC (SEQ ID NO: 385) hg-mPCSK9-AG-22-U5 AAAGUCCCCA (SEQ ID NO: 386) mg-mPCSK9- GU-11 CUCACCUGUCUCAUGGGUGC (SEQ ID NO: 324) hg-mPCSK9-GU-ll-Ul UGUGAGGCCAGGGCAGGGGC (SEQ ID NO: 350) hg-mPCSK9-GU-ll-U2 UUCCUGUGAGGCCAGGGCAG (SEQ ID NO: 351) hg-mPCSK9-GU-ll-U3 CCUUCCUGUGAGGCCAGGGC (SEQ ID NO: 352) hg-mPCSK9-GU-ll-U4 AAAACCUUCCUGUGAGGCCA (SEQ ID NO: 353) hg-mPCSK9-GU-ll-U5 GGAAAGAAAACCUUCCUGUG (SEQ ID NO: 354) hg-mPCSK9-GU-ll-Ul GGGCAGGGGC (SEQ ID NO: 387) hg-mPCSK9-GU-ll-U2 GCCAGGGCAG (SEQ ID NO: 388) hg-mPCSK9-GU-ll-U3 AGGCCAGGGC (SEQ ID NO: 389) hg-mPCSK9-GU-ll-U4 UGUGAGGCCA (SEQ ID NO: 390) hg-mPCSK9-GU-ll-U5 CCUUCCUGUG (SEQ ID NO: 391) mg-mPCSK9- CAG-16 UUCAGAGCAGGUGAAGGAGU (SEQ ID NO: 325) hg-mPCSK9-CAG-16-Ul AGGGCUGGAAUGCAAAAUCA (SEQ ID NO: 355) hg-mPCSK9-C AG-16-U2 CUGCUGCCAUGCCCCAGGGC (SEQ ID NO: 356) hg-mPCSK9-CAG-16-Ul UGCAAAAUCA (SEQ ID NO: 392) hg-mPCSK9-C AG-16-U2 GCCCCAGGGC (SEQ ID NO: 393) mg-mPCSK9- AG-17 GACCUGCCAGAGUCCAGAGA (SEQ ID NO: 326) hg-mPCSK9-AG-17-Ul GAGCACAUUGCAUCCAGUCA (SEQ ID NO: 357) hg-mPCSK9-AG-17-U2 GGAGCACAUUGCAUCCAGUC (SEQ ID NO: 358) hg-mPCSK9-AG-17-U3 CCAGAGUGAGGGAUGCCCCA (SEQ ID NO: 359) hg-mPCSK9-AG-17-Ul CAUCCAGUCA (SEQ ID NO: 394) hg-mPCSK9-AG-17-U2 GCAUCCAGUC (SEQ ID NO: 395) hg-mPCSK9-AG-17-U3 GGAUGCCCCA (SEQ ID NO: 396) mg-mPCSK9- TGG-18 CAGGGUCCAUCCUGCUUCGC (SEQ ID NO: 327) hg-mPCSK9-TGG-18-Ul CCAGAGUGAGGGAUGCCCCA (SEQ ID NO: 360) hg-mPCSK9-TGG-18-U2 CCCAGAGUGAGGGAUGCCCC (SEQ ID NO: 361) hg-mPCSK9-TGG-18-U3 GCUGUAGGCUCCCAGAGUGA (SEQ ID NO: 362) hg-mPCSK9-TGG-18-U4 CGCUGUAGGCUCCCAGAGUG (SEQ ID NO: 363) hg-mPCSK9-TGG-18-Ul GGAUGCCCCA (SEQ ID NO: 397) hg-mPCSK9-TGG-18-U2 GGGAUGCCCC (SEQ ID NO: 398) hg-mPCSK9-TGG-18-U3 CCCAGAGUGA (SEQ ID NO: 399) hg-mPCSK9-TGG-18-U4 UCCCAGAGUG (SEQ ID NO: 400) mg-mPCSK9- CAG-19 GUUCAGUGACAGCCUCAGGC (SEQ ID NO: 328) hg-mPCSK9-CAG-19-Ul CUGCCAUCUGCUGCCGGAGC (SEQ ID NO: 364) hg-mPCSK9-CAG-19-U2 UAGCUGCUGCCAUCUGCUGC (SEQ ID NO: 365) hg-mPCSK9-CAG-19-Ul CUGCCGGAGC (SEQ ID NO: 401) hg-mPCSK9-CAG-19-U2 CAUCUGCUGC (SEQ ID NO: 402) mg-monPCSK9 CAGGTTCCATGGGATGCTCT (SEQ ID NO: 1128) hg-monPCSK9 GGGGCTGGTATTCATCCGCC (SEQ ID NO: 1129) hg-monPCSK9 TTCATCCGCC (SEQ ID NO: 1130)

[00439] Table 7B the mgRNA spacer and the hgRNA spacer binding to ANGPTL3 gene mgRNA Sequence hgRNA mg-hANGPTL3-l GGCCUCCUUCAGUUGGGACA (SEQ ID NO: 403) hg-hANGPTL3-l-Ul CCAGAGCCAAAAUCAAGAUU (SEQ ID NO: 430) hg-hANGPTL3-l-U2 GCCAAAAUCAAGAUUUGCUA (SEQ ID NO: 431) hg-hANGPTL3-l-U3 AGAUUUGCUAUGUUAGACGA (SEQ ID NO: 432) hg-hANGPTL3-l-Ul AAUCAAGAUU (SEQ ID NO: 490) hg-hANGPTL3-l-U2 AGAUUUGCUA (SEQ ID NO: 491) hg-hANGPTL3-l-U3 UGUUAGACGA (SEQ ID NO: 492) mg-hANGPTL3-2 UUUCAAAAACUCAACAUAUU (SEQ ID NO: 404) hg-hANGPTL3-2-Ul GGCCUCCUUCAGUUGGGACA (SEQ ID NO: 433) hg-hANGPTL3-2-U2 AGACUUUGUCCAUAAGACGA (SEQ ID NO: 434) hg-hANGPTL3-2-Ul AGUUGGGACA (SEQ ID NO: 493) hg-hANGPTL3-2-U2 CAUAAGACGA (SEQ ID NO: 494) CUGCAAACCAGUGAAAUCAA hg-hANGPTL3-3-Ul mg-hANGPTL3-3 (SEQ ID NO: 405) UUUCAAAAACUCAACAUAUU (SEQ ID NO: 435) hg-hANGPTL3-3-U2 AAAACUCAACAUAUUUGAUC (SEQ ID NO: 436) hg-hANGPTL3-3-Ul UCAACAUAUU (SEQ ID NO: 495) hg-hANGPTL3-3-U2 AUAUUUGAUC (SEQ ID NO: 496) mg-hANGPTL3-4 ACUACAAGUCAAAAAUGAAG (SEQ ID NO: 406) hg-hANGPTL3-4-Ul UGAAAUCAAAGAAGAAGAAA (SEQ ID NO: 437) hg-hANGPTL3-4-Ul GAAGAAGAAA (SEQ ID NO: 497) mg-hANGPTL3-5 CAACAAAAAGUGAAAUAUUU (SEQ ID NO: 407) hg-hANGPTL3-5-Ul GAGGUAAAGAAUAUGUCACU (SEQ ID NO: 438) hg-hANGPTL3-5-U2 CUUGAACUCAACUCAAAACU (SEQ ID NO: 439) hg-hANGPTL3-5-U3 AACUCAACUCAAAACUUGAA (SEQ ID NO: 440) hg-hANGPTL3-5-Ul AUAUGUCACU (SEQ ID NO: 498) hg-hANGPTL3-5-U2 ACUCAAAACU (SEQ ID NO: 499) hg-hANGPTL3-5-U3 AAAACUUGAA (SEQ ID NO: 500) mg-hANGPTL3-6 CAAAAUCAACCUGAAACUCC (SEQ ID NO: 408) hg-hANGPTL3-6-Ul AAAAUUCUACUUCAACAAAA (SEQ ID NO: 441) hg-hANGPTL3-6-U2 CAACAAAAAGUGAAAUAUUU (SEQ ID NO: 442) hg-hANGPTL3-6-U3 AAAAGUGAAAUAUUUAGAAG (SEQ ID NO: 443) hg-hANGPTL3-6-Ul UUCAACAAAA (SEQ ID NO: 501) hg-hANGPTL3-6-U2 UGAAAUAUUU (SEQ ID NO: 502) hg-hANGPTL3-6-U3 UAUUUAGAAG (SEQ ID NO: 503) mg-hANGPTL3-7 ACUUUAAGUGAAGUUACUUC (SEQ ID NO: 409) hg-hANGPTL3-7-Ul CCACAUUGAAAACAUAAACA (SEQ ID NO: 444) hg-hANGPTL3-7-U2 UUUUUUUAAAAGAUCCACAU (SEQ ID NO: 445) hg-hANGPTL3-7-U3 UUAGAAAUAUUUUUUUUAAA (SEQ ID NO: 446) hg-hANGPTL3-7-Ul AACAUAAACA (SEQ ID NO: 504) hg-hANGPTL3-7-U2 AGAUCCACAU (SEQ ID NO: 505) hg-hANGPTL3-7-U3 UUUUUUUAAA (SEQ ID NO: 506) mg-hANGPTL3-8 UUUCUACUUACUUUAAGUGA (SEQ ID NO: 410) hg-hANGPTL3-8-Ul CCACAUUGAAAACAUAAACA (SEQ ID NO: 447) hg-hANGPTL3-8-U2 UUUUUUUAAAAGAUCCACAU (SEQ ID NO: 448) hg-hANGPTL3-8-U3 UUAGAAAUAUUUUUUUUAAA (SEQ ID NO: 449) hg-hANGPTL3-8-Ul AACAUAAACA (SEQ ID NO: 507) hg-hANGPTL3-8-U2 AGAUCCACAU (SEQ ID NO: 508) hg-hANGPTL3-8-U3 UUUUUUUAAA (SEQ ID NO: 509) mg-hANGPTL3-9 AAAGUCUGGAUAUAGAGAGU (SEQ ID NO: 411) hg-hANGPTL3-9-Ul GGUCUUCCACGGUCUGGAGA (SEQ ID NO: 450) hg-hANGPTL3-9-U2 UAUAUUGGUCUUCCACGGUC (SEQ ID NO: 451) hg-hANGPTL3-9-U3 UUGUUUAUAUUGGUCUUCCA (SEQ ID NO: 452) hg-hANGPTL3-9-Ul GGUCUGGAGA (SEQ ID NO: 510) hg-hANGPTL3-9-U2 UUCCACGGUC (SEQ ID NO: 511) hg-hANGPTL3-9-U3 UGGUCUUCCA (SEQ ID NO: 512) mg-hANGPTL3- 10 AAACAAGAUAAUAGCAUCAA (SEQ ID NO: 412) hg-hANGPTL3-10-Ul GAAAUUAAUAGAAAAGAAAG (SEQ ID NO: 453) hg-hANGPTL3-10-Ul GAAAAGAAAG (SEQ ID NO...

Claims

1. A gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA,wherein the mgRNA comprises an mgRNA spacer and the hgRNA comprises an hgRNA spacer of about 10 to about 20 nucleotides, wherein the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 213-236, 317-328, and 1128;wherein the mgRNA spacer is capable of binding to a target sequence located in PCSK9 gene; andwherein the hgRNA spacer is capable of binding to a site on the PCSK9 gene that is close to the target sequence of the mgRNA spacer.

2. The gene editing system of claim 1, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 213, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 237-239, and 277279;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 214, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 240 and 280;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 215, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 241-242, and 281282;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 216, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 243-245, and 283285;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 217, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 246-247, and 286287;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 218, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 248-250, and 288290;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 219, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 251-253, and 291293;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 220, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 254 and 294;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 221, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 255-256, and 295296;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 222, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 257 and 297;when mgRNA spacer comprises a sequence represented by SEQ ID NO: 223, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 258-259, and 298299;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 224, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 260 and 300;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 225, the hgRNA spacer comprises a sequence selected from SEQ ID NO: 261 and 301;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 226, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 262 and 302;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 227, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 263 and 303;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 228, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 264 and 304;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 229, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 265 and 305;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 230, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 266 and 306;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 231, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 267 and 307;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 232, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 268 and 308;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 233, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 269 and 309;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 234, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 270 and 310;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 235, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 271-274 and 311314;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 236, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 275-276 and 315316;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 317, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 329-331 and 366368;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 318, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 332-333 and 369370;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 319, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 334-335 and 371372;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 320, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 336-337 and 373374;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 321, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 338-340 and 375377;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 322, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 341-344 and 378381;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 323, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 345-349 and 382386;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 324, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 350-354 and 387391;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 325, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 355-356 and 392393;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 326, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 357-359 and 394396;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 327, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 360-363 and 397400;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 328, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 364-365 and 401-402;andwhen the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1128, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1129 and 1130.

3. The gene editing system according to claim 1 or 2, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 218, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 248-250, and 288290.when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 319, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 334-335, and 371372.when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1128, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1129 and 1130.

4. The gene editing system according to claim 1 or 2, whereinwhen the mgRNA comprises a sequence represented by SEQ ID NO: 1109, the hgRNA comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122 and 1123;when the mgRNA comprises a sequence represented by SEQ ID NO: 1110, the hgRNA comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122 and 1123;when the mgRNA comprises a sequence represented by SEQ ID NO: 1119, the hgRNA comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122 and 1123;when the mgRNA comprises a sequence represented by SEQ ID NO: 1121, the hgRNA comprises a sequence selected from SEQ ID NOs: 1108, 1118, 1120, 1122 and 1123;when the mgRNA comprises a sequence represented by SEQ ID NO: 1125, the hgRNA comprises a sequence represented by SEQ ID NOs: 1124; andwhen the mgRNA comprises a sequence represented by SEQ ID NO: 1127, the hgRNA comprises a sequence represented by SEQ ID NOs: 1126.

5. A gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA,wherein the mgRNA comprises an mgRNA spacer and the hgRNA comprises an hgRNA spacer of about 10 to about 20 nucleotides, wherein the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 403-429 and 550-552;wherein the mgRNA spacer is capable of binding to a target sequence located in ANGPTL3 gene; andwherein the hgRNA spacer is capable of binding to a site on the ANGPTL3 gene that is close to the target sequence of the mgRNA spacer.

6. The gene editing system of claim 5, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 403, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 430-432 and 490492;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 404, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 433-434 and 493494;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 405, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 435-436 and 495496;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 406, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 437 and 497;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 407, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 438-440 and 498500;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 408, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 441-443 and 501503;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 409, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 444-446 and 504506;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 410, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 447-449 and 507509;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 411, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 450-452 and 510512;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 412, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 453 and 513;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 413, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 454-456 and 514516;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 414, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 457-458 and 517518;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 415, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 459-461 and 519521;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 416, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 462-463 and 522523;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 417, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 464-465 and 524525;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 418, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 466-468 and 526528;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 419, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 469-470 and 529530;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 420, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 471-472 and 531532;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 421, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 473 and 533;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 422, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 474-475 and 534535;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 423, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 476-477 and 538;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 424, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 478 and 538;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 425, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 479-481 and 539541;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 426, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 482-484 and 542544;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 427, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 485 and 545;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 428, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 486-487 and 546547;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 429, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 488-489 and 548549;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 550, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 553 and 558;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 551, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 554-555 and 559-560;andwhen the mgRNA spacer comprises a sequence represented by SEQ ID NO: 552, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 556-557 and 561562.

7. The gene editing system according to claim 5 or 6, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 406, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 437 and 497;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 551, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 554-555 and 559560.

8. The gene editing system according to claim 5 or 6, wherein:when the mgRNA comprises a sequence represented by SEQ ID NO: 1132, the hgRNA comprises a sequence represented by SEQ ID NO: 1131;when the mgRNA comprises a sequence represented by SEQ ID NO: 1134, the hgRNA comprises a sequence represented by SEQ ID NO: 1133; andwhen the mgRNA comprises a sequence represented by SEQ ID NO: 1136, the hgRNA comprises a sequence represented by SEQ ID NOs: 1135.

9. A gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA,wherein the mgRNA comprises an mgRNA spacer and the hgRNA comprises an hgRNA spacer of about 10 to about 20 nucleotides, wherein the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 563-584 and 677-684;wherein the mgRNA spacer is capable of binding to a target sequence located in ASGR1 gene; andwherein the hgRNA spacer is capable of binding to a site on the ASGR1 gene that is close to the target sequence of the mgRNA spacer.

10. The gene editing system of claim 9, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 563, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 585 and 631;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 564, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 586 and 632;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 565, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 587-588 and 633634;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 566, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 589-590 and 635636;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 567, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 591-593 and 637639;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 568, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 594-596 and 640642;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 569, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 597-598 and 643644;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 570, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 599-601 and 645647;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 571, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 602-604 and 648650;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 572, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 605-606 and 651652;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 573, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 607-608 and 653654;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 574, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 609-610 and 655656;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 575, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 611-612 and 657658;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 576, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 613-614 and 659660;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 577, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 615-616 and 661662;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 578, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 617-619 and 663665;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 579, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 620-622 and 666668;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 580, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 623-625 and 669671;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 581, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 626 and 672;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 582, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 627 and 673;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 583, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 628 and 674;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 584, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 629-630 and 675676;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 677, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 685-687 and 701703;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 678, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 688-689 and 704705;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 679, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 690-691 and 706707;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 680, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 692-693 and 708709;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 681, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 694 and 710;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 682, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 695-696 and 711712;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 683, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 697-698 and 713-714;andwhen the mgRNA spacer comprises a sequence represented by SEQ ID NO: 684, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 699-700 and 715716.

11. The gene editing system according to claim 9 or 10, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 563, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 585 and 631;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 569, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 597-598 and 643644;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 570, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 599, and 645.when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 584, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 629-630 and 675676;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 677, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 685-687 and 701703;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 680, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 692-693 and 708709;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 681, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 694 and 710; andwhen the mgRNA spacer comprises a sequence represented by SEQ ID NO: 683, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 697-698 and 713714.

12. A gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA,wherein the mgRNA comprises an mgRNA spacer and the hgRNA comprises an hgRNA spacer of about 10 to about 20 nucleotides, wherein the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 717-750;wherein the mgRNA spacer is capable of binding to a target sequence located in LPA gene; andwherein the hgRNA spacer is capable of binding to a site on the LPA gene that is close to the target sequence of the mgRNA spacer.

13. The gene editing system of claim 12, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 717, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 751-755 and 838842;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 718, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 756-760 and 843847;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 719, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 761-765 and 848852;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 720, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 766-769 and 853856;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 721, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 770-773 and 857860;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 722, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 774-775 and 861862;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 723, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 776-778 and 863865;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 724, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 779 and 866;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 725, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 780-782 and 867869;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 726, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 783-785 and 870872;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 727, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 786-788 and 873875;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 728, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 789 and 876;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 729, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 790-792 and 877879;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 730, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 793 and 880;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 731, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 794-795 and 881882;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 732, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 796-798 and 883885;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 733, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 799 and 886;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 734, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 800-802 and 887889;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 735, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 803-804 and 890891;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 736, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 805-806 and 892893;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 737, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 807 and 894;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 738, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 808 and 895;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 739, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 809-810 and 896897;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 740, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 811-813 and 898900;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 741, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 814-815 and 901902;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 742, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 816-818 and 903905;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 743, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 819-820 and 906907;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 744, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 821-823 and 908910;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 745, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 824-825 and OH-912;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 746, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 826-828 and 913915;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 747, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 829-831 and 916918;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 748, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 932-833 and 919920;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 749, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 834 and 921; andwhen the mgRNA spacer comprises a sequence represented by SEQ ID NO: 750, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 835-837 and 922924.

14. The gene editing system according to claim 12 or 13, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 735, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 803 and 890;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 741, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 814 and 901; andwhen the mgRNA spacer comprises a sequence represented by SEQ ID NO: 743, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 820 and 907.

15. A gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA,wherein the mgRNA comprises an mgRNA spacer and the hgRNA comprises an hgRNA spacer of about 10 to about 20 nucleotides, wherein the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 925-961;wherein the mgRNA spacer is capable of binding to a target sequence located in AGT gene; andwherein the hgRNA spacer is capable of binding to a site on the AGT gene that is close to the target sequence of the mgRNA spacer.

16. The gene editing system of claim 15, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 925, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 962-964 and 10341036;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 926, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 965-966 and 10371038;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 927, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 967-968 and 10391040;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 928, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 969-970 and 10411042;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 929, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 971-972 and 10431044;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 930, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 973-974 and 10451046;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 931, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 975-977 and 10471049;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 932, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 978-980 and 10501052;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 933, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 981 and 1053;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 934, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 982-984 and 10541056;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 935, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 985-987 and 10571059;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 936, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 988-989 and 10601061;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 937, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 990-991 and 10621063;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 938, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 992-993 and 10641065;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 939, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 994-995 and 10661067;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 940, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 996-997 and 10681069;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 941, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 998-999 and 10701071;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 942, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1000-1001 and 1072-1073;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 943, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1002-1003 and 1074-1075;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 944, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1004-1005 and 1076-1077;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 945, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1006-1007 and 1078-1079;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 946, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1008-1009 and 1080-1081;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 947, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1010-1011 and 1082-1083;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 948, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1012 and 1084;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 949, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1013 and 1085;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 950, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1014-1015 and 1086-1087;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 951, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1016-1017 and 1088-1089;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 952, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1018-1019 and 1090-1091;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 953, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1020 and 1092;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 954, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1021-1022 and 1093-1094;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 955, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1023 and 1095;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 956, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1024 and 1096;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 957, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1025-1026 and 1097-1098;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 958, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1027-1028 and 1099-1100;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 959, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1029-1030 and 1101-1102;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 960, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1031 and 1103; andwhen the mgRNA spacer comprises a sequence represented by SEQ ID NO: 961, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1032-1033 and 1104-1105.

17. The gene editing system according to claim 15 or 16, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 925, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 962 and 1034;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 932, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 978-980 and 10501052;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 935, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 986 and 1058; andwhen the mgRNA spacer comprises a sequence represented by SEQ ID NO: 947, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1010 and 1082.

18. A gene editing system comprising a main guide RNA (mgRNA) and a helper guide RNA (hgRNA), or at least one DNA polynucleotide encoding the mgRNA and / or the hgRNA,wherein the mgRNA comprises an mgRNA spacer and the hgRNA comprises an hgRNA spacer of about 10 to about 20 nucleotides, wherein the nucleic acid sequence of the mgRNA spacer comprises a sequence selected from SEQ ID NOs: 1249-1251;wherein the mgRNA spacer is capable of binding to a target sequence located in APOC3 gene; andwherein the hgRNA spacer is capable of binding to a site on the APOC3 gene that is close to the target sequence of the mgRNA spacer.

19. The gene editing system of claim 18, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1249, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1252-1254, and 1259-1261;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1250, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1255-1256, and 1262-1263;when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1251, the hgRNA spacer comprises a sequence selected from SEQ ID NOs: 1257-1258, and 1264-1265.

20. The gene editing system according to claim 18 or 19, wherein:when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1266, the hgRNA spacer comprises a sequence selected from SEQ ID NO: 1267.when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1268, the hgRNA spacer comprises a sequence selected from SEQ ID NO: 1269.when the mgRNA spacer comprises a sequence represented by SEQ ID NO: 1270, the hgRNA spacer comprises a sequence selected from SEQ ID NO: 1271.

21. The gene editing system according to claim 18 or 19, whereinwhen the mgRNA comprises a sequence represented by SEQ ID NO: 1272, the hgRNA comprises a sequence selected from SEQ ID NO: 1273;when the mgRNA comprises a sequence represented by SEQ ID NO: 1274, the hgRNA comprises a sequence selected from SEQ ID NO: 1275;when the mgRNA comprises a sequence represented by SEQ ID NO: 1276, the hgRNA comprises a sequence selected from SEQ ID NO: 1277.

22. The gene editing system of any one of claims 1-21, comprising:a. the hgRNA comprising a CRISPR motif, the hgRNA spacer, and a first protein-binding motif, or a DNA polynucleotide encoding the hgRNA,b. the mgRNA comprising a second CRISPR motif and the mgRNA spacer, or a DNA polynucleotide encoding the mgRNA,c. a first CRISPR-associated protein (Cas protein), or a polynucleotide encoding the first Cas protein, wherein the first Cas protein is capable of binding to the first CRISPR motif,d. a second Cas protein, or a polynucleotide encoding the second Cas protein, wherein the second Cas protein is capable of binding to the second CRISPR motif,e. a first fusion protein comprising a nucleobase deaminase or a catalytic domain thereof and a first RNA binding domain, or a polynucleotide encoding the first fusion protein, wherein the nucleobase deaminase or the catalytic domain thereof and the first RNA binding domain are optionally connected by a linker, and wherein the first RNA binding domain is capable of binding to the first protein-binding motif.wherein the first Cas protein and second Cas protein are the same or different.

23. The gene editing system of claim 22, further comprising:a. a protease, or a polynucleotide encoding the protease, andb. a nucleobase deaminase inhibitor domain,wherein the nucleobase deaminase inhibitor domain is connected to the nucleobase deaminase or the catalytic domain thereof in the first fusion protein optionally by a linker, and wherein there is a cleavage site for the protease between the nucleobase deaminase inhibitor domain and the nucleobase deaminase or the catalytic domain thereof.

24. The gene editing system of claim 23, further comprising:a second fusion protein comprising the protease and a second RNA binding domain, or a polynucleotide encoding the second fusion protein,wherein the protease and the second RNA binding domain are optionally connected by a linker,wherein the mgRNA further comprises a second protein-binding motif,and wherein the second RNA binding domain binds to the second protein-binding motif.

25. The gene editing system of claim 23, wherein the protease is split into a first protease fragment and a second protease fragment, wherein the first and / or second protease fragment alone is not able to cleave the cleavage site.

26. The gene editing system of claim 25, further comprising:a. a second fusion protein comprising the first protease fragment and a second RNA binding domain, or a polynucleotide encoding the second fusion protein, wherein the first protease fragment and the second RNA binding domain are optionally connected by a linker, andb. a third fusion protein comprising the second protease fragment and a third RNA binding domain, or a polynucleotide encoding the third fusion protein, wherein the second protease fragment and the third RNA binding domain are optionally connected by a linker,wherein the mgRNA further comprises a second protein-binding motif and a third protein-binding motif,wherein the second RNA binding domain is capable of binding to the second protein-binding motif, andwherein the third RNA binding domain is capable of binding to the third proteinbinding motif.

27. The gene editing system of claim 26, wherein the second and third RNA binding domains are the same or different, and the second and third protein-binding motifs are the same or different.

28. The gene editing system of claim 25, further comprising:a second fusion protein comprising the first protease fragment and a second RNA binding domain, or a polynucleotide encoding the second fusion protein,wherein the first protease fragment and the second RNA binding domain are optionally connected by a linker,wherein the mgRNA further comprises a second protein-binding motif, andwherein the second RNA binding domain is capable of binding to the second proteinbinding motif.

29. The gene editing system of any one of claims 19-24, wherein the protease is a TEV protease, a TuMV protease, a PPV protease, a PVY protease, a ZIKV protease, or a WNV protease.

30. The gene editing system in claim 29, wherein the protease is a TEV protease comprising a sequence of SEQ ID NO: 195.

31. The gene editing system in claim 30, wherein the first TEV protease fragment comprises a sequence of SEQ ID NO: 196 or 197.

32. The gene editing system in any one of claims 23-31, wherein the nucleobase deaminase inhibitor is an inhibitory domain of a nucleobase deaminase.

33. The gene editing system in any one of claims 23-32, wherein the nucleobase deaminase inhibitor is an inhibitory domain of a cytidine deaminase.

34. The gene editing system in claim 33, wherein the inhibitory domain of a cytidine deaminase comprises an amino acid sequence selected from SEQ ID NO: 1145-1234.

35. The gene editing system in claim 33, wherein the inhibitory domain of a cytidine deaminase comprises an amino acid sequence selected from SEQ ID NO: 1145 and 1146.

36. The gene editing system in any one of claims 22-35, wherein the nucleotide deaminase of the first fusion protein is a cytidine deaminase.

37. The gene editing system in claim 36, wherein the cytidine deaminase is selected from the group consisting of APOBEC3A (A3A), APOBEC3B (A3B), APOBEC3C (A3C), APOBEC3D (A3D), APOBEC3F (A3F), APOBEC3G (A3G), APOBEC3H (A3H), APOBEC 1 (Al), APOBEC3 (A3), APOBEC2 (A2), APOBEC4 (A4), and AICDA (AID).

38. The gene editing system in claim 36, wherein the cytidine deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 159-194.

39. The gene editing system in claim 36, wherein the cytidine deaminase is a human cytidine deaminase, a monkey cytidine deaminase, or mouse cytidine deaminase.

40. The gene editing system in claim 39, wherein the catalytic domain of the cytidine deaminase is a mouse A3 cytidine deaminase domain 1 (mA3-CDAl) or human A3B cytidine deaminase domain 2 (hA3B-CDA2).

41. The gene editing system in claim 40, wherein the catalytic domain has at least 85% sequence identity to amino acid residues 35-141 of SEQ ID NO: 1143 and comprises at least one substitution, relative to SEQ ID NO: 1143, at a residue selected from the group consisting of Y35, K40, W102, and N66 or a combination thereof.

42. The gene editing system of claim 41, wherein the substitution is selected from the group consisting of Y35D, K40H, W102Y, N66A, N66L, N66V and N66Q or a combination thereof.

43. The gene editing system of claim 41, wherein the substitution is Y35D.

44. The gene editing system of claim 41, wherein the catalytic domain comprises the amino acid sequence of SEQ ID NO: 1235.

45. The gene editing system of claim 41, wherein the substitution is K40H and W102Y.

46. The gene editing system of claim 41, wherein the catalytic domain comprises the amino acid sequence of SEQ ID NO: 1236.

47. The gene editing system of claim 41, wherein the substitution is K40H.

48. The gene editing system of claim 41, wherein the catalytic domain comprises the amino acid sequence of SEQ ID NO: 1237.

49. The gene editing system of claim 41, wherein the substitution is N66A.

50. The gene editing system of claim 41, wherein the catalytic domain comprises the amino acid sequence of SEQ ID NO: 1238.

51. The gene editing system of claim 41, wherein the substitution is N66L.

52. The gene editing system of claim 41, wherein the catalytic domain comprises the amino acid sequence of SEQ ID NO: 1239.

53. The gene editing system of claim 41, wherein the substitution is N66V.

54. The gene editing system of claim 41, wherein the catalytic domain comprises the amino acid sequence of SEQ ID NO: 1240.

55. The gene editing system of claim 41, wherein the substitution is N66Q.

56. The gene editing system of claim 41, wherein the catalytic domain comprises the amino acid sequence of SEQ ID NO: 1241.

57. The gene editing system in any one of claims 22-35, wherein the nucleotide deaminase of the first fusion protein is an adenosine deaminase.

58. The gene editing system in claim 57, wherein the adenosine deaminase is selected from tRNA-specific adenosine deaminase (TadA), adenosine deaminase tRNA specific 1 (ADAT1), adenosine deaminase tRNA specific 2 (ADAT2), adenosine deaminase tRNA specific 3 (ADAT3), adenosine deaminase RNA specific Bl (ADARBI), adenosine deaminase RNA specific B2 (ADARB2), adenosine monophosphate deaminase 1 (AMPD1), adenosine monophosphate deaminase 2 (AMPD2), adenosine monophosphate deaminase 3 (AMPD3), adenosine deaminase (ADA), adenosine deaminase 2 (ADA2), adenosine deaminase like (ADAL), adenosine deaminase domain containing 1 (ADAD1), adenosine deaminase domain containing 2 (ADAD2), and adenosine deaminase RNA specific (ADAR).

59. The gene editing system in claim 58, wherein the adenosine deaminase comprises an amino acid sequence selected from SEQ ID NO: 66-158.

60. The gene editing system of any one of claims 22-59, wherein the first fusion protein further comprises an uracil glycosylase inhibitor (UGI).

61. The gene editing system of any one of claims 22-60, wherein the Cas protein is Cas9, a dead Cas9 (dCas9), or a Cas9 nickase (nCas9) selected from the group consisting of SpCas9, FnCas9, StlCas9, St3Cas9, NmCas9, SaCas9, AsCpfl, LbCpfl, FnCpfl, VQR Cas9, EQR Cas9, VRER Cas9, Cas9-NG, xCas9, eCas9, SpCas9-HFl, HypaCas9, HiFiCas9, sniper-Cas9, SpG, SpRY, KKH SaCas9, CjCas9, Cas9-NRRH, Cas9-NRCH, Cas9-NRTH, SsCpfl, PcCpfl, BpCpfl, LiCpfl, PmCpfl, Lb2Cpfl, PbCpfl, PeCpfl, PdCpfl, MbCpfl, EeCpfl, CmtCpfl, BsCpfl, BhCasl2b, AkCasl2b, BsCasl2b, AmCasl2b, AaCasl2b, RfxCasl3d, LwaCasl3a, PspCasl3b, PguCasl3b, and RanCasl3b.

62. The gene editing system of any one of claims 22-61, wherein the first protein-binding RNA motif and the first RNA binding domain, the second protein-binding RNA motif and the second RNA binding domain, and the third protein-binding RNA motif and the third RNA binding domain, are each independently selected from the group consisting of: a MS2 phage operator stem- loop and MS2 coat protein (MCP) or an RNA-binding section thereof,a BoxB and N22P or an RNA-binding section thereof,a telomerase Ku binding motif and Ku protein or an RNA-binding section thereof,a telomerase Sm7 binding motif and Sm7 protein or an RNA-binding section thereof,a PP7 phage operator stem - loop and PP7 coat protein (PCP) or an RNA-binding section thereof,a SfMu phage Com stem-loop and Com RNA binding protein or an RNA-binding section thereof, anda non-natural RNA aptamer and corresponding aptamer ligand or an RNA-binding section thereof.

63. The gene editing system of any one of claims 1-62, wherein the mgRNA and / or the hgRNA comprise a dual-RNA structure.

64. The gene editing system of claim 63, wherein the dual-RNA structure is formed by a CRISPR RNA (crRNA) and a trans-activating crRNA (tracrRNA), wherein the crRNA comprises the spacer.

65. The gene editing system of claim 63 or 64, wherein the mgRNA comprises a mcrRNA and a first tracrRNA, and the mcrRNA comprises the mgRNA spacer, wherein the hgRNA comprises a hcrRNA and a second tracrRNA, and the hcrRNA comprises the hgRNA spacer, and wherein the first tracrRNA and the second tracrRNA are same or different.

66. The gene editing system of claim 65, wherein the mcrRNA and the hcrRNA area. SEQ ID NO: 1112 and SEQ ID NO: 1111, respectively; orb. SEQ ID NO. 1114 and SEQ ID NO: 1113, respectively; orc. SEQ ID NO. 1116 and SEQ ID NO: 1115, respectively.

67. The gene editing system of claim 65, wherein the mcrRNA and the hcrRNA area.  SEQ ID NO. 1138 and SEQ ID NO: 1137, respectively; orb. SEQ ID NO. 1140 and SEQ ID NO: 1139, respectively; orc. SEQ ID NO. 1142 and SEQ ID NO: 1141, respectively.

68. The gene editing system of any one of claims 64-67, wherein the tracrRNA is SEQ IDNO: 1117 and 1242.

69. A polynucleotide encoding the hgRNA and / or the mgRNA in any one of claims 1-21.

70. A polynucleotide encoding all components except the first and the second Cas proteins in the gene editing system in any one of claims 22-69.

71. A polynucleotide encoding all components except the mgRNA and hgRNA in the gene editing system in any one of claims 22-69.

72. A polynucleotide encoding all components except the mgRNA, hgRNA, and the first and second Cas proteins in the gene editing system in any one of claims 22-69.

73. A kit comprisinga. the polynucleotide in claim 70,b. a polynucleotide encoding the first and / or second Cas protein in any one of claims 22-68.

74. A kit comprising the polynucleotide in claim 69 and the polynucleotide in claims 71.

75. A kit comprising the polynucleotide in claim 72 and a polynucleotide encoding the mgRNA, hgRNA and the first and / or second Cas protein in any one of claims 22-68.

76. A vector comprising the polynucleotide in claim 69.

77. A vector comprising the polynucleotide in claim 70.

78. A vector comprising the polynucleotide in claim 71.

79. A vector comprising the polynucleotide in claim 72.

80. The vector of any one of claim 76-79, wherein the vector is selected from a plasmid, a viral vector, and a lipid nanoparticle (LNP) vector, or a non-viral vector.

81. The vector of any one of claims 76-79, wherein the vector is an AAV vector.

82. A kit comprising:a. the vector in claim any one of claim 76-79,b. a vector comprising the polynucleotide encoding the first and / or second Cas protein in any one of claims 22-68.

83. A cell comprising the gene editing system in any one of claims 1-68.

84. A cell comprising the polynucleotide of claim 69 or 72.

85. The cell in claim 84, further comprising a polynucleotide encoding the first and / or second Cas protein in any one of claims 22-68.

86. A cell comprising the vector in any one of claims 76-79.

87. The cell in claim 86, further comprising a vector comprising a polynucleotide encoding the first and / or second Cas protein in any one of claims 22-68.

88. The cell of any one of claims 83-87, wherein the cell is a stem cell.

89. The cell in claim 88, wherein the stem cell is a pluripotent stem cell.

90. The cell in claim 89, wherein the pluripotent stem cell is an induced pluripotent stem cell (iPSC) or an embryonic stem cell.

91. The cell of any one of claims 83-87, wherein the cell is a somatic cell.

92. The cell in any one of claims 83-87, wherein the cell is a hepatocyte.

93. The cell in any one of claims 83-92, wherein the cell is a primary cell or a differentiated cell.

94. A composition comprising the gene editing system in any one of claims 1-68.

95. A composition comprising the cell in any one of claims 83-93.

96. A method for disrupting or regulating the expression of a gene selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT, and APOC3 gene in a cell, comprising introducing into the cell the gene editing system in any one of claims 1-68.

97. A method for disrupting or regulating the expression of PCSK9 gene in a cell, comprising introducing into the cell the gene editing system in any one of claims 1-4.

98. A method for disrupting or regulating the expression of ANGPTL3 gene in a cell, comprising introducing into the cell the gene editing system in any one of claims 5-8.

99. A method for disrupting or regulating the expression of ASGR1 gene in a cell, comprising introducing into the cell the gene editing system in any one of claims 911.

100. A method for disrupting or regulating the expression of LPA gene in a cell, comprising introducing into the cell the gene editing system in any one of claims 1214.

101. A method for disrupting or regulating the expression of AGT gene in a cell, comprising introducing into the cell the gene editing system in any one of claims 1517.

102. A method for disrupting or regulating the expression of APOC3 gene in a cell, comprising introducing into the cell the gene editing system in any one of claims 1821.

103. A method for disruption or regulation the expression of two or more genes selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT, and APOC3 gene in a cell, comprising introducing into the cell two or more gene editing systems,wherein when the two or more genes include the PCSK9 gene, the two or more gene editing systems include the gene editing systems in any one of claims 1-4,wherein when the two or more genes include the ANGPTL3 gene, the two or more gene editing systems include the gene editing systems in any one of claims 5-8,wherein when the two or more genes include the ASGR1 gene, the two or more gene editing systems include the gene editing systems in any one of claims 9-11,wherein when the two or more genes include the LPA gene, the two or more gene editing systems include the gene editing systems in any one of claims 12-14,wherein when the two or more genes include the AGT gene, the two or more gene editing systems include the gene editing systems in any one of claims 15-17,wherein when the two or more genes include the APOC3 gene, the two or more gene editing systems include the gene editing systems in any one of claims 18-21.

104. The method of claim 103, wherein the expression of two genes selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT, and APOC3 gene are disrupted or regulated.

105. The method of claim 104, wherein the two genes are PCSK9 gene and ANGPTL3 gene.

106. The method of claim 103, wherein the expression of three genes selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT, and APOC3 gene are disrupted or regulated.

107. A method for regulating Low-Density Lipoprotein cholesterol (LDL-C) metabolism in a subject, comprising introducing into a cell of the subject the gene editing system according to any one of claims 1-11 and 18-21.

108. A method for treating hypercholesterolemia in a subject, comprising introducing into a cell of the subject a therapeutically effective amount of the gene editing system according to any one of claims 1-11 and 18-21.

109. A method for lowering LDL-C level in a subject, comprising introducing into a cell of the subject the gene editing system according to any one of claims 1-11 and 18-21.

110. A method for regulating triglyceride-rich remnant particles and / or lipoprotein(a) (Lp(a)) metabolism in a subject, comprising introducing into a cell of the subject the gene editing system according to any one of claims 9-14 and 18-21.

111. A method for lowering the level of triglyceride-rich remnant particles and / or lipoprotein(a) (Lp(a)) in a subject, comprising introducing into a cell of the subject the gene editing system according to any one of claims 9-14 and 18-21.

112. A method for regulating blood pressure in a subject, comprising introducing into a cell of the subject the gene editing system according to any one of claims 15-17.

113. A method for reducing the expression of angiotensinogen in a subject, comprising introducing into a cell of the subject the gene editing system according to any one of claims 15-17.

114. A method for treating hypertension in a subject, comprising introducing into a cell of the subject a therapeutically effective amount of the gene editing system according to any one of claims 15-17.

115. A method for treating cardiovascular disease (CVD) in a subject, comprising introducing into the subject a therapeutically effective amount of the gene editing system according to any one of claims 1-68.

116. A method for treating cardiovascular disease (CVD), comprising lowering blood lipid level with a method of claim 109, lowering the level of circulating lipoprotein particles with a method of claim 111, or lowering blood pressure with a method of claim 113.

117. The method in claim 116, wherein the cardiovascular disease is associated with the expression of genes selected from PCSK9, ANGPTL3, ASGR1, LPA, AGT, and APOC3 gene.

118. The method in claim 116, wherein the cardiovascular disease is selected from atherosclerosis, congestive heart failure, peripheral vascular disease, cerebrovascular disease, rheumatic heart disease, arrhythmia, hypertension, and coronary artery disease.

119. The method in any one of claims 96-114, wherein the cell is a stem cell.

120. The method in claim 119, wherein the stem cell is a pluripotent stem cell.

121. The method in claim 120, wherein the pluripotent stem cell is an inducedpluripotent stem cell (iPSC) or an embryonic stem cell.5       122. The method in any one of claims 96-114, wherein the cell is somatic cell.

123. The method in any one of claims 96-114, wherein the cell is a hepatocyte.

124. The method in any one of claims 96-114, wherein the cell is a primary cell or a differentiated cell.

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