Compositions and methods for altering complement activation

Abstract

Compositions and methods for reducing complement activation by introducing one or more alterations into a complement factor B (CFB) polynucleotide in a cell. In particular embodiments, the invention of the disclosure features a base editor system (e.g., a fusion protein or complex comprising a programmable DNA binding protein, a nucleobase editor, and gRNA) for modifying a CFB polynucleotide, where the modification is associated with reduced expression, and / or reduced activity of the CFB polypeptide encoded by the polynucleotide.

Description

[0001] ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 COMPOSITIONS AND METHODS FOR ALTERING COMPLEMENT ACTIVATION CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Application No. 63 / 601,145 filed November 20, 2023, the entire contents of which are hereby incorporated by reference in its entirety. SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The Sequence Listing XML file, created on November 20, 2024, is named 180802-055803PCT_SL.xml and is 4,134,393 bytes in size. BACKGROUND The complement system is an important part of the innate immune system and is involved in the clearance of microbes and cellular debris, as well as the activation of inflammation and diverse immune pathways. Overactivation of the complement system or inappropriate targeting to one’s own cells can lead to disease; however, inhibition of complement system activity has been successfully and safely shown to provide therapeutic benefit for patients suffering from an overactive complement system. Therefore, improved methods for reducing complement system activation in such patients are of interest. SUMMARY As described below, the present disclosure features compositions and methods for reducing complement activation by introducing one or more alterations into a complement factor B (CFB) polynucleotide in a cell. In particular embodiments, the invention of the disclosure features a base editor system (e.g., a fusion protein or complex comprising a programmable DNA binding protein, a nucleobase editor, and gRNA) for modifying a CFB polynucleotide, where the modification is associated with reduced expression, and / or reduced activity of the factor B polypeptide encoded by the polynucleotide. Non-limiting examples of alterations include base edits. In another aspect, the disclosure provides a method of treating a disease or disorder associated with inappropriate activation of the complement system in a subject in need ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 thereof. The method involves altering a nucleobase of a complement factor B (CFB) polynucleotide in the subject by administering to the subject one or more guide polynucleotides, or one or more polynucleotides encoding the one or more guide polynucleotides, and a base editor containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a deaminase domain, or one or more polynucleotides encoding the base editor. The method involves (a), (b), (c), and / or (d), where in (a) the one or more guide polynucleotides targets the base editor to effect an alteration of a nucleobase of the CFB polynucleotide that: i. disrupts a splice site in the CFB polynucleotide, ii. alters a start codon in the CFB polynucleotide, iii. alters a TATA box in the CFB polynucleotide, iv. introduces a new stop codon in the CFB polynucleotide, and / or v. alters a nucleobase in a codon encoding an amino acid residue within a region of the CFB polypeptide encoded by the CFB polynucleotide selected from one or more of: serine protease (SP) active site, Mg2+binding loop, cleavage site, salt bridge, and oxyanion-hole. In (b) the deaminase domain contains a TadA variant (TadA*) containing an amino acid sequence having at least 90% sequence identity to the following TadA*7.10 amino acid sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), or a fragment thereof lacking only the N-terminal methionine, where the TadA* further contains a combination of amino acid alterations compared to the TadA*7.10 amino acid sequence selected from one or more of: i. Y123H, Y147R, and Q154R, ii. I76Y, Y133H, Y147R, and Q154R, iii. V82S, and Q164R, iv. I76Y, V82S, Y123H, Y147R, and Q154R, v. I76Y, V82T, Y123H, Y147R, and Q154R, and vi. I76Y, V82T, Y123H, Y147T, and Q154S. In (c) the one or more guide polynucleotides contain a nucleic acid sequence containing at least 10-23 contiguous nucleotides of a spacer nucleic acid sequence selected from CCUCAGAUGUCUAUGUGUUU (SEQ ID NO: 1524),UGCUUACAAUGACUGAGAUCU (SEQ ID NO: 1535),UUGCUCCCCAUGGCGUUGGA (SEQ ID NO: 3476), CCCCAUGGCGUUGGAAGGCA (SEQ ID NO: 3443), andUGCUCCCCAUGGCGUUGGAA (SEQ ID NO: 3467) and / or listed in any one of Tables 2A to 2H. In (d) the one or more guide polynucleotides targets the base editor to effect an alteration of a nucleobase in one or more codons encoding an amino acid residue selected from one or more of amino acid residue 1, 171, 175, 176, 177, 202, 203, 229, 230, 231, 232, 233, 254, 255, 256, 257, 258, 259, 260, 275, 276, 277, 278, 279, 280, 281, 351, 353, 354, 389, 470, 471, 472, 525, 526, 529, 574, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 575, 576, 696, 697, and 699 relative to the following complement factor B reference amino acid sequence: MGSNLSPQLCLMPFILGLLSGGVTTTPWSLAQPQGSCSLEGVEIKGGSFRLLQEGQALEYVC PSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVS DEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDS VTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAE DGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYG LVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDV PPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLV NQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQ AKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPN YNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKE ELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLC TGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHIN LFQVLPWLKEKLQDEDLGFL (SEQ ID NO: 426), or a corresponding position in another CFB polypeptide sequence. The method results in altering the nucleobase of the CFB polynucleotide. In another aspect, the disclosure provides a method of treating a disease or disorder associated with inappropriate activation of the complement system in a subject in need thereof. The method involves altering a nucleobase of a complement factor B (CFB) polynucleotide in the subject by administering to the subject one or more guide polynucleotides, or one or more polynucleotides encoding the guide polynucleotides, and a base editor containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a deaminase domain, or one or more polynucleotides encoding the base editor. The method involves (a) and (b), where in (a) the deaminase domain contains a cytidine deaminase or a TadA variant (TadA*) containing an amino acid sequence having at least 90% sequence identity to the following TadA*7.10 amino acid sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), or a fragment thereof lacking only the N-terminal methionine, where the TadA* further contains a combination of amino acid alterations compared to the TadA*7.10 amino acid sequence selected from one or more of: i. Y123H, Y147R, and Q154R, ii. I76Y, Y133H, Y147R, and Q154R, iii. V82S, and Q164R, iv. I76Y, V82S, Y123H, Y147R, and Q154R, v. I76Y, V82T, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Y123H, Y147R, and Q154R, and vi. I76Y, V82T, Y123H, Y147T, and Q154S. In (b) the one or more guide polynucleotides contain a spacer containing a nucleotide sequence selected from one or more of: AGGUGAUUCUGGCGGCCCCU (SEQ ID NO: 1719; gRNA1536), CGCCAGAAUCACCUGCAAGG (SEQ ID NO: 1715; gRNA1532), CUAUGACGUUGCCCUGAUCA (SEQ ID NO: 1723; gRNA1540), UGCUCCCCAUGGCGUUGGAA (SEQ ID NO: 3467; gRNA3657), UUGCUCCCCAUGGCGUUGGA (SEQ ID NO: 3476; gRNA3658), CCCCAUGGCGUUGGAAGGCA (SEQ ID NO: 3443; gRNA3660), CCUCAGAUGUCUAUGUGUUU (SEQ ID NO: 1524; TSBTx3826), GCUUACAAUGACUGAGAUCU (SEQ ID NO: 1534; TSBTx3837), UGCUUACAAUGACUGAGAUCU (SEQ ID NO: 1535; TSBTx3837), and UCUCACCUCUGCAAGUAUUG (SEQ ID NO: 1529; TSBTx3835). The method results in treating the disease or disorder associated with inappropriate activation of the complement system in the subject. In any aspect or embodiment of the disclosure, the splice site is located near the 3ʹ end of Exon 1, Exon 10, Exon 11, Exon 12, Exon 14, Exon 15, or Exon 16 of the CFB polynucleotide. In any aspect or embodiment of the disclosure, the splice site is located near the 5ʹ end of Exon 5, Exon 8, Exon 9, Exon 10, Exon 11, Exon 14, or Exon 18 or the CFB polynucleotide. In any aspect or embodiment of the disclosure, the one or more guide polynucleotides target the base editor to effect an alteration of a nucleobase in a codon encoding an amino acid residue selected from one or more of M1, P171, V177, R203, E232, E255, K258, R259, K260, D276, S278, S280, T353, D389, E471, H526, Y575, D576, G697, and S699 relative to the following complement factor B reference amino acid sequence: MGSNLSPQLCLMPFILGLLSGGVTTTPWSLAQPQGSCSLEGVEIKGGSFRLLQEGQALEYVC PSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVS DEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDS VTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAE DGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYG LVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDV PPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLV NQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQ AKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPN ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 YNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKE ELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLC TGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHIN LFQVLPWLKEKLQDEDLGFL (SEQ ID NO: 426). In any aspect or embodiment of the disclosure, the one or more guide polynucleotides contain a spacer complementary to both a human CFB polynucleotide and a non-human primate CFB polynucleotide. In any aspect or embodiment of the disclosure, the one or more guide polynucleotides contains a spacer complementary to a human CFB polynucleotide but not to a non-human primate CFB polynucleotide. In any aspect or embodiment of the disclosure, the one or more guide polynucleotides contain a spacer containing only 20 or 21 nucleotides. In any aspect or embodiment of the disclosure, the one or more guide polynucleotides contain a spacer containing a nucleotide sequence selected from one or more of:AGGUGAUUCUGGCGGCCCCU (SEQ ID NO: 1719; gRNA1536), CGCCAGAAUCACCUGCAAGG (SEQ ID NO: 1715; gRNA1532), CUAUGACGUUGCCCUGAUCA (SEQ ID NO: 1723; gRNA1540), UGCUCCCCAUGGCGUUGGAA (SEQ ID NO: 3467; gRNA3657), UUGCUCCCCAUGGCGUUGGA (SEQ ID NO: 3476; gRNA3658), CCCCAUGGCGUUGGAAGGCA (SEQ ID NO: 3443; gRNA3660), CCUCAGAUGUCUAUGUGUUU (SEQ ID NO: 1524; TSBTx3826), GCUUACAAUGACUGAGAUCU (SEQ ID NO: 1534; TSBTx3837), UGCUUACAAUGACUGAGAUCU (SEQ ID NO: 1535; TSBTx3837) and UCUCACCUCUGCAAGUAUUG (SEQ ID NO: 1529; TSBTx3835). In any aspect or embodiment of the disclosure, the deaminase domain is an adenosine deaminase containing the TadA*7.10 amino acid sequence further containing a combination of amino acid alterations selected from one or more of: i. Y123H, Y147R, and Q154R, ii. I76Y, Y133H, Y147R, and Q154R, iii. V82S, and Q164R, iv. I76Y, V82S, Y123H, Y147R, and Q154R, v. I76Y, V82T, Y123H, Y147R, and Q154R, and vi. I76Y, V82T, Y123H, Y147T, and Q154S. In any aspect or embodiment of the disclosure, the napDNAbp is a nickase. In any aspect or embodiment of the disclosure, the napDNAbp binds a protospacer adjacent motif (PAM) selected from one or more ofNGA,NGC,NGG, andNNNRRT, where “N” is any nucleotide and “R” is A or G. In any aspect or embodiment of the disclosure, the napDNAbp is a Cas9 polypeptide. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 In any aspect or embodiment of the disclosure, the one or more guide polynucleotides contain a modified nucleotide. In any aspect or embodiment of the disclosure, the one or more guide polynucleotides contain a sequence selected from one or more of: End-mod SpCas9 guide polynucleotide mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCU AGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU (SEQ ID NO: 440); End-mod SaCas9 guide polynucleotide mNsmNsmNsNNNNNNNNNNNNNNNNNNGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUA CUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU (SEQ ID NO: 441); HM01: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmUmAmGmAmAmAmUmAmGmCAAGU UAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGmUmGmGmCmAmCmCmG mAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 440); HM07: mNsmNsmNsmNmNmNmNmNmNmNNNNNNNNNNNmGUUUUAGmAmGmCmUmAmGmAmAmAmUm AmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUmGmAmAm AmAmAmGmUmGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 440); NLS (bpsv40): mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCU AGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmUsmUsmUsmU-NHC6-CrossL- ac- CKRTADGSEFESPKKKRKV (SEQ ID NOs: 440 and 446); LONGEST: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGUGmG mCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 445); NLS + LONGEST: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGmUmG mGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU-NHC5-CrossL- CKRTADGSEFESPKKKRKV (SEQ ID NOs: 445 and 446); and ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 LONGEST + GOLD: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAmUmCAAmCmUmUGGACUUCGGUCCmAmAm GUGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 447); where “N” represents any nucleotide, “mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following nucleotide by a phosphorothioate (PS), and where the number of N nucleotides is between 15 and 25. In any aspect or embodiment of the disclosure, the nucleobase alteration effects an alteration to an encoded amino acid residue that results in disruption of Mg2+binding to the CFB polypeptide encoded by the CFB polynucleotide. In any aspect or embodiment of the disclosure, the nucleobase alteration effects an alteration to an encoded amino acid residue that results in a reduction or elimination of serine protease activity of the CFB polypeptide encoded by the CFB polynucleotide. In any aspect or embodiment of the disclosure, the nucleobase alteration effects an alteration to an encoded amino acid residue that eliminates a salt bridge of the CFB polypeptide encoded by the CFB polynucleotide. In any aspect or embodiment of the disclosure, the nucleobase alteration effects an alteration to an encoded amino acid residue that reduces cleavage of the CFB polypeptide encoded by the CFB polynucleotide by a factor D polypeptide. In any aspect or embodiment of the disclosure, the CFB polynucleotide is in a cell. In any aspect or embodiment of the disclosure, the cell is a mammalian cell. In any aspect or embodiment of the disclosure, the cell is a retinal cell or other cell of the eye, a nerve cell, or a hepatocyte. In any aspect or embodiment of the disclosure, the one or more guide polynucleotides target the base editor to effect an alteration of the nucleobase of the CFB polynucleotide that disrupts a splice site in the CFB polynucleotide. In any aspect or embodiment of the disclosure, the napDNAbp is a nickase. In any aspect or embodiment of the disclosure, the napDNAbp binds a protospacer adjacent motif (PAM) selected from one or more of NGA,NGC,NGG, andNNNRRT, where “N” is any nucleotide and “R” is A or G. In any aspect or embodiment of the disclosure, the napDNAbp is a Cas9 polypeptide. In any aspect or embodiment of the disclosure, CFB activity, protein concentration, and / or mRNA concentration is reduced by at least about 15% as compared to a control ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 subject without the alteration. In any aspect or embodiment of the disclosure, the inappropriate activation of the complement system is associated with increased levels of one or more of inflammation, the presence of autoantibodies, neural degeneration, and microthrombosis. In any aspect or embodiment of the disclosure, the inappropriate activation of the complement system is associated with damage to the central nervous system (CNS), the eyes, the gastrointestinal system, the pulmonary system, the musculoskeletal system, the circulatory system, the integumentary system, blood cells, thyroid, kidney, joints, gastrointestinal system, or transplanted organs. In any aspect or embodiment of the disclosure, the disease or disorder is selected from one or more of acute antibody-mediated rejection, age-related macular degeneration, allergic bronchopulmonary aspergillosis, allergic neuritis, allergic rhinitis, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), anaphylaxis, scleritis, atopic dermatitis, atypical hemolytic syndrome (aHUS), autoimmune hemolytic anemia, Bechet’s disease, bronchiolitis, IC-MPGN / C3 glomerulopathy, central nervous system (CNS) inflammatory disorders, choroidal neovascularization (CNV), choroiditis, chronic allograft vasculopathy, chronic hepatitis, chronic muscle inflammation, chronic pain, chronic pancreatitis, chronic urticaria, Churg-Strauss syndrome, conjunctivitis, cyclitis, demyelinating disease, dermatitis, dermatomyositis, diabetic retinopathy, encephalitis, eosinophilic pneumonia, geographic atrophy, giant cell arteritis, glaucoma, glomerulonephritis, graft or transplant rejection or failure, HELLP syndrome, Henoch- Schonlein purpura, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), IgA nephropathy (IgAN), inflammatory bowel diseases, inflammatory joint conditions, inflammatory skin diseases, infusion reactions, interstitial pneumonia, iridocyclitis, iritis, ischemia / reperfusion injury, Kawasaki disease, keratitis, lupus nephritis, membranoproliferative glomerulonephritis (MPGN), meningitis, microscopic polyangiitis, myasthenia gravis, myocarditis, nasal polyposis, neuromyelitis optica, neuropathic pain, ocular inflammation, osteoarthritis, pancreatitis, panniculitis, paroxysmal nocturnal hemoglobinuria (PNH), pars planitis, pemphigoid, pemphigus, polyarteritis nodosa, polymyositis, primary membranous nephropathy, proliferative vitreoretinopathy, proteinuria, psoriasis, pulmonary fibrosis, renal disease, respiratory distress syndrome, retinal neovascularization (RNV), retinopathy of prematurity, rheumatoid arthritis (RA), rhinosinusitis, sarcoid, sarcoidosis, scleritis, scleroderma, sclerodermatomyositis, sclerosis, Sjögren syndrome, systemic lupus erythematosus, systemic scleroderma, Takayasu's arteritis, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Tautopathies, thyroiditis, thyroidoisis, ulcerative colitis, uveitis, vasculitis, and Wegener’s granulomatosis. In any aspect or embodiment of the disclosure, the administration is local administration to an eye, to spinal fluid, or to the liver. In any aspect or embodiment of the disclosure, the CFB polynucleotide is contacted with two or more guide polynucleotides, and where each guide polynucleotide binds a different location within the CFB polynucleotide. In any aspect or embodiment of the disclosure, the subject is a mammal. In any aspect or embodiment of the disclosure, the deaminase domain contains a cytidine deaminase or a TadA variant (TadA*) containing an amino acid sequence having at least 90% sequence identity to the following TadA*7.10 amino acid sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), where the TadA* further contains a combination of amino acid alterations compared to the TadA*7.10 amino acid sequence selected from one or more of: i. Y123H, Y147R, and Q154R, ii. I76Y, Y133H, Y147R, and Q154R, iii. V82S, and Q164R, iv. I76Y, V82S, Y123H, Y147R, and Q154R, v. I76Y, V82T, Y123H, Y147R, and Q154R, and vi. I76Y, V82T, Y123H, Y147T, and Q154S. In any aspect provided herein, or embodiments thereof, the method is not a process for modifying the germline genetic identity of human beings. In any aspect provided herein, or embodiments thereof, the adenosine deaminase domain contains a combination of mutations selected from those listed in Table 5G. Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 By “adenine” or “ 9H-Purin-6-amine” is meant a purine nucleobase with the molecular formula C H N , having t 5 5 5 he structure , and corresponding to CAS No.73-24-5. By “adenosine” or “ 4-Amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl]pyrimidin-2(1H)-one” is meant an adenine molecule attached to a ribose sugar via a glycosidic bond, having the structure , and corresponding to CAS No.65-46-3. Its molecular formula is C10H13N5O4. By “adenosine deaminase” or “adenine deaminase” is meant a polypeptide or fragment thereof capable of catalyzing the hydrolytic deamination of adenine or adenosine. In some embodiments, the deaminase or deaminase domain is an adenosine deaminase catalyzing the hydrolytic deamination of adenosine to inosine or deoxy adenosine to deoxyinosine. In some embodiments, the adenosine deaminase catalyzes the hydrolytic deamination of adenine or adenosine in deoxyribonucleic acid (DNA). The adenosine deaminases (e.g., engineered adenosine deaminases, evolved adenosine deaminases) provided herein may be from any organism (e.g., eukaryotic, prokaryotic), including but not limited to algae, bacteria, fungi, plants, invertebrates (e.g., insects), and vertebrates (e.g., amphibians, mammals). In some embodiments, the adenosine deaminase is an adenosine deaminase variant with one or more alterations and is capable of deaminating both adenine and cytosine in a target polynucleotide (e.g., DNA, RNA) and may be referred to as a “dual deaminase”. Non-limiting examples of dual deaminases include those described in PCT / US22 / 22050. In some embodiments, the target polynucleotide is single or double stranded. In some embodiments, the adenosine deaminase variant is capable of deaminating both adenine and cytosine in DNA. In some embodiments, the adenosine deaminase variant is capable of deaminating both adenine and cytosine in single-stranded DNA. In some embodiments, the ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 adenosine deaminase variant is capable of deaminating both adenine and cytosine in RNA. In embodiments, the adenosine deaminase variant is selected from those described in PCT / US2020 / 018192, PCT / US2020 / 049975, PCT / US2017 / 045381, PCT / US2021 / 016827, PCT / US2022 / 073781, PCT / US24 / 34189, or PCT / US2020 / 028568, the full contents of which are each incorporated herein by reference in their entireties for all purposes. Further non- limiting examples of adenosine deaminases include those disclosed or referenced in Rufflow, et al., “Design of highly functional genome editors by modeling of the universe of CRISPR- Cas Sequences,” bioRxiv, posted April 22, 2024, doi: 10.1101 / 2024.04.22.590591, the disclosure of which is incorporated herein by reference in its entirety for all purposes, which were designed using artificial intelligence. Further exemplary adenosine deaminase amino acid sequenes include: TadA-8e (SEQ ID NO: 3575), Tad1 (SEQ ID NO: 3576), Tad2 (SEQ ID NO: 3577), Tad3 (SEQ ID NO: 3578), Tad4 (SEQ ID NO: 3579), Tad6 (SEQ ID NO: 3580), Tad6-SR (SEQ ID NO: 3581), TadA9 (SEQ ID NO: 3582), TadA20 (SEQ ID NO: 3583), Staphylococcus aureus TadA (SEQ ID NO: 3584), Bacillus subtilis TadA (SEQ ID NO: 3585), Salmonella typhimurium TadA (SEQ ID NO: 3586), Shewanella putrefaciens (SEQ ID NO: 3587), Haemophilus influenzae F3031 TadA (SEQ ID NO: 3588), Caulobacter crescentus TadA (SEQ ID NO: 3589), Geobacter sulfurreducens TadA (SEQ ID NO: 3590), Streptococcus pyogenes TadA (SEQ ID NO: 3591), Aquifex aeolicus TadA (SEQ ID NO: 3592), and E. coli TadA deaminase (ecTadA) (SEQ ID NO: 3593). By “adenosine deaminase activity” is meant catalyzing the deamination of adenine or adenosine to guanine in a polynucleotide. By “Adenosine Base Editor (ABE)” is meant a base editor comprising an adenosine deaminase. By “Adenosine Base Editor (ABE) polynucleotide” is meant a polynucleotide encoding an ABE. By “Adenosine Base Editor 8 (ABE8) polypeptide” or “ABE8” is meant a base editor as defined herein comprising an adenosine deaminase or adenosine deaminase variant comprising one or more of the alterations listed in Table 5B, one of the combinations of alterations listed in Table 5B, or an alteration at one or more of the amino acid positions listed in Table 5B, where such alterations are relative to the following reference sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), or a corresponding position in another adenosine deaminase. In embodiments, ABE8 comprises ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 alterations at amino acids 82 and / or 166 of SEQ ID NO: 1. In some embodiments, ABE8 comprises further alterations, as described herein, relative to the reference sequence. By “Adenosine Base Editor 8 (ABE8) polynucleotide” is meant a polynucleotide encoding an ABE8 polypeptide. “Administering” is referred to herein as providing one or more compositions described herein to a patient or a subject. By way of example and without limitation, composition administration (e.g., injection) can be performed by intravenous (i.v.) injection, sub-cutaneous (s.c.) injection, intradermal (i.d.) injection, intraperitoneal (i.p.) injection, or intramuscular (i.m.) injection. One or more such routes can be employed. Parenteral administration can be, for example, by bolus injection or by gradual perfusion over time. In some embodiments, parenteral administration includes infusing or injecting intravascularly, intravenously, intramuscularly, intraarterially, intrathecally, intratumorally, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly and intrasternally. Alternatively, or concurrently, administration can be by the oral route. By “agent” is meant any small molecule chemical compound, antibody, nucleic acid molecule, polypeptide, or functional fragments thereof. By “alteration” is meant a change in the level, structure, or activity of an analyte, gene or polypeptide as detected by standard art known methods such as those described herein. As used herein, an alteration includes a change (e.g., increase or reduction) in expression levels. In embodiments, the increase or reduction in expression levels is by 10%, 25%, 40%, 50% or greater. In some embodiments, an alteration includes an insertion, deletion, or substitution of a nucleobase or amino acid (by, e.g., genetic engineering). By “ameliorate” is meant reduce, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease. By “analog” is meant a molecule that is not identical but has analogous functional or structural features. For example, a polypeptide analog retains the biological activity of a corresponding naturally-occurring polypeptide, while having certain biochemical modifications that enhance the analog’s function relative to a naturally occurring polypeptide. Such biochemical modifications could increase the analog’s protease resistance, membrane permeability, or half-life, without altering, for example, ligand binding. An analog may include an unnatural amino acid. By “base editor (BE),” or “nucleobase editor polypeptide (NBE)” is meant an agent that binds a polynucleotide and has nucleobase modifying activity. In various embodiments, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 the base editor comprises a nucleobase modifying polypeptide (e.g., a deaminase) and a polynucleotide programmable nucleotide binding domain (e.g., Cas9 or Cpf1). Representative nucleic acid and protein sequences of base editors include those sequences having about or at least about 85% sequence identity to any base editor sequence provided in the sequence listing, such as those corresponding to SEQ ID NOs: 2-11. By “BE4 cytidine deaminase (BE4) polypeptide,” is meant a base editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain, a cytidine deaminase domain, and two uracil glycosylase inhibitor domains (UGIs). In embodiments, the napDNAbp is a Cas9n (D10A) polypeptide. Non-limiting examples of cytidine deaminase domains include rAPOBEC, ppAPOBEC, RrA3F, AmAPOBEC1, and SsAPOBEC3B. By “BE4 cytidine deaminase (BE4) polynucleotide,” is meant a polynucleotide encoding a BE4 polypeptide. By “base editing activity” is meant acting to chemically alter a base within a polynucleotide. In one embodiment, a first base is converted to a second base. In one embodiment, the base editing activity is cytidine deaminase activity, e.g., converting target C•G to T•A. In another embodiment, the base editing activity is adenosine or adenine deaminase activity, e.g., converting A•T to G•C. The term “base editor system” refers to an intermolecular complex for editing a nucleobase of a target nucleotide sequence. In various embodiments, the base editor (BE) system comprises (1) a polynucleotide programmable nucleotide binding domain, a deaminase domain (e.g., cytidine deaminase or adenosine deaminase) for deaminating nucleobases in the target nucleotide sequence; and (2) one or more guide polynucleotides (e.g., guide RNA) in conjunction with the polynucleotide programmable nucleotide binding domain. In various embodiments, the base editor (BE) system comprises a nucleobase editor domain selected from an adenosine deaminase or a cytidine deaminase, and a domain having nucleic acid sequence specific binding activity. In some embodiments, the base editor system comprises (1) a base editor (BE) comprising a polynucleotide programmable DNA binding domain and a deaminase domain for deaminating one or more nucleobases in a target nucleotide sequence; and (2) one or more guide RNAs in conjunction with the polynucleotide programmable DNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the base editor is a cytidine base editor (CBE). In some embodiments, the base editor is an adenine or adenosine base editor (ABE). In some embodiments, the base editor is an adenine or adenosine base editor (ABE) or a cytidine or ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 cytosine base editor (CBE). In some embodiments, the base editor system (e.g., a base editor system comprising a cytidine deaminase) comprises a uracil glycosylase inhibitor or other agent or peptide (e.g., a uracil stabilizing protein such as provided in WO2022015969, the disclosure of which is incorporated herein by reference in its entirety for all purposes) that inhibits the inosine base excision repair system. The term “Cas9” or “Cas9 domain” refers to an RNA guided nuclease comprising a Cas9 protein, or a fragment thereof (e.g., a protein comprising an active, inactive, or partially active DNA cleavage domain of Cas9, and / or the gRNA binding domain of Cas9). A Cas9 nuclease is also referred to sometimes as a casnl nuclease or a CRISPR (clustered regularly interspaced short palindromic repeat) associated nuclease. The term “conservative amino acid substitution” or “conservative mutation” refers to the replacement of one amino acid by another amino acid with a common property. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz, G. E. and Schirmer, R. H., Principles of Protein Structure, Springer-Verlag, New York (1979)). According to such analyses, groups of amino acids can be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure (Schulz, G. E. and Schirmer, R. H., supra). Non-limiting examples of conservative mutations include amino acid substitutions of amino acids, for example, lysine for arginine and vice versa such that a positive charge can be maintained; glutamic acid for aspartic acid and vice versa such that a negative charge can be maintained; serine for threonine such that a free –OH can be maintained; and glutamine for asparagine such that a free –NH2can be maintained. Amino acids generally can be grouped into classes according to the following common side- chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, He; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe. In some embodiments, conservative substitutions can involve the exchange of a member of one of these classes for another member of the same class. In some embodiments, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 non-conservative amino acid substitutions can involve exchanging a member of one of these classes for another class. The term “coding sequence” or “protein coding sequence” as used interchangeably herein refers to a segment of a polynucleotide that codes for a protein. Coding sequences can also be referred to as open reading frames. The region or sequence is bounded nearer the 5′ end by a start codon and nearer the 3′ end with a stop codon. Stop codons useful with the base editors described herein include the following: TAG, TAA, and TGA. By “complement factor B (CFB) polypeptide” or “factor B (FB) polypeptide” is meant a factor B protein with at least about 85% amino acid sequence identity to GenBank Accession No. AAA16820.1, which is provided below, or a fragment thereof that is capable of mediating activation of the complement system. In embodiments, CFB is capable of cleaving an Arg-Ser bond in complement component C3 to yield C3a and C3b and / or an Arg- Ser bond in complement component C5 to yield C5a and C5b. >AAA16820.1 complement factor B [Homo sapiens] MGSNLSPQLCLMPFILGLLSGGVTTTPWSLAQPQGSCSLEGVEIKGGSFRLLQEGQALEYVC PSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVS DEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDS VTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAE DGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYG LVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDV PPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLV NQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQ AKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPN YNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKE ELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLC TGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHIN LFQVLPWLKEKLQDEDLGFL (SEQ ID NO: 426) By “complement factor B (CFB) polynucleotide” or “factor B (FB) polynucleotide” is meant a nucleic acid molecule encoding a CFB polypeptide, as well as the introns, exons, 3′ untranslated regions, 5′ untranslated regions, and regulatory sequences associated with its expression, or fragments thereof. In embodiments, a CFB polynucleotide is the genomic sequence, cDNA, mRNA, or gene associated with and / or required for CFB expression. An exemplary CFB nucleotide sequences from Homo Sapiens is provided below (GenBank: L15702.1:41-2335; Ensembl: ENST00000425368.7): ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 >L15702.1:41-2335 Human complement factor B mRNA, complete cds ATGGGGAGCAATCTCAGCCCCCAACTCTGCCTGATGCCCTTTATCTTGGGCCTCTTGTCTGG AGGTGTGACCACCACTCCATGGTCTTTGGCCCAGCCCCAGGGATCCTGCTCTCTGGAGGGGG TAGAGATCAAAGGCGGCTCCTTCCGACTTCTCCAAGAGGGCCAGGCACTGGAGTACGTGTGT CCTTCTGGCTTCTACCCGTACCCTGTGCAGACACGTACCTGCAGATCTACGGGGTCCTGGAG CACCCTGAAGACTCAAGACCAAAAGACTGTCAGGAAGGCAGAGTGCAGAGCAATCCACTGTC CAAGACCACACGACTTCGAGAACGGGGAATACTGGCCCCGGTCTCCCTACTACAATGTGAGT GATGAGATCTCTTTCCACTGCTATGACGGTTACACTCTCCGGGGCTCTGCCAATCGCACCTG CCAAGTGAATGGCCGGTGGAGTGGGCAGACAGCGATCTGTGACAACGGAGCGGGGTACTGCT CCAACCCGGGCATCCCCATTGGCACAAGGAAGGTGGGCAGCCAGTACCGCCTTGAAGACAGC GTCACCTACCACTGCAGCCGGGGGCTTACCCTGCGTGGCTCCCAGCGGCGAACGTGTCAGGA AGGTGGCTCTTGGAGCGGGACGGAGCCTTCCTGCCAAGACTCCTTCATGTACGACACCCCTC AAGAGGTGGCCGAAGCTTTCCTGTCTTCCCTGACAGAGACCATAGAAGGAGTCGATGCTGAG GATGGGCACGGCCCAGGGGAACAACAGAAGCGGAAGATCGTCCTGGACCCTTCAGGCTCCAT GAACATCTACCTGGTGCTAGATGGATCAGACAGCATTGGGGCCAGCAACTTCACAGGAGCCA AAAAGTGTCTAGTCAACTTAATTGAGAAGGTGGCAAGTTATGGTGTGAAGCCAAGATATGGT CTAGTGACATATGCCACATACCCCAAAATTTGGGTCAAAGTGTCTGAAGCAGACAGCAGTAA TGCAGACTGGGTCACGAAGCAGCTCAATGAAATCAATTATGAAGACCACAAGTTGAAGTCAG GGACTAACACCAAGAAGGCCCTCCAGGCAGTGTACAGCATGATGAGCTGGCCAGATGACGTC CCTCCTGAAGGCTGGAACCGCACCCGCCATGTCATCATCCTCATGACTGATGGATTGCACAA CATGGGCGGGGACCCAATTACTGTCATTGATGAGATCCGGGACTTGCTATACATTGGCAAGG ATCGCAAAAACCCAAGGGAGGATTATCTGGATGTCTATGTGTTTGGGGTCGGGCCTTTGGTG AACCAAGTGAACATCAATGCTTTGGCTTCCAAGAAAGACAATGAGCAACATGTGTTCAAAGT CAAGGATATGGAAAACCTGGAAGATGTTTTCTACCAAATGATCGATGAAAGCCAGTCTCTGA GTCTCTGTGGCATGGTTTGGGAACACAGGAAGGGTACCGATTACCACAAGCAACCATGGCAG GCCAAGATCTCAGTCATTCGCCCTTCAAAGGGACACGAGAGCTGTATGGGGGCTGTGGTGTC TGAGTACTTTGTGCTGACAGCAGCACATTGTTTCACTGTGGATGACAAGGAACACTCAATCA AGGTCAGCGTAGGAGGGGAGAAGCGGGACCTGGAGATAGAAGTAGTCCTATTTCACCCCAAC TACAACATTAATGGGAAAAAAGAAGCAGGAATTCCTGAATTTTATGACTATGACGTTGCCCT GATCAAGCTCAAGAATAAGCTGAAATATGGCCAGACTATCAGGCCCATTTGTCTCCCCTGCA CCGAGGGAACAACTCGAGCTTTGAGGCTTCCTCCAACTACCACTTGCCAGCAACAAAAGGAA GAGCTGCTCCCTGCACAGGATATCAAAGCTCTGTTTGTGTCTGAGGAGGAGAAAAAGCTGAC TCGGAAGGAGGTCTACATCAAGAATGGGGATAAGAAAGGCAGCTGTGAGAGAGATGCTCAAT ATGCCCCAGGCTATGACAAAGTCAAGGACATCTCAGAGGTGGTCACCCCTCGGTTCCTTTGT ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ACTGGAGGAGTGAGTCCCTATGCTGACCCCAATACTTGCAGAGGTGATTCTGGCGGCCCCTT GATAGTTCACAAGAGAAGTCGTTTCATTCAAGTTGGTGTAATCAGCTGGGGAGTAGTGGATG TCTGCAAAAACCAGAAGCGGCAAAAGCAGGTACCTGCTCACGCCCGAGACTTTCACATCAAC CTCTTTCAAGTGCTGCCCTGGCTGAAGGAGAAACTCCAAGATGAGGATTTGGGTTTTCTATA A (SEQ ID NO: 427) >chromosome:GRCh38:6:31945050:31952686:1 (ENST00000425368.7), where exons are shown in bold text, untranslated regions are underlined, introns correspond to plain text regions between bold text regions, and a TATA box is shown by double-underlined text. The sequence contains 18 exons, where Exon 1 corresponds to the first exon from the 5′ end of the sequence, Exon 2 corresponds to the second exon from the 5′ end of the sequence, and so on to Exon 18. AGGACCCAGGGGTTACAGGATCTCAGCCTTGTTGGGGGGATGAGGGAGGCCTTTGAGGGATC TAGGGAGGTTGGGGCTTACAGTTGGGGCTGTGGCAGCCTCCCAGCCAGTTCTCTCCTTTTCT CCAGGTGGGTCTGGTGAGCTGGGGTCTTTACAACCCCTGCCTTGGCTCTGCTGACAAAAACT CCCGCAAAAGGGCCCCTCGTAGCAAGGTCCCGCCGCCACGAGACTTTCACATCAATCTCTTC CGCATGCAGCCCTGGCTGAGGCAGCACCTGGGGGATGTCCTGAATTTTTTACCCCTCTAGCC ATGGCCACTGAGCCCTCTGCTGCCCTGCCAGAATCTGCCGCCCCTCCATCTTCTACCTCTGA ATGGCCACCCTTAGACCCTGTGATCCATCCTCTCTCCTAGCTGAGTAAATCCGGGTCTCTAG GATGCCAGAGGCAGCGCACACAAGCTGGGAAATCCTCAGGGCTCCTACCAGCAGGACTGCCT CGCTGCCCCACCTCCCGCTCCTTGGCCTGTCCCCAGATTCCTTCCCTGGTTGACTTGACTCA TGCTTGTTTCACTTTCACATGGAATTTCCCAGTTATGAAATTAATAAAAATCAATGGTTTCC ACATCTCTCAGTGCCTCTATCTGGAGGCCAGGTAGGGCTGGCCTTGGGGGAGGGGGAGGCCA GAATGACTCCAAGAGCTACAGGAAGGCAGGTCAGAGACCCCACTGGACAAACAGTGGCTGGA CTCTGCACCATAACACACAATCAACAGGGGAGTGAGCTGGATCCTTATTTCTGGTCCCTAAG TGGGTGGTTTGGGCTTACTGGGGAGGAGCTAAGGCCGGAGAGGAGGTACTGAAGGGGAGAGT CCTGGACCTTTGGCAGCAAAGGGTGGGACTTCTGCAGTTTCTGTTTCCTTGACTGGCAGCTC AGCGGGGCCCTCCCGCTTGGATGTTCCGGGAAAGTGATGTGGGTAGGACAGGCGGGGCGAGC CGCAGGTGCCAGAACACAGATTGTATAAAAGGCTGGGGGCTGGTGGGGAGCAGGGGAAGGGA ATGTGACCAGGTCTAGGTCTGGAGTTTCAGCTTGGACACTGAGCCAAGCAGACAAGCAAAGC AAGCCAGGACACACCATCCTGCCCCAGGCCCAGCTTCTCTCCTGCCTTCCAACGCCATGGGG AGCAATCTCAGCCCCCAACTCTGCCTGATGCCCTTTATCTTGGGCCTCTTGTCTGGAGGTAA GCGAGGGTAACCTTCCCTTCCTGCTGTCTCCAGCATCCCTCCTTGGCCTTTTGGGGCCAGGC TTCATCAGCCTTTCTCTTCAGGTGTGACCACCACTCCATGGTCTTTGGCCCGGCCCCAGGGA TCCTGCTCTCTGGAGGGGGTAGAGATCAAAGGCGGCTCCTTCCGACTTCTCCAAGAGGGCCA ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 GGCACTGGAGTACGTGTGTCCTTCTGGCTTCTACCCGTACCCTGTGCAGACACGTACCTGCA GATCTACGGGGTCCTGGAGCACCCTGAAGACTCAAGACCAAAAGACTGTCAGGAAGGCAGAG TGCAGAGGTTTGAGGGCAATGAGTGTGGGCAGTGGCCTAAGGCAGAAACAGGGCAGGCGGCA GCAAGGTCAGGACTAGGATGAGACTAGGCAGGGTGACAAGGTGGGCTGACCGGGAGTAGGAG CAGTTTTAGGGTGGCAGGCGGAAAGGGGGCAAGAAAAAGCGGAGTTAACCCTTACTAAGCAT TTACCCTGGGCTTCCAGGCAGCCCTGGAAGTCAAGAGAACACTCAGAAATGGGGAGGGAGAA GCAGTGGAAATCCATATGGGTTGAGGAGTAGGTAAGATGCTGCTTCTGCGGGACTGGGAATG CGCTGTTTCTCAGTGACATGGTCTCCGAGACCAGGAGGGATACACCTAAGGCAGCCTTTCCC TCTTGATGACTTCTACTTGTCCCCCCTTCTCAAAGCAATCCACTGTCCAAGACCACACGACT TCGAGAACGGGGAATACTGGCCCCGGTCTCCCTACTACAATGTGAGTGATGAGATCTCTTTC CACTGCTATGACGGTTACACTCTCCGGGGCTCTGCCAATCGCACCTGCCAAGTGAATGGCCG ATGGAGTGGGCAGACAGCGATCTGTGACAACGGAGGTGAGAAGCATCCCCTCCCCCTACATT GCTGTCTCCCTGACGGCGCCCAGCCCGAGGAGTGGGCACTCGGCTCCGGACACTGTAACTCT TGCTCTCTACCTTGCTCACGGGGCCTCAGGCTTCAGTGCTTACCTCGATGTCTCATACCTCT GCAGCGGGGTACTGCTCCAACCCGGGCATCCCCATTGGCACAAGGAAGGTGGGCAGCCAGTA CCGCCTTGAAGACAGCGTCACCTACCACTGCAGCCGGGGGCTTACCCTGCGTGGCTCCCAGC GGCGAACGTGTCAGGAAGGTGGCTCTTGGAGCGGGACGGAGCCTTCCTGCCAAGGTGACCTT TGACCTGTACCCCCAGGTCAGATCCTGGTCTTCCATCCTACTGTCTTCTCTCCCCACCTCAA CCCTGCTCTTTCCTCACTTTGTTTAAACCTCCCTGTACAACTATCTCACTTCTGAGCCTTTT ATACCCTGGAAACCCATGATCCCCCGTCTCTTTGGTCACTGTATCCCTGACACTCCCAGACA TTTGACCTCATTTCTGACTCTCCCAGACTCCTTCATGTACGACACCCCTCAAGAGGTGGCCG AAGCTTTCCTGTCTTCCCTGACAGAGACCATAGAAGGAGTCGATGCTGAGGATGGGCACGGC CCAGGTTTGAAGACAGAGAAGGGAGGCAGGGCAGGGAACTGGGGGAAAATGGAGAAGGGACA GAACTGTTAATGCTGGAGCCTGAGCCACTCTCCTGGCACCCAGGGGAACAACAGAAGCGGAA GATCGTCCTGGACCCTTCAGGCTCCATGAACATCTACCTGGTGCTAGATGGATCAGACAGCA TTGGGGCCAGCAACTTCACAGGAGCCAAAAAGTGTCTAGTCAACTTAATTGAGAAGGTGGAA TCCTCCTATCCCTGAACTCGGGGGAATGGAATCTCGCTGATCTTCCAGGACTAGCTCCCTGA TCATTCCAGCCCCTCTGAACAACAGGGCCCCAGGAAAATCTCCAGGTCCTATTCTGTCCTCC TTCCCTTTTACTTGAAGCAGTTTCTTGACTGGTAATTCCTCCATGAACCTCAGCCCTTGAGC CTCTTACTGAGAGCCTCCCTGTCCCAGCAAAGTCGCTGAAATCTCCCAATCACAGTATTCTA TTTTCAATGCCATGGCGCCTTGTTCTCCTCACCCACAGGTGGCAAGTTATGGTGTGAAGCCA AGATATGGTCTAGTGACATATGCCACATACCCCAAAATTTGGGTCAAAGTGTCTGAAGCAGA CAGCAGTAATGCAGACTGGGTCACGAAGCAGCTCAATGAAATCAATTATGAAGGTCAGAGGT TAGGGAATGGTGGGAGGTTCACTTTGGGGTCAGGAGGTTCAGGGTGGAGGGGGTCATGAGAC ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 TACCTTGAGGGCGACAGGGAGGACCACTTTGTAGTCAAAAGTTGAACAGCAGGATCGTTGGG CAATGGAGGTTAGTGGGAACCTGTTGGGGGCTGGAAGGGCCACTTTGTGGTCAAAGGGAAGT CCGTGTAATGATGATTAACTTAAAAAGTTGAAAGATGTGGGATTTCAGTTGCAGATTGGTCT CTGGGGTTAAAAGATGGCTTGGAAGACCAGGTGAGGTGATGGTCTCTTCCCTCTCCACAGAC CACAAGTTGAAGTCAGGGACTAACACCAAGAAGGCCCTCCAGGCAGTGTACAGCATGATGAG CTGGCCAGATGACGTCCCTCCTGAAGGCTGGAACCGCACCCGCCATGTCATCATCCTCATGA CTGATGGTCAGAAGGGACCTCTCTCCTGTCCCAGCCTCCCCACCTTCTCAGACCAGCATGTG GCCCTTAAGTCCACTTGTAACACTATACCCATGGTTGGGGCCCTGAATGTGACTCATAGCTG GCTGTTCATCTCTCCTGTGACCCTTCATAAGGAATTCTTCCTAAGCCCTGTGATCAACTATC TCTAACCCTTCCTCAACTTGCTCACCCTGCCATGTGTATCCCTGCCTTTAGCCAGTTTATCT TCCTTATCTCCTACCCTCATGGTCCTGTCTCTTCTGCAGGATTGCACAACATGGGCGGGGAC CCAATTACTGTCATTGATGAGATCCGGGACTTGCTATACATTGGCAAGGATCGCAAAAACCC AAGGGAGGATTATCTGGGTGAGTAACCTGCCTAGGACCCAGCACCCCACTTCCTCAGGGCTT GGACCCTCATCCTTCCTTTTTATCCCTCAGATGTCTATGTGTTTGGGGTCGGGCCTTTGGTG AACCAAGTGAACATCAATGCTTTGGCTTCCAAGAAAGACAATGAGCAACATGTGTTCAAAGT CAAGGATATGGAAAACCTGGAAGATGTTTTCTACCAAATGATCGGTAGGGAGATACAAGGGA ATAAAGAACACAACTCTCCTCAGGTTCCCCTGAAGTAATTCATTCTTCCTCTACACCTGAAG CTCTAGTTGCCTGGAAAGCCTTCTTCATTCCTCCTTCTCTACCTCAGTGTCACTATTCTTGT TTCCTGGCACTGTTCACTTAACCTTAGAATCACAGAGCTCTGAGCACTTCAGAGATCTTTCT ATAGTCCTACATTTGACACGTGGAAACAGAAGCCAAAGGAGGTCAAGGGACAGCAAGTTAGC AACAAGGGTGGGCTTGAAAACAGCCAGGCCTCTGACAGCTTGATCCCAAGTTCTTTCCCTTT TCAGTCCACCATAGCAGTTTTCTCCTAACACGAGGAAACAAATACCCGTGGTCTTTCCCTTT CTCCTTTTGGGCCTTTGCTCCCCATAGACTCCTACCCAAAAGGCTGCTGCCATTTGGGAATG AAGTGTTCCGAGTTTTCAGCACATTCTCCTTCTCTGCCAGATGAAAGCCAGTCTCTGAGTCT CTGTGGCATGGTTTGGGAACACAGGAAGGGTACCGATTACCACAAGCAACCATGGCAGGCCA AGATCTCAGTCATTGTAAGCACAGAATCCCAGTAGTGGGGACTTGGGGGAGGTGAGGTCAAG GTGAAATGGGAGTAGGGGAAGGAAAAAATGGCCATAAGAGATGGTGGTTTGTGAAAGTTGAG CTTTCCCTCTCTACTGTTGTGTCCCCAGCGCCCTTCAAAGGGACACGAGAGCTGTATGGGGG CTGTGGTGTCTGAGTACTTTGTGCTGACAGCAGCACATTGTTTCACTGTGGATGACAAGGAA CACTCAATCAAGGTCAGCGTAGGTAAGGATGCAACTGAAGGTCCTGGGCTGCACCTATGCTC TCCAGGCAACACCTCCCACTTTCTACAGATCCTACACTCCACCCATCCTCAATGCAGCCCCA TTCCTTGCACCCCAGACCAGTCAGGGATGGGGGAAGACGTGAAGTTAGGAATGACACGGGGC CAGAGGCAGGAAGCTGCCCACAAAGAGGTGGTACCTACTCTCCTACTTCAGGAGGGGAGAAG CGGGACCTGGAGATAGAAGTAGTCCTATTTCACCCCAACTACAACATTAATGGGAAAAAAGA ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 AGCAGGAATTCCTGAATTTTATGACTATGACGTTGCCCTGATCAAGCTCAAGAATAAGCTGA AATATGGCCAGACTATCAGGTGAGAGCGTCCAGATCCCTGAGGAAAGGCTGGGAAAGGCTGG AGGACTGGGGTGAGGAGCAGGCCTGGTTTGCTGTTCTCCTTGTCCTTTATAGGCCCATTTGT CTCCCCTGCACCGAGGGAACAACTCGAGCTTTGAGGCTTCCTCCAACTACCACTTGCCAGCA ACAAAGTAAGACATACTTGGCAAGAGGATAAGGATGAGATCCCAAGAGACAAGTGGGGCATG AGAGGGAGGTGCAATAGGAAGAGATGATGCCTGGCCCAGAACCTAGCTCTAGAAGGGCTTAG GGGACATCTACTGAGTGACAAAGGCAATGGGGAGATGACAGTGGTGGGAGCAGCTGAAGTGA CGCAGTCTATTCGTCCAGAGGAAGAGCTGCTCCCTGCACAGGATATCAAAGCTCTGTTTGTG TCTGAGGAGGAGAAAAAGCTGACTCGGAAGGAGGTCTACATCAAGAATGGGGATAAGGTGAG AAACGGGCATCCTAAGGAGGCACTCTAGGCCCCAATCCTTCCTAAGCCACTTCTGTTCATTA CTTCTCCATGCTTCCCACCTCCCCTACAGAAAGGCAGCTGTGAGAGAGATGCTCAATATGCC CCAGGCTATGACAAAGTCAAGGACATCTCAGAGGTGGTCACCCCTCGGTTCCTTTGTACTGG AGGAGTGAGTCCCTATGCTGACCCCAATACTTGCAGAGGTGAGAGAATGCTCTTTGGTTGTG CTACAAGTGCCCAAGGCCCAACAGTCCTTTTCTCTACAGCTTCTCCTCTCCTTGCAGGTGAT TCTGGCGGCCCCTTGATAGTTCACAAGAGAAGTCGTTTCATTCAAGTGAGTCCTCCCTTTCC TATCTGGGGAGATGCCAAGTGGTCAGCATGGGCCCCAAAGCAGGAAAGCTCAATGCATGTGG CTAGTAATTCGAGGTAGGCAGAGCCTGCCTCACCTTAGGACCGCATGTCTTGCCTGCGTGTG TCAAGAACGAGGCTGAGCTGGGTCCCTAGTCTGATTCCTTTAGGTCAGCTAAGACACAAGCA GGAACAGCCATGCTTCCAGGATTAGGAATTCTACTGAATGATCCATGGCACCCCACTGCCTC TGCAGGTTGGTGTAATCAGCTGGGGAGTAGTGGATGTCTGCAAAAACCAGAAGCGGCAAAAG CAGGTACCTGCTCACGCCCGAGACTTTCACATCAACCTCTTTCAAGTGCTGCCCTGGCTGAA GGAGAAACTCCAAGATGAGGATTTGGGTTTTCTATAAGGGGTTTCCTGCTGGACAGGGGCGT GGGATTGAATTAAAACAGCTGCGACAACACCTGTGTTCCAGATCCTTTTGGGGCAAGGGAGT GGGGAACAGGCACTGGCCATGTTGTTACACTGAGATCAAACCTGACAGCCGTTTTTAAAGGT TTAACCCCAATCCCAAGTGCTGAAAAACCAGAGGCTGAGGGAGATGTGTAAGCTTCCACCTC AGTGTTTTACTGAGACCAGCATTGGGGCATATGAGGCACAAGGAATCCAGCTCTGTTCCCTA GAAGCCATCCACAAGGTTTTCCTTGTAGACGTCATCACTGTAGACAATCTGGGTCCTCTTGT CCCGGTGGCAACCCTTAGGGCTGTTCTGGACAGCTAGGGAGGGAGGAGAGGAACAGTTAAGG TCTAAAGGAGATCATAGAACAGACCCTGAGGCTGACTCCTGACCACCTCACTCCTGGCCACT GGCCCCTGGAAGCCCAGTTTCCACGCTGCCCTCTGGTGGCCAGGATGGCCTGTCTTCCTTAG CTCCTTTGTGCCAACCCATGGCCAAGAAAAGTATAAGTGGACATTTTGATGAATGTTTTGTT CTTAGAAAAATCCCAAATGTCATTGTTGAGACACGTGAATGATATTAACCCACTACTTACAG TCAGTATGTCA (SEQ ID NO: 428) ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 By “complex” is meant a combination of two or more molecules whose interaction relies on inter-molecular forces. Non-limiting examples of inter-molecular forces include covalent and non-covalent interactions. Non-limiting examples of non-covalent interactions include hydrogen bonding, ionic bonding, halogen bonding, hydrophobic bonding, van der Waals interactions (e.g., dipole-dipole interactions, dipole-induced dipole interactions, and London dispersion forces), and π-effects. In an embodiment, a complex comprises polypeptides, polynucleotides, or a combination of one or more polypeptides and one or more polynucleotides. In one embodiment, a complex comprises one or more polypeptides that associate to form a base editor (e.g., base editor comprising a nucleic acid programmable DNA binding protein, such as Cas9, and a deaminase) and a polynucleotide (e.g., a guide RNA). In an embodiment, the complex is held together by hydrogen bonds. It should be appreciated that one or more components of a base editor (e.g., a deaminase, or a nucleic acid programmable DNA binding protein) may associate covalently or non-covalently. As one example, a base editor may include a deaminase covalently linked to a nucleic acid programmable DNA binding protein (e.g., by a peptide bond). Alternatively, a base editor may include a deaminase and a nucleic acid programmable DNA binding protein that associate noncovalently (e.g., where one or more components of the base editor are supplied in trans and associate directly or via another molecule such as a protein or nucleic acid). In an embodiment, one or more components of the complex are held together by hydrogen bonds. By “cytosine” or “4-Aminopyrimidin-2(1H)-one” is meant a purine nucleobase with the molecular formula C4H5N3O, having the structure corresponding to CAS No.71-30-7.

[0002] ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 By “cytidine” is meant a cytosine molecule attached to a ribose sugar via a glycosidic bond, having the structure , and corresponding to CAS No.65-46-3. Its molecular formula is C9H13N3O5. By “Cytidine Base Editor (CBE)” is meant a base editor comprising a cytidine deaminase. Non-limiting examples of cytidine deaminase base editor amino acid sequences include amino acid sequences for BE4max (SEQ ID NO: 3658), YE1-BE4 (SEQ ID NO: 3659), YE2-BE4 (SEQ ID NO: 3660), YEE-BE4 (SEQ ID NO: 3661), EE-BE4 (SEQ ID NO: 3662), R33A-BE4 (SEQ ID NO: 3663), R33A+K34A-BE4 (SEQ ID NO: 3664), APOBEC3A (A3A)-BE4 (SEQ ID NO: 3665), APOBEC3B (A3B)-BE4 (SEQ ID NO: 3666), APOBEC3G (A3G)-BE4 (SEQ ID NO: 3667), AID-BE4 (SEQ ID NO: 3668), CDA-BE4 (SEQ ID NO: 3669), FERNY-BE4 (SEQ ID NO: 3670), evolved APOBEC3A (eA3A)-BE4 (SEQ ID NO: 3671), AALN-BE4 (SEQ ID NO: 3672), BE4max modified with SpCas9-NG (SEQ ID NO: 3673), YE1-SpCas9-NG (YE1-NG) (SEQ ID NO: 3674), YE2-SpCas9-NG (SEQ ID NO: 3675), YEE-SpCas9-NG (SEQ ID NO: 3676), EE-SpCas9-NG (SEQ ID NO: 3677), R33A+K34A-SpCas9-NG (SEQ ID NO: 3678), YE1-CP1028 (YE1-BE4-CP1028, or YE1-CP) (SEQ ID NO: 3679), YE2-CP1028 (YE2-BE4-CP1028) (SEQ ID NO: 3680), YEE- CP1028 (YEE-BE4-CP1028) (SEQ ID NO: 3681), EE-CP1028 (EE-BE4-CP1028) (SEQ ID NO: 3682), R33A+K34A-CP1028 (R33A+K34A-BE4-CP1028) (SEQ ID NO: 3683), BE4max (with nickase) (SEQ ID NO: 3702), BE4 (SEQ ID NO: 3703), BE4 with His tag (SEQ ID NO: 3704), BE4max (SEQ ID NO: 3705), AncBE4max 689 (SEQ ID NO: 3706), and AncBE4max 687 (SEQ ID NO: 3707). By “Cytidine Base Editor (CBE) polynucleotide” is meant a polynucleotide encoding a CBE. Non-limiting examples of polynucleotide sequences encoding cytidine deaminase base editors include those encoding BE4max (SEQ ID NO: 3721), AncBE4max689 (SEQ ID NO: 3722), and AncBE4max687 (SEQ ID NO: 3723). By “cytidine deaminase” or “cytosine deaminase” is meant a polypeptide or fragment thereof capable of deaminating cytidine or cytosine. In embodiments, the cytidine or cytosine is present in a polynucleotide. In one embodiment, the cytidine deaminase converts cytosine ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 to uracil or 5-methylcytosine to thymine. The terms “cytidine deaminase” and “cytosine deaminase” are used interchangeably throughout the application. Petromyzon marinus cytosine deaminase 1 (PmCDA1) (SEQ ID NO: 13-14), Activation-induced cytidine deaminase (AICDA) (SEQ ID NOs: 15-21), and APOBEC (SEQ ID NOs: 12-61) are exemplary cytidine deaminases. Further exemplary cytidine deaminase (CDA) sequences are provided in the Sequence Listing as SEQ ID NOs: 62-66 and SEQ ID NOs: 67-189. Non- limiting examples of cytidine deaminases include those described in PCT / US20 / 16288, PCT / US2018 / 021878, 180802-021804 / PCT, PCT / US2018 / 048969, PCT / US2016 / 058344, PCT / US2020 / 062428, and PCT / US2019 / 033848, the disclosures of which are incorporated herein by reference in their entireties for all purposes. Non-limiting examples of cytidine deaminase amino acid sequences include amino acid sequences for Rat APOBEC1 (SEQ ID NO: 3684), Human APOBEC1 (SEQ ID NO: 3685), Human APOBEC3 (SEQ ID NO: 3686), Human APOBEC3B (SEQ ID NO: 3687), Human APOBEC3G (SEQ ID NO: 3688), evoAPOBEC3A(eA3A) (SEQ ID NO: 3689), evoCDA (SEQ ID NO: 3690), evoAPOBECl (SEQ ID NO: 3691), YE1 (SEQ ID NO: 3692), YE2 (SEQ ID NO: 3693), YEE (SEQ ID NO: 3694), EE (SEQ ID NO: 3695), R33A (SEQ ID NO: 3696), R33A+K34A (SEQ ID NO: 3697), AALN (SEQ ID NO: 3698), FERNY (SEQ ID NO: 3699), evoFERNY (SEQ ID NO: 3700), APOBEC (SEQ ID NO: 3724), Anc686 APOBEC (SEQ ID NO: 3725), Human APOBEC-3G D316R_D317R (SEQ ID NO: 5726), Human APOBEC-3G chain A (SEQ ID NO: 3727), Human APOBEC3-G chain A D120R_D121R (SEQ ID NO: 3728), Mouse APOBEC3 (SEQ ID NO: 3729), Rat APOBEC3 (SEQ ID NO: 3730), Rhesus macaque APOBEC-3G (SEQ ID NO: 3731), Chimpanzee APOBEC-3G (SEQ ID NO: 3732), Green Monkey APOBEC-3G (SEQ ID NO: 3733), Human APOBEC-3G (SEQ ID NO: 3734), Human APOBEC-3F (SEQ ID NO: 3735), Human APOBEC-3B (SEQ ID NO: 3736), Rat APOBEC-3B (SEQ ID NO: 3737), Bovine APOBEC-3B (SEQ ID NO: 3738), Chimpanzee APOBEC-3B (SEQ ID NO: 3739), Gorilla APOBEC-3C (SEQ ID NO: 3740), Human APOBEC-3A (SEQ ID NO: 3741), Rhesus macaque APOBEC-3A (SEQ ID NO: 3742), Bovine APOBEC-3A (SEQ ID NO: 3743), Human APOBEC-3H (SEQ ID NO: 3744), Human APOBEC-3D (SEQ ID NO: 3745), Rat ABOPEC1 (SEQ ID NO: 3746), Anc689 APOBEC (SEQ ID NO: 3747), Anc687 APOBEC (SEQ ID NO: 3748), Anc686 APOBEC (SEQ ID NO: 3749), Anc655 APOBEC (SEQ ID NO: 3750), and Anc733 APOBEC (SEQ ID NO: 3751). By “cytidine deaminase polynucleotide” is meant a polynucleotide encoding a cytidine deaminase. Non-limiting examples of polynucleotide sequences encoding cytidine ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 deaminase domains include those encoding Rat APOBEC1 (SEQ ID NO: 3709), Anc689 APOBEC (SEQ ID NO: 3710), Anc687 APOBEC (SEQ ID NO: 3711), Anc686 APOBEC (SEQ ID NO: 3712), Anc655 APOBEC (SEQ ID NO: 3713), Anc733 APOBEC (SEQ ID NO: 3714), Rat APOBEC1 (SEQ ID NO: 3715), Anc689 APOBEC (SEQ ID NO: 3716), Anc687 APOBEC (SEQ ID NO: 3717), Anc686 APOBEC (SEQ ID NO: 3718), Anc655 APOBEC (SEQ ID NO: 3719), and Anc733 APOBEC (SEQ ID NO: 3720). By “cytosine deaminase activity” is meant catalyzing the deamination of cytosine or cytidine. In one embodiment, a polypeptide having cytosine deaminase activity converts an amino group to a carbonyl group. In an embodiment, a cytosine deaminase converts cytosine to uracil (i.e., C to U) or 5-methylcytosine to thymine (i.e., 5mC to T). In some embodiments, a cytosine deaminase as provided herein has increased cytosine deaminase activity (e.g., at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold or more) relative to a reference cytosine deaminase. The term “deaminase” or “deaminase domain,” as used herein, refers to a protein or fragment thereof that catalyzes a deamination reaction. The term “detect” refers to identifying the presence, absence or amount of the analyte to be detected. In one embodiment, a sequence alteration in a polynucleotide or polypeptide is detected. In another embodiment, the presence of indels is detected. By “detectable label” is meant a composition that when linked to a molecule of interest renders the latter detectable, via spectroscopic, photochemical, biochemical, immunochemical, or chemical means. For example, useful labels include radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes (for example, as commonly used in an enzyme linked immunosorbent assay (ELISA)), biotin, digoxigenin, or haptens. By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. Exemplary diseases include diseases amenable to treatment with involving introducing an alteration to a complement complement factor B (CFB) polynucleotide in a cell that results in a reduction in activity and / or expression of a CFB polypeptide in the cell. In some instances, the disease is a disease associated with inappropriate activation of the complement system in the subject. Non-limiting examples of diseases associated with inappropriate activation of the complement system include blood disorders, transplant or graft rejection, inflammatory diseases or disorders, eye diseases or disorders, kidney diseases or disorders, heart disorders, respiratory diseases or disorders, autoimmune disorders, inflammatory bowel diseases or disorders, arthritis, neurodegenerative ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 diseases or disorders, musculoskeletal diseases or disorders associated with inflammation, disorders affecting the integumentary system, diseases or disorders affecting the central nervous system, diseases or disorders affecting the circulatory system, diseases or disorders affecting the gastrointestinal system, diseases or disorders affecting the thyroid, chronic pain, allergies, and pulmonary diseases. Further non-limiting examples of diseases associated with inappropriate activation of the complement system include paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic syndrome (aHUS), HELLP syndrome, autoimmune hemolytic anemia, transplant rejection, ischemia / reperfusion injury, transplant damage, hyperacute rejection, graft rejection or failure, acute antibody-mediated rejection, chronic inflammation, chronic allograft vasculopathy, chronic rejection of a transplant or graft, age-related macular degeneration (e.g., wet or dry age-related macular degeneration), diabetic retinopathy, glaucoma, uveitis, autoimmune diseases, myasthenia gravis, neuromyelitis optica (NMO), renal disease, membranoproliferative glomerulonephritis (MPGN) (e.g., MPGN type I, type II, or type III), IgA nephropathy (IgAN), primary membranous nephropathy, C3 glomerulopathy, proteinuria, a neurodegenerative disease, neuropathic pain, rhinosinusitis, nasal polyposis, cancer, sepsis, respiratory distress syndrome, anaphylaxis, infusion reaction, a respiratory disease or disorder (e.g., asthma or chronic obstructive pulmonary disease (COPD), oridiopathic pulmonary fibrosis, or asthma), a Th2-associated disorder (e.g., a disorder associated with high levels or high activation of CD4+ helper T cells of the Th2 subtype), a disorder associated with high levels or inappropriate activity of CD4+ helper T cells of the Th17 subtype, inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), inflammatory skin diseases, a chronic inflammatory disease, psoriasis, atopic dermatitis, systemic scleroderma, sclerosis, Bechet’s disease, dermatomyositis, polymyositis, multiple sclerosis (MS), dermatitis, meningitis, encephalitis, uveitis, osteoarthritis, lupus nephritis, rheumatoid arthritis (RA), Sjoren’s syndrome, vasculitis, central nervous system (CNS) inflammatory disorders, chronic hepatitis, chronic pancreatitis, glomerulonephritis, sarcoidosis, thyroiditis, pathologic immune responses to tissue / organ transplantation, bronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), periodontitis, gingivitis, a disorder associated with excessive or inappropriate activity of IgE-producing cells, neuromyelitis optica, pemphigoid, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), radiation-induced lung injury, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic pneumonia, interstitial pneumonia, sarcoid, Wegener’s granulomatosis, bronchiolitis obliterans, allergic rhinitis, an inflammatory joint condition (e.g., arthritis such as rheumatoid ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 arthritis or psoriatic arthritis, juvenile chronic arthritis, spondyloarthropathies Reiter’s syndrome, or gout), a dermatomyositis, polymyositis, chronic muscle inflammation, pemphigus, systemic lupus erythematosus, dermatomyositis, scleroderma, sclerodermatomyositis, Sjögren syndrome, chronic urticaria, a demyelinating disease, amyotrophic lateral sclerosis, chronic pain, stroke, allergic neuritis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, a disease of the circulatory system, polyarteritis nodosa, Wegener’s granulomatosis, giant cell arteritis, Churg-Strauss syndrome, microscopic polyangiitis, Henoch-Schonlein purpura, Takayasu's arteritis, Kawasaki disease, Behcet’s disease, ulcerative colitis, thyroiditis (e.g., Hashimoto’s thyroiditis, Graves’ disease, post- partum thyroiditis), myocarditis, hepatitis (e.g., hepatitis C), pancreatitis, glomerulonephritis (e.g., membranoproliferative glomerulonephritis or membranous glomerulonephritis), panniculitis, eye disorders, choroidal neovascularization (CNV), retinal neovascularization (RNV), ocular inflammation, retinopathy of prematurity, proliferative vitreoretinopathy, uveitis, keratitis, conjunctivitis, and scleritis, geographic atrophy, conjunctivitis, keratitis, scleritis, iritis, iridocyclitis, cyclitis, pars planitis, choroiditis, persistent asthma, and allergic asthma. In some cases, the disease is selected from glaucoma, diabetic retinopathy, age- related macular degeneration, and neurological diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease, and various Tauopathies. By “dual editing activity” or “dual deaminase activity” is meant having adenosine deaminase and cytidine deaminase activity. In one embodiment, a base editor having dual editing activity has both A^G and C^T activity, wherein the two activities are approximately equal or are within about 10% or 20% of each other. In another embodiment, a dual editor has A^G activity that no more than about 10% or 20% greater than C^T activity. In another embodiment, a dual editor has A^G activity that is no more than about 10% or 20% less than C^T activity. In some embodiments, the adenosine deaminase variant has predominantly cytosine deaminase activity, and little, if any, adenosine deaminase activity. In some embodiments, the adenosine deaminase variant has cytosine deaminase activity, and no significant or no detectable adenosine deaminase activity. Non-limiting examples of proteins having dual deaminase activity include those described in International Patent Application Publications No. WO 2024 / 040083 and WO 2022 / 204574, the disclosures of which are hereby incorporated by reference in their entireties for all purposes. By “effective amount” is meant the amount of an agent (e.g., a base editor, cell) as described herein, that is required to ameliorate the symptoms of a disease relative to an untreated patient or an individual without disease, i.e., a healthy individual, or is the amount ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 of the agent sufficient to elicit a desired biological response. The effective amount of active compound(s) used to practice embodiments of the present disclosure for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount. In one embodiment, an effective amount is the amount of a base editor of the disclosure sufficient to introduce an alteration in a gene of interest in a cell (e.g., a cell in vitro or in vivo). In one embodiment, an effective amount is the amount of a base editor required to achieve a therapeutic effect. Such therapeutic effect need not be sufficient to alter a pathogenic gene in all cells of a subject, tissue or organ, but only to alter the pathogenic gene in about 1%, 5%, 10%, 25%, 50%, 75% or more of the cells present in a subject, tissue or organ. In one embodiment, an effective amount is sufficient to ameliorate one or more symptoms of a disease. By “fragment” is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids. In some embodiments, the fragment is a functional fragment. By “guide polynucleotide” is meant a polynucleotide or polynucleotide complex which is specific for a target sequence and can form a complex with a polynucleotide programmable nucleotide binding domain protein (e.g., Cas9 or Cpf1). In an embodiment, the guide polynucleotide is a guide RNA (gRNA). gRNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. “Hybridization” means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. For example, adenine and thymine are complementary nucleobases that pair through the formation of hydrogen bonds. By “inappropriate activation” in the context of factor B is meant any increase in complement activation that is associated with a disease or disorder. In an embodiment, inappropriate activation is activation that is increased or elevated locally (e.g., in an organ or tissue, such as in the central nervous system or in an eye) or systemically relative to a healthy reference (e.g., a healthy subject). In some instances “inappropriate activation” is activation that is associated with chronic (e.g., lasting more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks) inflammation in a subject. In some cases, inappropriate activation is ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 activation that is directed against a tissue, cell, or organ of a subject and / or that leads to undesired damage to the tissue, cell, or organ of the subject. In embodiments, a disease or disorder associated with inappropriate activation of the complement system can be treated by any of the methods or compositions provided herein for reducing or eliminating expression and / or activity of a factor B polypeptide. In an embodiment, complement activation is detected by measuring levels of a factor B polypeptide and / or of a cleaved factor B polypeptide (e.g., a Ba fragment or a Bb fragment), where inappropriate activation can be determined as high levels of the factor B polypeptide and / or cleaved factor B polypeptide relative to a healthy reference subject. By “increases” is meant a positive alteration of at least 10%, 25%, 50%, 75%, or 100%, or about 1.5 fold, about 2 fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, or about 100-fold. The terms “inhibitor of base repair”, “base repair inhibitor”, “IBR” or their grammatical equivalents refer to a protein that is capable in inhibiting the activity of a nucleic acid repair enzyme, for example a base excision repair enzyme. An “intein” is a fragment of a protein that is able to excise itself and join the remaining fragments (the exteins) with a peptide bond in a process known as protein splicing. The process of an intein excising itself and joining the remaining portions of the protein is herein termed "protein splicing" or "intein-mediated protein splicing." In some embodiments, an intein is a trans-splicing intein (also referred to as a “split intein”). In the case of trans- splicing inteins, a full-length polypeptide is split into two separate fragments and the C- terminus of the N-terminal fragment is fused to an N-terminal fragment of a split intein intein (N-intein) and the N-terminus of the remaining C-terminal fragment is fused a C-terminal fragment of a split intein (C-intein). Not intending to be bound by theory or mechanism of action, contacting the two polypeptide sequences with one another results in excision of the intein and joining of the two polypeptide sequences together to form a full-length polypeptide sequence. In embodiments, contacting the two polypeptide fragments each fused to an intein fragment, or peptide derived from an intein fragment, is associated with a measured catalytic activity (e.g., deamination of a nucleobase in a polynucleotide sequence) in a cell that is greater than that observed when the two polypeptide fragments are contacted with one another in a cell and do not contain any intein fragments. Non-limiting examples of N-intein ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 and C-intein sequences include those sequences sharing at least 85% sequence identity to an amino acid sequence listed in Table A or Table B, or functional fragments thereof. Table A. Representative synthetic N-intein amino acid sequences. Table B. Representative synthetic C-intein amino acid sequences. The terms “isolated,” “purified,” or “biologically pure” refer to material that is free to varying degrees from components which normally accompany it as found in its native state. “Isolate” denotes a degree of separation from original source or surroundings. “Purify” denotes a degree of separation that is higher than isolation. A “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this disclosure is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography. The term “purified” can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified. By “isolated polynucleotide” is meant a nucleic acid molecule that is free of the genes which, in the naturally-occurring genome of the organism from which the nucleic acid molecule of the disclosure is derived, flank the gene. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote; or that exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. In addition, the term includes an RNA molecule that is transcribed from a DNA molecule, as well as a recombinant DNA that is part of a hybrid gene encoding additional polypeptide sequence. By an “isolated polypeptide” is meant a polypeptide of the disclosure that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. In embodiments, the preparation is at least 75%, at least 90%, or at least 99%, by weight, a polypeptide of the disclosure. An isolated polypeptide of the disclosure may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis. The term “linker”, as used herein, refers to a molecule that links two moieties. In one embodiment, the term “linker” refers to a covalent linker (e.g., covalent bond) or a non- covalent linker. By “marker” is meant any protein or polynucleotide having an alteration in expression, level, structure, or activity that is associated with a disease or disorder. In embodiments, the disease or disorder is associated with inappropriate activation of the complement system. In some cases, the marker is a factor B polynucleotide or polypeptide. The term “mutation,” as used herein, refers to a substitution of a residue within a sequence, e.g., a nucleic acid or amino acid sequence, with another residue, or a deletion or insertion of one or more residues within a sequence. Mutations are typically described herein by identifying the original residue followed by the position of the residue within the sequence and by the identity of the newly substituted residue. Various methods for making the amino acid substitutions (mutations) provided herein are well known in the art, and are provided by, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual (4thed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)). The terms “nucleic acid” and “nucleic acid molecule,” as used herein, refer to a compound comprising a nucleobase and an acidic moiety, e.g., a nucleoside, a nucleotide, or a polymer of nucleotides. Typically, polymeric nucleic acids, e.g., nucleic acid molecules comprising three or more nucleotides are linear molecules, in which adjacent nucleotides are linked to each other via a phosphodiester linkage. In some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising three or more individual nucleotide residues. As used herein, the terms “oligonucleotide” and “polynucleotide” can be used interchangeably to refer to a polymer of nucleotides (e.g., a string of at least three nucleotides). In some embodiments, “nucleic acid” encompasses RNA as well as single and / or double-stranded DNA. Nucleic acids may be naturally occurring, for example, in the context of a genome, a transcript, an mRNA, tRNA, rRNA, siRNA, snRNA, a plasmid, cosmid, chromosome, chromatid, or other naturally occurring nucleic acid molecule. On the other hand, a nucleic acid molecule may be a non-naturally occurring molecule, e.g., a recombinant DNA or RNA, an artificial chromosome, an engineered genome, or fragment thereof, or a synthetic DNA, RNA, DNA / RNA hybrid, or including non-naturally occurring nucleotides or nucleosides. Furthermore, the terms “nucleic acid,” “DNA,” “RNA,” and / or similar terms include nucleic acid analogs, e.g., analogs having other than a phosphodiester backbone. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids comprise nucleoside analogs such as analogs having chemically modified bases or sugars, and backbone modifications. A nucleic acid sequence is presented in the 5′ to 3′ direction unless otherwise indicated. In some embodiments, a nucleic acid is or comprises natural nucleosides (e.g. adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2- aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5- methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5- propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7- deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5′-N- phosphoramidite linkages). The term “nuclear localization sequence,” “nuclear localization signal,” or “NLS” refers to an amino acid sequence that promotes import of a protein into the cell nucleus. Nuclear localization sequences are known in the art and described, for example, in Plank et al., International PCT application, PCT / EP2000 / 011690, filed November 23, 2000, published as WO / 2001 / 038547 on May 31, 2001, the contents of which are incorporated herein by reference for their disclosure of exemplary nuclear localization sequences. In other embodiments, the NLS is an optimized NLS described, for example, by Koblan et al., Nature Biotech.2018 doi:10.1038 / nbt.4172. In some embodiments, an NLS comprises the amino acid sequence KRTADGSEFESPKKKRKV (SEQ ID NO: 190),KRPAATKKAGQAKKKK (SEQ ID NO: 191),KKTELQTTNAENKTKKL (SEQ ID NO: 192),KRGINDRNFWRGENGRKTR (SEQ ID NO: 193),RKSGKIAAIVVKRPRK (SEQ ID NO: 194),PKKKRKV (SEQ ID NO: 195),MDSLLMNRRKFLYQFKNVRWAKGRRETYLC (SEQ ID NO: 196), PKKKRKVEGADKRTADGSEFESPKKKRKV (SEQ ID NO: 328), or RKSGKIAAIVVKRPRKPKKKRKV (SEQ ID NO: 329). The term “nucleobase,” “nitrogenous base,” or “base,” used interchangeably herein, refers to a nitrogen-containing biological compound that forms a nucleoside, which in turn is a component of a nucleotide. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases – adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) – are called primary or canonical. Adenine and guanine are derived from purine, and cytosine, uracil, and thymine are derived from pyrimidine. DNA and RNA can also contain other (non-primary) bases that are modified. Non-limiting exemplary modified nucleobases can include hypoxanthine, xanthine, 7-methylguanine, 5,6- dihydrouracil, 5-methylcytosine (m5C), and 5-hydromethylcytosine. Hypoxanthine and xanthine can be created through mutagen presence, both of them through deamination (replacement of the amine group with a carbonyl group). Hypoxanthine can be modified from adenine. Xanthine can be modified from guanine. Uracil can result from deamination of cytosine. A “nucleoside” consists of a nucleobase and a five carbon sugar (either ribose or deoxyribose). Examples of a nucleoside include adenosine, guanosine, uridine, cytidine, 5- methyluridine (m5U), deoxyadenosine, deoxyguanosine, thymidine, deoxyuridine, and deoxycytidine. Examples of a nucleoside with a modified nucleobase includes inosine (I), ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 xanthosine (X), 7-methylguanosine (m7G), dihydrouridine (D), 5-methylcytidine (m5C), and pseudouridine (Ψ). A “nucleotide” consists of a nucleobase, a five carbon sugar (either ribose or deoxyribose), and at least one phosphate group. Non-limiting examples of modified nucleobases and / or chemical modifications that a modified nucleobase may include are the following: pseudo-uridine, 5-Methyl-cytosine, 2′-O-methyl-3′-phosphonoacetate, 2′-O- methyl thioPACE (MSP), 2′-O-methyl-PACE (MP), 2′-fluoro RNA (2′-F-RNA), constrained ethyl (S-cEt), 2′-O-methyl (‘M’), 2′-O-methyl-3′-phosphorothioate (‘MS’), 2′-O-methyl-3′- thiophosphonoacetate (‘MSP’), 5-methoxyuridine, phosphorothioate, and N1- Methylpseudouridine. The term “nucleic acid programmable DNA binding protein” or “napDNAbp” may be used interchangeably with “polynucleotide programmable nucleotide binding domain” to refer to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nucleic acid or guide polynucleotide (e.g., gRNA), that guides the napDNAbp to a specific nucleic acid sequence. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable RNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a Cas9 protein. A Cas9 protein can associate with a guide RNA that guides the Cas9 protein to a specific DNA sequence that is complementary to the guide RNA. In some embodiments, the napDNAbp is a Cas9 domain, for example a nuclease active Cas9, a Cas9 nickase (nCas9), or a nuclease inactive Cas9 (dCas9). Non-limiting examples of nucleic acid programmable DNA binding proteins include, Cas9 (e.g., dCas9 and nCas9), Cas12a / Cpfl, Cas12b / C2cl, Cas12c / C2c3, Cas12d / CasY, Cas12e / CasX, Cas12g, Cas12h, Cas12i, and Cas12j / CasΦ (Cas12j / Casphi). Non-limiting examples of Cas enzymes include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas8a, Cas8b, Cas8c, Cas9 (also known as Csn1 or Csx12), Cas10, Cas10d, Cas12a / Cpfl, Cas12b / C2cl, Cas12c / C2c3, Cas12d / CasY, Cas12e / CasX, Cas12g, Cas12h, Cas12i, Cas12j / CasΦ, Cpf1, Csy1 , Csy2, Csy3, Csy4, Cse1, Cse2, Cse3, Cse4, Cse5e, Csc1, Csc2, Csa5, Csn1, Csn2, Csm1, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx1S, Csx11, Csf1, Csf2, CsO, Csf4, Csd1, Csd2, Cst1, Cst2, Csh1, Csh2, Csa1, Csa2, Csa3, Csa4, Csa5, Type II Cas effector proteins, Type V Cas effector proteins, Type VI Cas effector proteins, CARF, DinG, homologues thereof, or modified or engineered versions thereof. Other nucleic acid programmable DNA binding proteins are also ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 within the scope of this disclosure, although they may not be specifically listed in this disclosure. See, e.g., Makarova et al. “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?” CRISPR J.2018 Oct;1:325-336. doi: 10.1089 / crispr.2018.0033; Yan et al., “Functionally diverse type V CRISPR-Cas systems” Science.2019 Jan 4;363(6422):88-91. doi: 10.1126 / science.aav7271, the entire contents of each are hereby incorporated by reference. Exemplary nucleic acid programmable DNA binding proteins and nucleic acid sequences encoding nucleic acid programmable DNA binding proteins are provided in the Sequence Listing as SEQ ID NOs: 197-231, 232-245, 254-257, 260, and 378. In some embodiments, the napDNAbp is a (CRISPR-associated system) Cas9 endonuclease, for example, Cas9 (Csnl) from Streptococcus pyogenes (e.g., SEQ ID NO: 197), Cas9 from Neisseria meningitidis (NmeCas9; SEQ ID NO: 208), Nme2Cas9 (SEQ ID NO: 209), Streptococcus constellatus (ScoCas9), or derivatives thereof (e.g., a sequence with at least about 85% sequence identity to a Cas9, such as Nme2Cas9 or spCas9). Further non-limiting examples of nucleic acid programmable DNA binding proteins include those disclosed or referenced in Rufflow, et al., “Design of highly functional genome editors by modeling of the universe of CRISPR-Cas Sequences,” bioRxiv, posted April 22, 2024, doi: 10.1101 / 2024.04.22.590591, the disclosure of which is incorporated herein by reference in its entirety for all purposes, which were designed using artificial intelligence. In some embodiments, the napDNAbp is OpenCRISPR-1, or a variant thereof (e.g., a variant comprising a D10A amino acid alteration and / or lacking an N-terminal methionine). Further non-limiting examples of nucleic acid programmable DNA binding proteins include those disclosed in International Patent Application No. PCT / US2019 / 047996. The terms “nucleobase editing domain” or “nucleobase editing protein,” as used herein, refers to a protein or enzyme that can catalyze a nucleobase modification in RNA or DNA, such as cytosine (or cytidine) to uracil (or uridine) or thymine (or thymidine), and adenine (or adenosine) to hypoxanthine (or inosine) deaminations, as well as non-templated nucleotide additions and insertions. In some embodiments, the nucleobase editing domain is a deaminase domain (e.g., an adenine deaminase or an adenosine deaminase; or a cytidine deaminase or a cytosine deaminase). As used herein, “obtaining” as in “obtaining an agent” includes synthesizing, purchasing, or otherwise acquiring the agent. By “OpenCRISPR-1 polypeptide” is meant a protein with an amino acid sequence having at least about 85% amino acid sequence identity to SEQ ID NO: 3568, or a fragment thereof that associates with a nucleic acid, such as a guide nucleic acid or guide ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 polynucleotide, that guides the napDNAbp to a specific nucleic acid sequence. Further details relating to the OpenCRISPR-1 polypeptide are disclosed in Rufflow, et al., “Design of highly functional genome editors by modeling of the universe of CRISPR-Cas Sequences,” bioRxiv, posted April 22, 2024, doi: 10.1101 / 2024.04.22.590591, the disclosure of which is incorporated herein by reference in its entirety for all purposes. By “OpenCRISPR-1 polynucleotide” is meant a nucleic acid molecule encoding an OpenCRISPR-1 polypeptide, as well as the introns, exons, 3′ untranslated regions, 5′ untranslated regions, and regulatory sequences associated with its expression, or fragments thereof. In embodiments, an OpenCRISPR-1 polynucleotide is the genomic sequence, cDNA, mRNA, or gene associated with and / or required for OpenCRISPR-1 expression. An exemplary OpenCRISPR-1 nucleotide sequence is provided at SEQ ID NO: 3569. In various embodiments, a guide RNA suitable for use in combination with an OpenCRISPR-1 polypeptide contains a scaffold having at least 85% sequence identity to a nucleotide sequence selected from the following, or fragments thereof capable of binding to an OpenCRISPR-1 polypeptide: GUUUUAGAGCUGUGUUGAAAAACACAGCAAGUUAAAAUAAGGCUUUGUCCGUAUCCAACUUG AAAAAGUGAGCACCGAUUCGGUGC (SEQ ID NO: 3570); GUUUUAGAGCUGGAAACAGCAAGUUAAAAUAAGGCUUUGUCCGUAUCCAACUUGAAA AAGUGAGCACCGAUUCGGUGC (SEQ ID NO: 3571); and GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGG CACCGAGUCGGUGC (SEQ ID NO: 3572). By “subject” or “patient” is meant a mammal, including, but not limited to, a human or non-human mammal. In embodiments, the mammal is a bovine, equine, canine, ovine, rabbit, rodent, nonhuman primate, or feline. In an embodiment, “patient” refers to a mammalian subject with a higher than average likelihood of developing a disease or a disorder. Exemplary patients can be humans, non-human primates, cats, dogs, pigs, cattle, cats, horses, camels, llamas, goats, sheep, rodents (e.g., mice, rabbits, rats, or guinea pigs) and other mammalians that can benefit from the therapies disclosed herein. Exemplary human patients can be male and / or female. “Patient in need thereof” or “subject in need thereof” is referred to herein as a patient diagnosed with, at risk or having, predetermined to have, or suspected of having a disease or disorder. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 The terms “pathogenic mutation”, “pathogenic variant”, “disease causing mutation”, “disease causing variant”, “deleterious mutation”, or “predisposing mutation” refers to a genetic alteration or mutation that is associated with a disease or disorder or that increases an individual’s susceptibility or predisposition to a certain disease or disorder. In some embodiments, the pathogenic mutation comprises at least one wild-type amino acid substituted by at least one pathogenic amino acid in a protein encoded by a gene. The terms “protein”, “peptide”, “polypeptide”, and their grammatical equivalents are used interchangeably herein, and refer to a polymer of amino acid residues linked together by peptide (amide) bonds. A protein, peptide, or polypeptide can be naturally occurring, recombinant, or synthetic, or any combination thereof. The term “fusion protein” as used herein refers to a hybrid polypeptide which comprises protein domains from at least two different proteins. The term “recombinant” as used herein in the context of proteins or nucleic acids refers to proteins or nucleic acids that do not occur in nature but are the product of human engineering. For example, in some embodiments, a recombinant protein or nucleic acid molecule comprises an amino acid or nucleotide sequence that comprises at least one, at least two, at least three, at least four, at least five, at least six, or at least seven mutations as compared to any naturally occurring sequence. By “reduces” is meant a negative alteration of at least 10%, 25%, 50%, 75%, or 100%. By “reference” is meant a standard or control condition. In one embodiment, the reference is a wild-type or healthy cell. In other embodiments and without limitation, a reference is an untreated cell that is not subjected to a test condition, or is subjected to placebo or normal saline, medium, buffer, and / or a control vector that does not harbor a polynucleotide of interest. In embodiments, a reference is a healthy subject or cell without inappropriate activation of the complement system. In some cases, a reference is an unedited or untreated cell (e.g., a hepatocyte), tissue (e.g., component of the central nervous system or an organ, such as a liver, eye) and / or subject. In embodiments, a reference is a subject not administered a composition of the disclosure or a component thereof. In some cases, a reference is a subject prior to a change in treatment. A “reference sequence” is a defined sequence used as a basis for sequence comparison. A reference sequence may be a subset of or the entirety of a specified sequence; for example, a segment of a full-length cDNA or gene sequence, or the complete cDNA or gene sequence. For polypeptides, the length of the reference polypeptide sequence will ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 generally be at least about 16 amino acids, at least about 20 amino acids, at least about 25 amino acids, about 35 amino acids, about 50 amino acids, or about 100 amino acids. For nucleic acids, the length of the reference nucleic acid sequence will generally be at least about 50 nucleotides, at least about 60 nucleotides, at least about 75 nucleotides, about 100 nucleotides or about 300 nucleotides or any integer thereabout or therebetween. In some embodiments, a reference sequence is a wild-type sequence of a protein of interest. In other embodiments, a reference sequence is a polynucleotide sequence encoding a wild-type protein. The term “RNA-programmable nuclease,” and “RNA-guided nuclease” refer to a nuclease that forms a complex with (e.g., binds or associates with) one or more RNA(s) that is not a target for cleavage. In some embodiments, an RNA-programmable nuclease, when in a complex with an RNA, may be referred to as a nuclease-RNA complex. Typically, the bound RNA(s) is referred to as a guide RNA (gRNA). In some embodiments, the RNA- programmable nuclease is the (CRISPR-associated system) Cas9 endonuclease, for example, Cas9 (Csnl) from Streptococcus pyogenes (e.g., SEQ ID NO: 197), Cas9 from Neisseria meningitidis (NmeCas9; SEQ ID NO: 208), Nme2Cas9 (SEQ ID NO: 209), Streptococcus constellatus (ScoCas9), or derivatives thereof (e.g., a sequence with at least about 85% sequence identity to a Cas9, such as Nme2Cas9 or spCas9). By “specifically binds” is meant a nucleic acid molecule, polypeptide, polypeptide / polynucleotide complex, compound, or molecule that recognizes and binds a polypeptide and / or nucleic acid molecule of the disclosure, but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample. By “substantially identical” is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence. In one embodiment, a reference sequence is a wild-type amino acid or nucleic acid sequence. In another embodiment, a reference sequence is any one of the amino acid or nucleic acid sequences described herein. In one embodiment, such a sequence is at least about 60%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, or even 99.99%, identical at the amino acid level or nucleic acid level to the sequence used for comparison. Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis.53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 deletions, and / or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. Nucleic acid molecules useful in the methods of the disclosure include any nucleic acid molecule that encodes a polypeptide of the disclosure or a functional fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. Nucleic acid molecules useful in the methods of the disclosure include any nucleic acid molecule that encodes a polypeptide of the disclosure or a functional fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. By “hybridize” is meant pair to form a double-stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or portions thereof, under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger (1987) Methods Enzymol.152:399; Kimmel, A. R. (1987) Methods Enzymol.152:507). By “split” is meant divided into two or more fragments. A “split polypeptide” or “split protein” refers to a protein that is provided as an N- terminal fragment and a C-terminal fragment translated as two separate polypeptides from a nucleotide sequence(s). The polypeptides corresponding to the N-terminal portion and the C- terminal portion of the split protein may be spliced in some embodiments to form a “reconstituted” protein. In embodiments, the split polypeptide is a nucleic acid programmable DNA binding protein (e.g. a Cas9) or a base editor. The term “target site” refers to a nucleotide sequence or nucleobase of interest within a nucleic acid molecule that is modified. In embodiments, the modification is deamination of a base. The deaminase can be a cytidine or an adenine deaminase. The fusion protein or base editing complex comprising a deaminase may comprise a dCas9-adenosine deaminase fusion protein, a Cas12b-adenosine deaminase fusion, or a base editor disclosed herein. As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and / or symptoms associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, reduces the intensity of, or cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease or condition. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of a composition as described herein. By “uracil glycosylase inhibitor” or “UGI” is meant an agent that inhibits the uracil- excision repair system. Base editors comprising a cytidine deaminase convert cytosine to uracil, which is then converted to thymine through DNA replication or repair. In various embodiments, a uracil DNA glycosylase (UGI) prevent base excision repair which changes the U back to a C. In some instances, contacting a cell and / or polynucleotide with a UGI and a base editor prevents base excision repair which changes the U back to a C. An exemplary UGI comprises an amino acid sequence as follows: >splP14739IUNGI_BPPB2 Uracil-DNA glycosylase inhibitor MTNLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSDA PEYKPWALVIQDSNGENKIKML (SEQ ID NO: 231). In some embodiments, the agent inhibiting the uracil-excision repair system is a uracil stabilizing protein (USP). See, e.g., WO 2022015969 A1, incorporated herein by reference. As used herein, the term "vector" refers to a means of introducing a nucleic acid molecule into a cell, resulting in a transformed cell. Vectors include plasmids, transposons, phages, viruses, liposomes, lipid nanoparticles, and episomes. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended. This wording indicates that specified elements, features, components, and / or method steps are present, but does not exclude the presence of other elements, features, components, and / or method steps. Any embodiments specified as “comprising” a particular component(s) or element(s) are also contemplated as “consisting of” or “consisting essentially of” the particular component(s) or element(s) in some embodiments. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure. The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 provides a schematic diagram depicting the alternative pathway of complement amplification. FIG.2 provides a bar graph showing maximum percent A to G base editing of a factor B polynucleotide measured in HEK293T cells transfected with base editor systems ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 containing an adenosine deaminase and the guides indicated along the x-axis. A base editor system containing the guide sg23 and an adenosine deaminase was used as a positive control for base editing. FIG.3 provides a bar graph showing maximum percent C to T base editing of a factor B polynucleotide measured in HEK293T cells transfected with base editor systems containing a cytidine deaminase and the guides indicated along the x-axis. A base editor system containing the guide sg23 and a cytidine deaminase was used as a positive control for base editing. FIG.4 provides a bar graph showing maximum percent A to G base editing of a factor B polynucleotide measured in HEK293T cells transfected with base editor systems containing the indicated adenosine deaminases and guide polynucleotides. In FIG.4, the term “NHP X-Reactivity” means “non-human primate cross-reactivity.” A base editor system with NHP X-Reactivity will edit both a human a non-human primate factor B polynucleotide. Each set of bars, from left-to-right, correspond to base editor systems containing the following guide polynucleotides, respectively: gRNA1193, gRNA1120, gRNA1230, gRNA1217, gRNA1204, gRNA1218, gRNA1203, gRNA1202, gRNA1190, gRNA1213, gRNA1210, and sg23. The guide polynucleotide sg23 was used as a positive control. FIG.5 provides a bar graph showing human complement factor B (hCFB) protein levels (left axis and left bar of each pair of bars) in primary human hepatocytes (PHH) at day 11 (D11) post transfection (P-TF) with the indicated base editor systems, and maximum percent A to G base editing (right axis and right bar of each pair of bars) of a factor B polynucleotide measured in the PHH at day 13 (D13) P-TF with the indicated base editor systems. In FIG.5, the listed editors are base editors containing the indicated TadA* adenosine deaminase domain, and the term “NHP X-Reactivity” means “non-human primate cross-reactivity.” A base editor system with NHP X-Reactivity will edit both a human a non- human primate factor B polynucleotide. The guide sg23 was used as a positive control. The guide polynucleotide gRNA1204 targeted the human factor B polynucleotide sequence GCTTACAATGACTGAGATCTTGG (SEQ ID NO: 429), which differs from the following non- human primate (cyno) factor B polynucleotide sequence at the G in bold: GCTTACAGTGACTGAGATCTTGG (SEQ ID NO: 430). An Abcam Elisa Kit (Human Factor B ELISA Kit (ab137973)) was used to measure protein levels (Range: 4.375 ng / ml - 140 ng / ml; lower limit of quantitation (LLOQ): 0.8 ng / mL). In FIG.5, the editor “spCas9” refers to an spCas9 endonuclease capable of inducing a double-stranded break of DNA. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 FIG.6 provides a bar graph showing the impact of guide polynucleotide spacer length on percent A to G base editing of a factor B polynucleotide in HEK293T cells. The cells were base edited using base editor systems containing the indicated adenosine deaminase base editor and the guide RNA with a spacer having the indicated nucleotide (nt) length ranging from 19 to 23 nucleotides. The first 5 bars from the left correspond to the base editor ABE8.8 with specificity for anNGG PAM sequence, the second 5 bars from the left correspond to the base editor ABE 8.13 with specificity for an NGG PAM sequence, the third 5 bars from the left correspond to the base editor ABE 8.8 with specificity for an NGG PAM sequence, and the rightmost bar corresponds to ABE8.8 with specificity for anNGG PAM sequence. FIGs.7A and 7B provide a bar graph and a schematic diagram relating to optimization of guide spacer length. FIG.7A provides a bar graph showing human complement factor B (hCFB) protein levels (left axis and left bar of each pair of bars) in human hepatocytes isolated from a PXB-mouse (PXB cells) at day 11 (D11) post transfection (P-TF) with the indicated base editor systems, and maximum percent A to G base editing (right axis and right bar of each pair of bars) of a factor B polynucleotide measured in the PXB cells at day 13 (D13) P-TF with the indicated base editor systems. FIG.7A, the listed editors are base editors containing the indicated TadA* adenosine deaminase domain, the term “NHP X-Reactivity” means “non-human primate cross-reactivity,” and the term “Protospacer Length(nt)” indicates the length (19-23 nucleotides) of the spacer in nucleotides (nt) corresponding to the indicated guide polynucleotides. A base editor system with NHP X- Reactivity will edit both a human a non-human primate factor B polynucleotide. The guide sg23 was used as a positive control. The guide polynucleotide gRNA1204 targeted the human factor B polynucleotide sequenceGCTTACAATGACTGAGATCTTGG (SEQ ID NO: 429), which differs from the following non-human primate (cyno) factor B polynucleotide sequence targeted by the guide polynucleotide gRNA1999 (gRNA1204 non-human primate surrogate) at the G in bold: GCTTACAGTGACTGAGATCTTGG (SEQ ID NO: 430). An Abcam Elisa Kit (Human Factor B ELISA Kit (ab137973)) was used to measure protein levels (Range: 4.375 ng / ml - 140 ng / ml; lower limit of quantitation (LLOQ): 0.8 ng / mL). An Abcam Elisa Kit (Human Factor B ELISA Kit (ab137973)) was used to measure protein levels (Range: 4.375 ng / ml - 140 ng / ml; lower limit of quantitation (LLOQ): 0.8 ng / mL). FIG.7B provides a schematic diagram describing the experiment used to gather the data presented in FIG.7A. In FIG.7B, the term “NGS” indicates next-generation sequencing. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 FIGs.8A and 8B provide bar graphs and a Western blot image showing complement factor B polynucleotide base editing efficiency measured in primary cyno hepatocytes (PCH) transfected with base editor systems containing an adenosine deaminase and one of the indicated guides, which were either non-human primate and human factor B cross-reactive or hon-human primate surrogate guide polynucleotides. FIG.8A provides a bar graph showing maximum percent A to G base editing of a factor B polynucleotide measured in PCH transfected with base editor systems containing an adenosine deaminase and the indicated guide polynucleotides. The guide polynucleotide gRNA2072 targeted the human factor B polynucleotide sequence GCTTACAATGACTGAGATCTTGG (SEQ ID NO: 429), which differs from the following non-human primate (cyno) factor B polynucleotide sequence at the G in bold: GCTTACAGTGACTGAGATCTTGG (SEQ ID NO: 430). The top panel of FIG.8B provides a Western blot showing levels of factor B measured in monkey serum, PCH supernatant, humanized mice serum, and in an Abcam human complement factor B (CFB) ELISA standard using an anti-complement factor B monoclonal antibody (Ab-CFB). The lower panel of FIG.8B provides a bar graph showing cyno CFB protein levels normalized to pre-treatment levels for cells corresponding to FIG.8A. FIGs.9A-9D provide bar graphs and plots showing maximum percent A to G base editing of a factor B polynucleotide measured in primary human hepatocytes (PHH) or human hepatoma cells (HepG2 cells) transfected with base editor systems containing the indicated mRNAs encoding an adenosine deaminase and the indicated guide polynucleotides. The base editors encoded by the MRNA molecules referenced in the figures (e.g., m3534 / MRNA3534) are described in Table 9. FIG.9A provides a bar graph showing maximum percent A to G base editing of a factor B polynucleotide measured in PHH transfected with the indicated base editor systems. The base editor system sg23 / m3534 was used as a positive control. FIGs.9B-9D provide plots showing maximum percent A to G base editing of a factor B polynucleotide measured in HepG2 cells transfected with base editor systems containing different doses of the guide polynucleotides TSBTx3826, TSBTx3837, and TSBTx3935, respectively, and a constant dose of the indicated mRNA molecules encoding a base editor. The base editors encoded by the MRNA molecules referenced in the figures (e.g., MRNA3534) are described in Table 9. FIGs.10A and 10B provide bar graphs showing human complement factor B (hCFB) maximum percent A to G base editing, insertion / deletion (indel) mutation rates, and protein levels in FRGTMliver-humanized mice administered a base editor system containing the ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 guide polynucleotide gRNA1193 and an ABE8.8 adenosine deaminase base editor. FIG.10A provides a bar graph showing hCFB maximum percent A to G base editing and indel mutation rates measured in FRGTMliver-humanized mice transfected with a base editor system containing an adenosine deaminase base editor and 2 mg / kg (mpk) or 0.3 mpk of the end-modified guide polynucleotide gRNA1193. The mice were administered tris buffered saline (TBS) as a negative control. FIG.10B provides a bar graph showing concentrations (Conc.) of hCFB protein (hCFB Pr.) measured in FRGTMliver-humanized mice transfected with a base editor system containing an adenosine deaminase base editor and 2 mg / kg (mpk) of the end-modified guide polynucleotide gRNA1193. In FIG.10B, each set of three bars corresponds, from left-to-right, to measurements taken at day 0 (D0) prior to transfection (i.e., “Predose”), at day 7 post-transfection, and at the end of the experiment (i.e., “Terminal”), which was day 14 post-transfection. The upper panel of FIG.10B shows unnormalized protein concentrations and the lower panel of FIG.10B shows protein concentrations normalized to day 0 (D0) concentrations. FIG.11 provides a set of plots showing a negative correlation between serum hC3 and hCFB protein levels in FRGTMliver-humanized mice transfected with a base editor system containing an ABE8.8 adenosine deaminase base editor and 2 mg / kg (mpk) or 0.3 mpk of the end-modified guide polynucleotide gRNA1193. The x-axis indicates the day post- transfection at which measurements were taken. In FIG.11, the arrows extending from each curve indicate the axis to which each curve corresponds. The mice were administered tris buffered saline (TBS) as a negative control. FIGs.12A and 12B provide bar graphs showing human complement factor B (hCFB) percent A to G base editing (FIG.12A) and protein levels (FIG.12B) in FRGTMliver- humanized mice administered a base editor system containing the guide polynucleotide TSBTx3826 with an NLS nucleotide modification scheme and one of the indicated adenosine deaminase base editors (i.e., ABE8.8, ABE8.20, or ABE9.52). A base editor system containing the guide polynucleotide sg23 was used as a positive control. In FIGs.12A and 12B the term “Mod Schem selection” indicates the nucleotide modification scheme of the guide polynucleotide, the term “BE selection (NLS)” indicates base editor selection using guide polynucleotides having an NLS nucleotide modification scheme, the term “Pre-dose” indicates a measurement taken prior to administration of the base editor system to the mice, and the terms “0.5 mpk” and “0.3 mpk” indicate the dose of guide polynucleotide administered to the mice. The TSBTx3826 guide polynucleotide was cross-reactive (i.e., targeted for base editing) both human and cyno CFB polynucleotides, and the location of the ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 target base edit was a splice site at the 5′-end of Exon 3 of the factor B polynucleotide. In FIGs.12A and 12B, the term “ABE9.52” refers to a base editor containing the following adenosine deaminase domain: TadA*8.20 with the amino acid alterations V82T, Y147T, and Q154S. FIG.13 provides a bar graph showing levels of the indicated human complement factor B (hCFB) exons in mRNA collected from tissues of FRGTMliver-humanized mice administered a base editor system containing the guide polynucleotide TSBTx3826 targeting a splice site at the 5′-end of Exon 10 and one of the indicated adenosine deaminase base editors. Measurements were taken at day 14 post-administration of the base editor system. In FIG 13, mRNA levels were normalized to mRNA levels measured for an actin beta (ACTB) gene. In FIG.13, the term “ALAS1 (sg23)” indicates levels of 5′-Aminolevulinate Synthase 1 (ALAS1) transcripts in mice administered a base editor system containing the guide polynucleotide sg23. In FIG.13, the term “ABE9.52” refers to a base editor containing the following adenosine deaminase domain: TadA*8.20 with the amino acid alterations V82T, Y147T, and Q154S. FIGs.14A and 14B provide bar graphs showing human complement factor B (hCFB) percent A to G base editing (FIG.14A) and protein levels (FIG.14B) in FRGTMliver- humanized mice administered a base editor system containing the guide polynucleotide TSBTx3837 with an HM01 nucleotide modification scheme and one of the indicated adenosine deaminase base editors (i.e., ABE8.8 or ABE8.20). Base editor systems containing the guide polynucleotide sg23 or TSBTx3826 having an NLS nucleotide modification scheme were used as controls. In FIGs.14A and 14B the term “Mod Schem selection” indicates the nucleotide modification scheme of the guide polynucleotide, the term “BE selection (NLS)” indicates base editor selection using guide polynucleotides having an NLS nucleotide modification scheme, the term “Pre-dose” indicates a measurement taken prior to administration of the base editor system to the mice, and the terms “0.5 mpk” and “0.3 mpk” indicate the dose of guide polynucleotide administered to the mice. The TSBTx3837 guide polynucleotide targeted hCFB and was not cross-reactive (i.e., targeted for base editing) cyno CFB polynucleotides because the TSBTx3837 guide polynucleotide target site differed from the corresponding cyno CFB target site by one (1) nucleotide, and the location of the target base edit was a splice site at the 3′-end of Exon 11 of the factor B polynucleotide. In FIGs. 14A and 14B, the term “ABE9.52” refers to a base editor containing the following adenosine deaminase domain: TadA*8.20 with the amino acid alterations V82T, Y147T, and Q154S. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 FIG.15 provides a bar graph showing levels of the indicated human complement factor B (hCFB) exons in mRNA collected from tissues of FRGTMliver-humanized mice administered a base editor system containing the guide polynucleotide TSBTx3837 targeting a splice site at the 3′-end of Exon 11 and one of the indicated adenosine deaminase base editors. Measurements were taken at day 14 post-administration of the base editor system. In FIG 15, mRNA levels were normalized to mRNA levels measured for an actin beta (ACTB) gene. In FIG.15, the term “ALAS1 (sg23)” indicates levels of 5′-Aminolevulinate Synthase 1 (ALAS1) transcripts in mice administered a base editor system containing the guide polynucleotide sg23. FIG.16A and 16B provide bar graphs showing human complement factor B (hCFB) percent A to G base editing (FIG.16A) and protein levels (FIG.16B) in FRGTMliver- humanized mice administered a base editor system containing the guide polynucleotide TSBTx3835 with an end-mod nucleotide modification scheme and one of the indicated adenosine deaminase base editors (i.e., ABE8.13 or ABE9.52). Base editor systems containing the guide polynucleotide sg23 or TSBTx3826 having an NLS nucleotide modification scheme were used as controls. In FIGs.16A and 16B the term “Mod Schem selection” indicates the nucleotide modification scheme of the guide polynucleotide, the term “BE selection (NLS)” indicates base editor selection using guide polynucleotides having an NLS nucleotide modification scheme, the term “Pre-dose” indicates a measurement taken prior to administration of the base editor system to the mice, and the terms “0.5 mpk” and “0.3 mpk” indicate the dose of guide polynucleotide administered to the mice. The TSBTx3835 guide polynucleotide targeted hCFB and was cross-reactive (i.e., targeted for base editing) with human and cyno CFB polynucleotides, and the location of the target base edit was a splice site at the 3′-end of Exon 16 of the factor B polynucleotide. In FIGs.16A and 16B, the term “ABE9.52” refers to a base editor containing the following adenosine deaminase domain: TadA*8.20 with the amino acid alterations V82T, Y147T, and Q154S. FIG.17 provides a bar graph showing levels of the indicated human complement factor B (hCFB) exons in mRNA collected from tissues of FRGTMliver-humanized mice administered a base editor system containing the guide polynucleotide TSBTx3835 targeting a splice site at the 3′-end of Exon 16 and one of the indicated adenosine deaminase base editors. Measurements were taken at day 14 post-administration of the base editor system. In FIG 17, mRNA levels were normalized to mRNA levels measured for an actin beta (ACTB) gene. In FIG.17, the term “ALAS1 (sg23)” indicates levels of 5′-Aminolevulinate Synthase 1 (ALAS1) transcripts in mice administered a base editor system containing the guide ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 polynucleotide sg23. In FIG.17, the term “ABE9.52” refers to a base editor containing the following adenosine deaminase domain: TadA*8.20 with the amino acid alterations V82T, Y147T, and Q154S. FIG.18 provides a plot showing complement factor B polynucleotide maximum percent A to G editing in primary human hepatocytes (PHH) or primary cyno hepatocytes (PCH), as indicated, transfected with base editor systems containing the indicated guide polynucleotides and an adenosine deaminase base editor. A base editor system containing an adenosine deaminase and the guide polynucleotide sg23 was used as a positive control. Cells were transfected with the guide polynucleotide and mRNA encoding the base editor at a mass ratio of 1-to-3 (1:3). The TSBTx3837 guide was used in combination with the base editor ABE8.20, and the guide had an HM01 nucleotide modification scheme. The TSBTx3826 guide was used in combination with a base editor containing a TadA*8.20 adenosine deaminase domain with the amino acid alterations V82T, Y147T, and Q154S, and the guide had an NLS nucleotide modification scheme. FIGs.19A-19D provide a schematic diagram and plots. FIG.19A provides a schematic diagram showing the sequence of a polynucleotide construct used to compare the potency of guide polynucleotides targeting human complement factor B (CFB) and / or non- human primate CFB for base editing. The binding sites for guide polynucleotides targeting a human CFB polynucleotide (i.e., “CFB guide-human”) and a non-human primate CFB polynucleotide (i.e., “CFB guide-NHP”) are indicated. In FIG.19A, the term “10bp” indicates a 10 nucleotide spacer, and the term “30 bp random spacer” indicates a randomized sequence of 30 nucleotides. In FIG.19A, the two nucleotide sequences depicted are reverse complements of one another. In FIG.19A, the upper nucleotide sequence is. CATGGCAGGCCAAGATCTCAGTCATTGTAAGCACAGAATCCCATATGGAAGGTCATTAGCTC CGGCAAGCAATCATGGCAGGCCAAGATCTCAGTCACTGTAAGCACAGAATCCCA (SEQ ID NO: 431), and the amino acid sequences are HGRPRSQSL (SEQ ID NO: 432) and AQNPIWKVISSGKQSWQAKISVTVSTES (SEQ ID NO: 433). The term “*” in the amino acid sequence of FIG.19A indicates a stop codon, and the term “CFB insert” indicates that the polynucleotide construct was inserted into the genome of HEK293T cells. FIGs.19B-19D show percent base editing in three separate experiments (i.e., Batch 1, Batch 2, and Batch 3, respectively) at the “CFB guide-human” and “CFB guide-NHP” sites in HEK293T cells transfected with base editor systems containing an adenosine deaminase and the indicated ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 doses of the guide gRNA2067 (TSBTx3837; targeting the CFB guide-human site) or the guide gRNA2072 (TSBTx2072; targeting the CFB guide-HNP site). FIG.20 provides a bar graph showing complement factor B (CFB) TATA box A to G editing in human hepatoma cells (HepG2 cells) transfected with the indicated base editor systems (i.e., Sample 1 to Sample 16, which are described in Table 12.1A) containing a guide polynucleotide and an adenosine deaminase. The cells were transfected with a saturating dose of 800 ng total of guide polynucleotide and mRNA encoding the base editor at a mass ratio of 1:3. The CFB TATA box was located at positions -157 to -151 relative to the CFB start codon. A base editor system containing an adenosine deaminase base editor and the guide sgRNA_088 (sg23) was used as a positive control. The bars of FIG.20 each correspond in order, from left-to-right, to base editor systems containing the base editors listed in Table 12.1A. FIGs.21A and 21B provide bar graphs showing complement factor B (CFB) start codon A to G editing in human hepatoma cells (HepG2 cells) (FIG.21A) or primary human hepatocyte (PHH) monolayer cells transfected with base editor systems (i.e., Sample 1 to Sample 8 of FIG.21A and Sample 1 to Sample 3 of FIG.21B, which are described in Table 12.1B) containing a guide polynucleotides and an adenosine deaminase. A base editor system containing an adenosine deaminase base editor and the guide sgRNA_088 (sg23) was used as a positive control. Beneath the x-axis of the bar graphs of FIGs.21A and 21B are listed the CFB amino acid alterations (e.g., M1T, G2E, G2R, L5P, or S3P) corresponding to the base edits corresponding to each bar. The cells were transfected with a saturating dose of 800 ng total of guide polynucleotide and mRNA encoding the base editor at a mass ratio of 1:3. FIGs.22A and 22B provide a bar graph and a schematic diagram relating to complement factor B (CFB) TATA-box and start codon disruption in primary human hepatocytes (PHH) for protein knock-down. FIG.22A provides a bar graph showing human complement factor B (hCFB) protein levels (left axis and left bar of each pair of bars) in PHH at day 12 (D12) post transfection (P-TF) with base editor systems (i.e., Sample 1 to Sample 16, which are described in Table 12.1C) containing an adenosine deaminase and a guide polynucleotide, and maximum percent A to G base editing (right axis and right bar of each pair of bars) of a factor B polynucleotide measured in the PXB cells at day 13 (D13) P-TF with the base editor systems. FIG.22A, a base editor system containing an adenosine deaminase and the guide polynucleotide sgRNA_088 (sg23) was used as a positive control for base editing. FIG.22B provides a schematic diagram describing the experiment used to gather the data presented in FIG.22A. In FIG.22B, the term “MC” indicates a media ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 change, and the term “NGS” indicates next-generation sequencing. The data of FIG.22A is not normalized; however, a similar pattern was observed with data normalization to protein levels prior to transfection (i.e., day 0). FIG.23 provides a set of bar graphs showing high editing and good reduction of complement factor B (CFB) protein levels in primary human hepatocyte (PHH) co-cultures transfected with base editor systems containing an adenosine deaminase with one of the indicated PAM specificities (e.g.,NGC,NGG, orNGA) and one of the indicated guide polynucleotides targeting the CFB start codon for base editing. Base editor systems containing an adenosine deaminase and the guide polynucleotide sg23 or gRNA1193 (TSBTx3826) were used as a positive control. In FIG.23, the term “dABE (-) Control” indicates a defective or “dead” adenosine base editor. The top panel of FIG.23 presents data collected using cells from a donor designated “JGC” and the lower panel of FIG.23 presents data collected using cells from a donor designated “MRW.” The base editor systems were administered to the cells at a saturating total dose of 800 ng of the guide polynucleotide and mRNA encoding the adenosine deaminase. None of the guide polynucleotides were cross- reactive with non-human primate target sites (i.e., the guides target a human CFB polynucleotide for base editing but not a cyno CFB polynucleotide). The target site for gRNA 3657 was TGCTCCCCATGGCGTTGGAAGGC (SEQ ID NO: 434), whereas the corresponding non-human primate (NHP) target site is TGCTCCCCATGGCATTAGAAGGC (SEQ ID NO: 435), where bold nucleotides indicate where the human gRNA 3657 target site differs from the corresponding NHP target site, and where the nucleotides corresponding to the CFB start codon are underlined. The target site for gRNA 3658 was TTGCTCCCCATGGCGTTGGAAGG (SEQ ID NO: 436), whereas the corresponding non-human primate (NHP) target site is CTGCTCCCCATGGCATTAGAAGG (SEQ ID NO: 437), where bold nucleotides indicate where the human gRNA 3658 target site differs from the corresponding NHP target site, and where the nucleotides corresponding to the CFB start codon are underlined. The target site for gRNA 3660 was CCCCATGGCGTTGGAAGGCAGGA (SEQ ID NO: 438), whereas the corresponding non-human primate (NHP) target site is CCCCATGGCATTAGAAGGCAGGA (SEQ ID NO: 439), where bold nucleotides indicate where the human gRNA 3660 target site differs from the corresponding NHP target site, and where the nucleotides corresponding to the CFB start codon are underlined. In FIG.23, for every set of three bars, the first two bars from the left correspond to hCFB protein level measurements taken at day 7 (D7) and day 13 (D13) post-transfection and normalized to levels measured prior to transfection (i.e., at day ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 0), and the bar on the right corresponds to CFB polynucleotide A to G editing measured at day 13. FIG.24 provides a ribbon diagram depicting the structure of complement factor B, where residues corresponding to the indicated protein regions (i.e., oxyanion hole, serine protease active site, salt bridges, cleavage site, verified mutations (i.e., mutations known to be associated with a reduction in CFB activity), or Mg2+binding loop) are shown as spheres. The ribbon diagram of FIG.24 corresponds to Protein Data Bank accession No.2ok5, the disclosure of which is incorporated herein by reference in its entirety for all purposes. FIG.25 provides a bar graph showing complement factor B (CFB) percent base editing rates measured in HEK293T cells transfected with base editor systems containing an adenosine deaminase base editor (ABE) or a cytidine deaminase base editor (CBE), as indicated, and one of the indicated guide polynucleotides. Base editor systems containing the guide polynucleotide sg23 and a CBE or an ABE were used as positive controls for base editing. The amino acid alterations corresponding to the percent base editing rates represented by each bar are indicated beneath the x-axis. In FIG.25 the term “Tier 1” refers to the Tier 1 amino acid residues listed in Table 13. FIG.26 provides a bar graph showing complement factor B (CFB) percent base editing rates measured in HEK293T cells transfected with base editor systems containing an adenosine deaminase base editor (ABE) or a cytidine deaminase base editor (CBE), as indicated, and one of the indicated guide polynucleotides. Base editor systems containing the guide polynucleotide sg23 and a CBE or an ABE were used as positive controls for base editing. The amino acid alterations corresponding to the percent base editing rates represented by each bar are indicated beneath the x-axis. In FIG.26 the term “Tier 1” refers to the Tier 1 amino acid residues listed in Table 13. FIG.27 provides a bar graph showing complement factor B (CFB) percent base editing rates measured in HEK293T cells transfected with base editor systems containing an adenosine deaminase base editor (ABE) or a cytidine deaminase base editor (CBE), as indicated, and one of the indicated guide polynucleotides. Base editor systems containing the guide polynucleotide sg23 and a CBE or an ABE were used as positive controls for base editing. The amino acid alterations corresponding to the percent base editing rates represented by each bar are indicated beneath the x-axis. In FIG.27 the term “Tier 2” refers to the Tier 2 amino acid residues listed in Table 13. FIG.28 provides a bar graph showing complement factor B (CFB) percent base editing rates measured in HEK293T cells transfected with base editor systems containing an ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 adenosine deaminase base editor (ABE) or a cytidine deaminase base editor (CBE), as indicated, and one of the indicated guide polynucleotides. Base editor systems containing the guide polynucleotide sg23 and a CBE or an ABE were used as positive controls for base editing. The amino acid alterations corresponding to the percent base editing rates represented by each bar are indicated beneath the x-axis. In FIG.28 the term “Tier 2” refers to the Tier 2 amino acid residues listed in Table 13. FIG.29 provides a bar graph showing complement factor B (CFB) percent base editing measured in a primary human hepatocyte (PHH) monolayer transfected with base editor systems containing an adenosine deaminase base editor (ABE) or a cytidine deaminase base editor (CBE), as indicated, and one of the indicated guide polynucleotides. Base editor systems containing the guide polynucleotide sg23, gRNA1193 (TSBTx3826), or gRNA2067 (TSBTx3837) and a CBE or an ABE were used as positive controls for base editing. The amino acid alterations corresponding to the percent base editing rates represented by each bar are indicated beneath the x-axis. The PHH monolayer was administered 200 ng of the indicated guide polynucleotide and 600 ng of mRNA encoding the base editor. FIG.29 presents a sub-portion of data from FIGs.25-28. FIG.30 provides a schematic diagram showing guide-dependent and guide- independent deamination of a nucleotide of a polynucleotide and lists representative methods by which the same may be predicted or measured. FIG.30 is adapted from Kempton and Lei, Science, 364:234-236 (2019), the disclosure of which is incorporated herein by reference in its entirety for all purposes. FIG.31 provides a bar graph showing an alternative presentation of data from FIG. 23 relating to start codon disruption of CFB in primary human hepatocyte co-cultures. In FIG.31, each pair of bars represents, from left-to-right, hCFB protein level and A to G editing. In FIG.31, “dABE (-) Ctrl” indicates negative control base editor systems containing a catalytically inactive base editor. The base editor systems of FIG.31 (i.e., Sample 1 to Sample 9) are described in Table 12.1D. FIGs.32A and 32B provide a bar graph and a schematic diagram relating to a functional assessment of start codon targeting guides in a long-term HepG2 culture system. FIG.6 provides a bar graph showing base editing rates for the indicated target sites achieved using the indicated active or inactive base editor systems corresponding to Sample 1 to Sample 8, which are described in FIG.12.1E. FIG.32B provides a schematic diagram describing the experiment used to collect the data presented in FIG.32A. In FIG.32B, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 “MC” indicates a media change, “TF” indicates transfection with a base editor system, and “NGS” indicates next-generation sequencing. FIG.33 provides plots showing human complement factor B (hCFB) protein levels in long-term HepG2 culture systems containing cells transfected with the indicated active (left panel) or inactive (right panel) base editor systems corresponding to Sample 1 to Sample 8, which are described in Table 12.1E, and targeting the indicated sites for editing at the indicated days post-transfection (post-TF). In the left panel of FIG.33, the lines at 10-days post-TF correspond, from top-to-bottom, to Sample 1, Sample 7, Sample 2, Sample 6 / Sample 5, Sample 3, and Sample 4, and the third line from the bottom at 22 days corresponds to Sample 5. In the right panel of FIG.33, the lines at 10-days post-TF correspond, from top-to- bottom, Sample 1, Sample 6, Sample 2, Sample 3, Sample 7, Sample 4, and Sample 5. “Inactive editors” contained a catalytically inactive base editor. FIGs.34A and 34B provide bar graphs showing rates of base editing of complement factor B (CFB) target sites in non-human primates using the indicated base editing systems, which are described in Table 18. FIG.34A provides a bar graph showing CFB base editing rates observed in two liver biopsies, each taken from a different section of the liver, collected from non-human primates at 15-days post-administration of the indicated base editor systems. FIG.34B provides a bar graph showing CFB base editing rates observed in the indicated liver sections for the non-human primate at 60-days post-administration of the indicated base editor systems. The doses indicated in FIGs.34A and 34B are expressed as total gRNA administered. In FIG.34B, “LLR” represents Liver, left lateral lobe (proximal, distal, and median from the hilus), “LLC” represents Liver, right lateral lobe (proximal and distal from the hilus), “LC” represents Liver, caudate lobe Liver, left median lobe, “LMR” represents Liver, right median lobe, and “LML” represents Liver, center papillary Lung (right diaphragmatic, 2 samples). FIG.35 provides plots showing change from baseline of the indicated biomarkers (i.e., AH-50, Bb, and C3a) in non-human primates administered the indicated base editor systems corresponding to Grp1 (Control gRNA) or Grp5 (CFB 11.5mg / kg) of Table 18 at the indicated days following administration of the base editor systems. AH-50 indicates the hemolytic assay measuring alternative pathway. The y-axis of the top panel of FIG.35 represents percent change from baseline in plasma levels of complement factor B protein (FBL) or Bb. The top panel of FIG.35 provides a plot showing the mean reductions in plasma full-length Factor B levels (FBL) and the split product of Factor B (Bb) as a percentage of baseline concentration in cynomolgus monkeys that were administered a base ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 editor system intravenously at a dose of 1.5 mg total RNA per kilogram of body weight on day 0. The animals were followed for 57 days. A control group received control LNPs that did not contain base editor systems targeting CFB for editing. The bottom panel of FIG.35 provides a plot showing the mean reductions in serum alternative complement activity as a percentage of baseline concentration in cynomolgus monkeys that were administered a base editor system intravenously at a dose of 1.5 mg total RNA per kilogram of body weight on day 0. The animals were followed for 57 days. A control group received control LNPs that did not contain base editor systems targeting CFB for editing. FIG.36 provides a bar graph showing maximum A to G percent editing at a human complement factor B (hCFB) target site in transgenic mice administered the indicated base editor systems corresponding to Grp1 (ALAS1) and Grp5 (CFB 1 at a total gRNA dose of 0.1 mg / kg (mpk), 0.3mpk, or 1mpk) of Table 18. In FIG.36, “HOM” indicates mice homozygous for hCFB and “HET” indicates mice that are heterozygous for hCFB. FIG.37 provides an image of an immunoblot demonstrating that transgenic (Tg) mice heterozygous (Het) for hCFB administered a total gRNA dose of 0.3 mg / kg or 1 mg / kg of the base editor system corresponding to Grp5 of Table 18 showed reduced plasma levels of hCFB at day 15 (D15) post-administration relative to pre-administration (Pre). FIG.38 provides a bar graph demonstrating that transgenic (Tg) mice heterozygous (Het) or homozygous (Homo) for hCFB administered the indicated total gRNA dose of the base editor system (“CFB”) corresponding to Grp5 of Table 18 showed reduced plasma levels of hCFB at day 15 (D15) post-administration relative to pre-dosing (PD) and relative to control mice. The term “Control gRNA” in FIG.38 indicates a base editor system corresponding to Grp1 of Table 18. FIG.39 provides a schematic diagram describing the experiment undertaken to collect the data corresponding to FIGs.40 and 41 and Table 22. FIG.40 provides a bar graph showing hCFB base editing rates observed at day 14 post-dosing in the livers of transgenic mice administered the indicated doses of the indicated base editor systems (see also Table 22). The four sets of bars presented in FIG.40 correspond, from left-to-right, to ALAS1 (one bar; Group 1 of Table 22), CFB 1 NLS (four bars; Groups 2 to 5 of Table 22; Formulation 1), CFB 1 End-Mod (four bars; Groups 6 to 9 of Table 22; Formulation 2), and CFB 2 (four bars; Groups 10 to 13 of Table 22; Formulation 3). Group 3, animal 3012, with a scheduled death on D4 of dosing was excluded from analysis (4.78% editing). Group 4 animals 3013, 3015, and 3016; Group 10 animal ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 3040; and Group 13 animal 3049 were all found dead and no tissue was preserved for editing assessment. FIG.41 provides a bar graph showing results from an Elisa analysis showing percent change from baseline of hCFB protein levels at day 14 post-dosing in the mice of FIG.40. The terms “NLS”, “End-Mod”, and “Lit Mod1 / HMO1” in FIG.41 correspond to Formulations 1, 2, and 3 of Table 22, respectively. DETAILED DESCRIPTION Provided herein are base editors, endonucleases, and guide RNAs (gRNAs) for use in editing, modifying, or altering a target polynucleotide. In particular embodiments, a base editor or endonuclease of the present disclosure modifies a complement factor B (CFB) polynucleotide. In particular embodiments, a base editor of the invention introduces a stop codon, or missense mutation (e.g., a mutation resulting in a CFB with reduced activity) alteration in a CFB polynucleotide or disrupts a TATA box, start site, or splice site in the CFB polynucleotide. The alterations are associated with a reduction in activity or levels of a CFB polypeptide and / or polynucleotide in a cell. The invention of the disclosure is based, at least in part, on the discovery that the alternative pathway of the complement system requires the protein factor B for complement pathway amplification and function. The invention is further based, at least in part, upon the discovery that base editing (e.g., disruption of splice acceptor or splice donor, or introduction of a stop codon, missense mutation, or indel alteration) can be used to reduce the expression of a factor B polypeptide in a cell associated with a dysregulated complement system (e.g., inappropriate activation). In particular, reducing activity and / or expression of the factor B polypeptide in a subject diagnosed with a disease or disorder associated with over-activation of the complement system can be an effective treatment strategy. This reduction in activity and / or expression can be effected using any of the base editing systems and / or endonucleases and methods provided herein. Accordingly, the invention features compositions and methods for editing a factor B polynucleotide. The edit to the factor B polynucleotide is associated with a reduction in expression and / or activity of a factor B polypeptide in a cell, tissue, and / or body fluid of a subject, as well as a reduction in symptoms associated with overactivation or otherwise pathogenic activation of the complement system in a subject. Accordingly, as described in the examples provided herein base editor systems were successfully developed to disrupt complement system activity through functional disruption of factor B at the gene level. Factor B disruption was carried out using two separate ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 approaches: 1) silencing / knock-out of the factor B gene and 2) generation of mutations that disrupted specific factor B functions (see, e.g., those sites listed in Table 14 below). In embodiments, the methods of the present disclosure include disrupting splicing of a factor B polynucleotide transcript. For example, the base editors or base editor systems provided herein can be used for editing a nucleobase in the splice acceptor situated 5′ of an exon of the factor B polynucleotide. In some embodiments, the target sequence is a splice acceptor in a portion of an intron adjacent to an exon of the factor B polynucleotide and editing a nucleobase in the splice acceptor is associated with a change in the splice acceptor compared to a wild-type splice acceptor site. In some embodiments, the deamination of an A or C nucleobase in the splice acceptor results in disruption of splicing of the mRNA transcript during or after transcription. In some embodiments, the subject has or has the potential to develop a dysregulated and / or over-activated complement system and any disease or disorder associated therewith. In some instances, the methods of the present disclosure include modifying the factor B polynucleotide to introduce an amino acid alteration in a factor B polypeptide encoded thereby. In embodiments, the amino acid alteration disrupts cleavage of the factor B polypeptide by a plasma factor D to yield a Ba fragment and the active protease Bb fragment. In some instances, the methods of the present disclosure include modifying a factor B polynucleotide to introduce a stop codon, start site disruption, TATA box disruption, or missense mutation associated with a reduction in levels or activity of the complement factor B polynucleotide and / or polypeptide. The alterations can be effected by a base editor system, such as those described herein. In some embodiments, the present disclosure provides base editors that efficiently generate an intended mutation, such as a point mutation, in a nucleic acid molecule (e.g., a nucleic acid within a genome of a subject) without generating a significant number of unintended mutations, such as unintended point mutations. In some embodiments, an intended mutation is a mutation that is generated by a base editor system containing a specific base editor (e.g., an adenosine base editor or a cytidine base editor), where the base editor system is specifically designed to generate the intended mutation. In some embodiments, the intended mutation is an adenine (A) to guanine (G) point mutation within the non-coding region of a gene. In some embodiments, the intended mutation is a cytosine (C) to thymine (T) point mutation within the non-coding region of a gene. In some embodiments, the intended mutation is a mutation of a splice acceptor in an intron of a gene associated with a disease or disorder. In some cases, the intended mutation is an indel mutation. In some ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 embodiments, the intended mutation is an adenine (A) to guanine (G) point mutation in the splice acceptor site in an intron of a gene associated with a disease or disorder. In some embodiments, the intended mutation is a missense mutation. The intended mutation can include the introduction of a stop codon to a polynucleotide sequence. In some embodiments, the intended mutation is a mutation that disrupts normal splicing of a complete transcript of a gene, for example, an A to G change in a splice acceptor site within an intron of a disease- causing or a disease-associated gene. In some embodiments, the intended mutation is a mutation in a splice acceptor site that disrupts splicing of a gene transcript and results in an alternative transcript that encodes a truncated and / or nonfunctional protein product. In some embodiments, any of the base editors or endonucleases provided herein are capable of generating a ratio of intended mutations to unintended mutations (e.g., intended point mutations : unintended point mutations) that is greater than 1 : 1. In some embodiments, any of the base editors provided herein are capable of generating a ratio of intended mutations to unintended mutations (e.g., intended point mutations : unintended point mutations) that is at least 1.5: 1, at least 2: 1, at least 2.5: 1, at least 3: 1, at least 3.5: 1, at least 4: 1, at least 4.5: 1, at least 5: 1, at least 5.5: 1, at least 6: 1, at least 6.5: 1, at least 7: 1, at least 7.5: 1, at least 8: 1, at least 10: 1, at least 12: 1, at least 15: 1, at least 20: 1, at least 25: 1, at least 30: 1, at least 40: 1, at least 50: 1, at least 100: 1, at least 150: 1, at least 200: 1, at least 250: 1, at least 500: 1, or at least 1000: 1, or more. In some embodiments, editing of a plurality of nucleobase pairs in one or more genes using the methods provided herein results in formation of at least one intended mutation. In some embodiments, the formation of the at least one intended mutation is in a splice acceptor site and results in disruption of splicing of the mRNA transcript of a disease-associated gene. In some embodiments, the formation of the at least one intended mutation results in a reduction in activity and / or expression of a disease-associated gene. It should be appreciated that multiplex editing can be accomplished using any method or combination of methods provided herein. The present disclosure provides methods for the treatment of a subject diagnosed with a dysregulated and / or over-activated complement system or any disease or disorder associated therewith. For example, in some embodiments, a method is provided that comprises administering to a subject having or having a propensity to develop a dysregulated and / or over-activated complement system, an effective amount of a nucleobase editor (e.g., an adenosine deaminase base editor or a cytidine deaminase base editor) to effect an alteration in a factor B polynucleotide sequence. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 THE COMPLEMENT SYSTEM AND FACTOR B Complement is a system consisting of numerous plasma and cell-bound proteins that plays an important role in both innate and adaptive immunity. The proteins of the complement system act in a series of enzymatic cascades through a variety of protein interactions and cleavage events. The complement system is a component of the innate immune system and is important for the clearance of pathogens and dead or dying cells. Complement activation results in: formation of a membrane attack complex and cell cytolysis; opsonization of foreign material, targeting it for phagocytosis; and activation of inflammation and diverse immune components. Many complement components are circulating factors primarily produced in the liver. The complement system plays an important role in defending the body against infectious agents. The complement system contains over 30 serum and cellular proteins that are involved in three major pathways, known as the classical, alternative, and lectin pathways. The classical pathway is typically triggered by binding of a complex of antigen and IgM or IgG antibody to C1 (though certain other activators can also initiate the pathway). Activated C1 cleaves C4 and C2 to produce C4a and C4b, in addition to C2a and C2b. C4b and C2a combine to form C3 convertase, which cleaves C3 at a defined cleavage site to form C3a and C3b. Binding of C3b to C3 convertase produces C5 convertase, which cleaves C5 into C5a and C5b. C3a, C4a, and C5a are anaphylotoxins and mediate multiple reactions in the acute inflammatory response. C3a and C5a are also chemotactic factors that attract immune system cells such as neutrophils. Further details relating to C3 are provided in Ricklin, et al. “Complement component C3 - The ‘Swiss Army Knife’ of innate immunity and host defense.” Immunol Rev.2016 Nov; 274(1):33-58; and in Janssen, et al., “Structures of complement component C3 provide insights into the function and evolution of immunity.” Nature.2005 Sep 22;437(7058):505-11, the disclosures of which are incorporated herein by reference in their entireties for all purposes. The alternative pathway (see, e.g., FIG.1) is typically initiated by and amplified at microbial surfaces and various complex polysaccharides. The alternative pathway is triggered by the covalent binding of C3b to a pathogen or cell surface. Next, factor B binds to surface bond C3b, making it susceptible to plasma factor D cleavage. The result is production of Ba and active protease Bb, which remains bound to C3b creating C3bBb, which is the C3 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 convertase of the alternative complement pathway. This starts the amplification loop with the C3 convertase generating more C3b on the cell surface and the process repeats. Ultimately, there is C3b saturation on the cell surface with release of C3a, a small inflammatory mediator. Eventually, some of the C3b binds to preexisting C3 convertase producing C3b2Bb, which is the alternative pathway's C5 convertase. This cleaves C5 into C5b, which generates the membrane attack complex (MAC), and C5a, a potent proinflammatory mediator. Complement-mediated endothelial cell injury creates a prothrombotic state. It exposes subendothelial collagens and releases vWF and fibrinogen formation. Normally the presence of complement regulatory proteins on cell surfaces prevents significant complement activation from occurring thereon. A more detailed description of the alternative pathway is provided in Keir, L. and Coward, R.J.M., 2011. Pediatr. Nephrol.26, 523–533, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Complement factor B (CFB; alternatively “factor B”) is a serine protease and a key component of the complement alternative pathway (AP) / amplification loop. Complement factor D (CFD), another serine protease, cleaves CFB to form Ba and Bb. Bb forms an integral part of the convertase complexes of the AP, which serve to activate the central complement proteins C3 and C5 through proteolytic cleavage. The C5 convertases produced in both pathways cleave C5 to produce C5a and C5b. C5b then binds to C6, C7, and C8 to form C5b-8, which catalyzes polymerization of C9 to form the C5b-9 membrane attack complex (MAC), also known as the terminal complement complex (TCC). The MAC inserts itself into target cell membranes and causes cell lysis. Small amounts of MAC on the membrane of cells may have a variety of consequences other than cell death. If the TCC does not insert into a membrane, it can circulate in the blood as soluble sC5b-9 (sC5b-9). Levels of sC5b-9 in the blood may serve as an indicator of complement activation. The lectin complement pathway can be initiated by binding of mannose-binding lectin (MBL) and MBL-associated serine protease (MASP) to carbohydrates. The MB1-1 gene (known as LMAN-1 in humans) encodes a type I integral membrane protein localized in the intermediate region between the endoplasmic reticulum and the Golgi. The MBL-2 gene encodes the soluble mannose-binding protein found in serum. In the human lectin pathway, MASP-1 and MASP-2 are involved in the proteolysis of C4 and C2, leading to a C3 convertase described above. Accordingly, the present disclosure provides methods for disrupting complement activation by altering a polynucleotide encoding factor B. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 DISEASES AND / OR DISORDERS ASSOCIATED WITH UNDESIRABLY INCREASED ACTIVATION OF THE COMPLEMENT SYSTEM Inappropriate activation of the complement system can lead to various diseases and / or disorders in a subject. For example, inappropriate activation of the complement system in a subject damages cells resulting in increased inflammation, the presence of autoantibodies, neural degeneration, and microthrombosis, among others. Inappropriate activation of the complement system is associated with damage to the nervous system (e.g., the Central Nervous System (CNS)), circulatory system, kidneys, eyes, blood cells (e.g., red and white blood cells and platelets), and transplanted organs, as well as damage to other organs or tissues, which may be associated with the presence of micro-emboli. Therefore, an effective treatment for such diseases and / or disorders can involve altering a factor B nucleotide sequence to reduce and / or eliminate expression and / or activity of a factor B polypeptide in a subject, thereby reducing activation of the complement system in an organ, cell, and / or tissue. In embodiments, the organ or tissue is an eye, kidney, nervous system component, heart, or thyroid. Not intending to be bound by theory, complement protein levels in the eye may be dependent on circulating levels of complement proteins generated in the liver. Some important indications for a subject requiring treatment for inappropriate activation (e.g., overactivation or dysregulation) of the complement system include paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and IC-MPGN / C3 glomerulopathy. PNH is associated with hemolysis of red blood cells (RBCs) resulting in anemia and thrombosis. The disorder aHUS is associated with hemolysis of RBCs as well as thrombocytopenia and acute kidney failure caused by abnormal clot formation in small blood vessels in the kidney. IC-MPGN and C3 glomerulopathy are associated with kidney malfunction and end-stage renal disease caused by damage to glomeruli of the kidney. Non-limiting examples of diseases associated inappropriate activation of the complement system include blood disorders, transplant or graft rejection, inflammatory diseases or disorders, eye diseases or disorders, kidney diseases or disorders, heart disorders, respiratory / pulmonary diseases or disorders, autoimmune disorders, inflammatory bowel diseases or disorders, arthritis, neurodegenerative diseases or disorders, musculoskeletal diseases or disorders associated with inflammation, disorders affecting the integumentary system, diseases or disorders affecting the central nervous system, diseases or disorders affecting the circulatory system, diseases or disorders affecting the gastrointestinal system, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 diseases or disorders affecting the thyroid, chronic pain, allergies, and pulmonary diseases. Further non-limiting examples of diseases associated with inappropriate activation of the complement system include acute antibody-mediated rejection, age-related macular degeneration (e.g. wet or dry age-related macular degeneration), allergic asthma, allergic bronchopulmonary aspergillosis, allergic neuritis, allergic rhinitis, Alzheimer’s disease, amyotrophic lateral sclerosis, anaphylaxis, atopic dermatitis, atypical hemolytic syndrome (aHUS), autoimmune diseases, autoimmune hemolytic anemia, Bechet’s disease, Behcet’s disease, bronchiolitis, bronchiolitis obliterans, C3 glomerulopathy, cancer, central nervous system (CNS) inflammatory disorders, choroidal neovascularization (CNV), choroiditis, chronic allograft vasculopathy, chronic hepatitis, chronic inflammation, chronic inflammatory diseases, chronic muscle inflammation, chronic pain, chronic pancreatitis, chronic rejection of a transplant or graft, chronic urticaria, Churg-Strauss syndrome, conjunctivitis, COVID-19, cyclitis, demyelinating diseases, dermatitis, dermatomyositis, diabetic retinopathy, diseases of the circulatory system, disorders associated with excessive or inappropriate activity of IgE-producing cells, disorders associated with high levels or inappropriate activity of CD4+ helper T cells of the Th17 subtype, encephalitis, eosinophilic pneumonia, eye disorders, geographic atrophy, giant cell arteritis, gingivitis, glaucoma, glomerulonephritis, glomerulonephritis (e.g., membranoproliferative glomerulonephritis or membranous glomerulonephritis), graft rejection or failure, GPA / MPA (granulomatosis with polyangiitis, microscopic), HELLP syndrome, Henoch-Schonlein purpura, hepatitis (e.g. hepatitis C), Huntington’s disease, hyperacute rejection, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), IgA nephropathy (IgAN), inflammatory bowel diseases (e.g. Crohn’s disease or ulcerative colitis), inflammatory joint conditions (e.g. arthritis such as rheumatoid arthritis or psoriatic arthritis, juvenile chronic arthritis, spondyloarthropathies Reiter’s syndrome, or gout), inflammatory skin diseases, infusion reaction, interstitial pneumonia, iridocyclitis, iritis, ischemia / reperfusion injury, Kawasaki disease, keratitis, lupus nephritis, membranoproliferative glomerulonephritis (MPGN) (e.g. MPGN type I, type II, or type III), meningitis, microscopic polyangiitis, multiple sclerosis (MS), myasthenia gravis, myocarditis, nasal polyposis, neurodegenerative diseases, neuromyelitis optica, neuromyelitis optica (NMO), neuropathic pain, ocular inflammation, osteoarthritis, pancreatitis, panniculitis, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria (PNH), pars planitis, pathologic immune responses to tissue / organ transplantation, pemphigoid, pemphigus, periodontitis, persistent asthma, polyarteritis nodosa, polymyositis, primary membranous nephropathy, proliferative vitreoretinopathy, proteinuria, psoriasis, pulmonary fibrosis (e.g. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 idiopathic pulmonary fibrosis), radiation-induced lung injury, renal disease, respiratory disease or disorders (e.g. asthma or chronic obstructive pulmonary disease (COPD), oridiopathic pulmonary fibrosis, or asthma), respiratory distress syndrome, retinal neovascularization (RNV), retinopathy of prematurity, rheumatoid arthritis (RA), rhinosinusitis, sarcoid, sarcoidosis, scleritis, scleroderma, sclerodermatomyositis, sclerosis, sepsis, Sjögren syndrome, Sjoren’s syndrome, stroke, systemic lupus erythematosus, systemic scleroderma, Takayasu's arteritis, Th2-associated disorders (e.g. a disorder associated with high levels or high activation of CD4+ helper T cells of the Th2 subtype), thyroiditis (e.g. Hashimoto’s thyroiditis, Graves’ disease, or post-partum thyroiditis), thyroiditis, transplant damage, transplant rejection, ulcerative colitis, uveitis, vasculitis, and Wegener’s granulomatosis. In embodiments, the methods of the invention involve reducing complement- mediated hemolysis in a subject. Further non-limiting examples of diseases include Creutzfeldt-Jakob disease, Pick’s disease, mild cognitive impairment, fibromyalgia, frontotemporal dementia, dementia with Lewy bodies, multiple system atrophy, chronic inflammatory, demyelinating polyneuropathy, Guillain–Barré syndrome, multifocal motor neuropathy, non-alcoholic fatty liver disease (NAFLD) e.g., non-alcoholic steatohepatitis (NASH), and Stargardt macular dystrophy. Paroxysmal nocturnal hemoglobinuria is associated with mutations in PigA (Phosphatidyl inositol glycan anchor biosynthesis class a) that prevent GPI-anchor production and attachment of CD59 and CD55 to red blood cells (RBCs), which leads to the lysis of RBCs. In some embodiments, inappropriate activation of the complement system is implicated in the progression and pathogenesis of a disease selected from glaucoma, diabetic retinopathy, age-related macular degeneration, and neurological diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease, and various Tauopathies. Existing treatments for diseases associated with inappropriate activation of the complement system often require regular, sometimes invasive, dosing regimens. There is, therefore, a present need for improved treatments for diseases associated with inappropriate activation of the complement system. The methods and compositions of the present disclosure are suitable in embodiments for use in treatment of any of the above-listed diseases or disorders related to improper activation of the complement system. In various instances, the methods involve introducing a modification to a factor B polynucleotide that results in reduced expression and / or activity of a factor B polypeptide in a cell. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 EDITING OF TARGET GENES Exemplary spacer sequences and guide polynucleotide sequences suitable for use in guide RNAs that can be used to produce the polynucleotide edits described herein (e.g., missense mutations, introduction of stop codons, splice-site disruption mutations, TATA box alterations, start codon alterations, etc.) are listed in Tables 1A to 2H below. To produce the polynucleotide edits, cells (e.g., cells in or from a subject) are contacted with one or more guide RNAs containing one or more of the spacer sequences listed in Tables 2A to 2H below, or fragments thereof, and a nucleobase editor polypeptide or complex containing a nucleic acid programmable DNA binding protein (napDNAbp) and one or more deaminases with cytidine deaminase and / or adenosine deaminase activity (e.g., a “dual deaminase” which has cytidine and adenosine deaminase activity). In embodiments, the base editor and / or endonuclease is introduced to the cell using a polynucleotide sequence (e.g., mRNA) encoding the base editor and / or endonuclease. Tables 1A to 1H below list representative guide polynucleotide sequences suitable for use in methods of the disclosure for altering a CFB polynucleotide. Tables 2A to 2H below list representative guide RNA spacer sequences that may be used in various embodiments in combination with indicated base editors. In embodiments, guide RNAs containing the spacer sequences listed in Tables 2A to 2H may be used to target the target sequences listed in Tables 2A to 2H, optionally to effect the edits (e.g., amino acid or nucleotide alterations) listed in any of Tables 2A to 2H. In some instances, the gRNA is added directly to a cell. In some embodiments, the gRNA comprises nucleotide analogs. These nucleotide analogs can inhibit degradation of the gRNA from cellular processes. Tables 2A to 2H provide target sequences to be used for gRNAs. Further exemplary spacer sequences suitable for use in gRNA sequences for use in the methods provided herein include fragments of any of the spacers provided in Tables 2A to 2H as well as any of the spacers provided in Tables 2A to 2H modified to include an extension or truncation at the 3′ and / or 5′ end(s). In embodiments, a spacer sequence of Tables 2A to 2H can be modified to include a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide extension or truncation at the 3′ and / or 5′ end(s). Variants of the spacer sequences provided herein comprising 1, 2, 3, 4, or 5 nucleobase alterations are contemplated. For example, variation of a target polynucleotide sequence within a population (e.g., single nucleotide polymorphisms) may require said alterations to a spacer sequence to allow the spacer to better bind a variant of a target sequence in a subject. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 In various instances, it is advantageous for a spacer sequence to include a 5′ and / or a 3′ “G” nucleotide. In some cases, for example, any spacer sequence or guide polynucleotide provided herein comprises or further comprises a 5′ “G”, where, in some embodiments, the 5′ “G” is or is not complementary to a target sequence. In some embodiments, the 5′ “G” is added to a spacer sequence that does not already contain a 5′ “G.” For example, it can be advantageous for a guide RNA to include a 5′ terminal “G” when the guide RNA is expressed under the control of a U6 promoter or the like because the U6 promoter prefers a “G” at the transcription start site (see Cong, L. et al. “Multiplex genome engineering using CRISPR / Cas systems. Science 339:819-823 (2013) doi: 10.1126 / science.1231143). In some cases, a 5′ terminal “G” is added to a guide polynucleotide that is to be expressed under the control of a promoter but is optionally not added to the guide polynucleotide if or when the guide polynucleotide is not expressed under the control of a promoter. In some embodiments, a guide polynucleotide of the disclosure contains a spacer and scaffold containing one of the following nucleotide modification schemes (“mod schemes”), where “N” represents any nucleotide, “mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following nucleotide by a phosphorothioate (PS): End-mod SpCas9 guide polynucleotide mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCU AGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU (SEQ ID NO: 440) End-mod SaCas9 guide polynucleotide mNsmNsmNsNNNNNNNNNNNNNNNNNNGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUA CUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU (SEQ ID NO: 441) HM01: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmUmAmGmAmAmAmUmAmGmCAAGU UAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGmUmGmGmCmAmCmCmG mAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 440) ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 HM07: mNsmNsmNsmNmNmNmNmNmNmNNNNNNNNNNNmGUUUUAGmAmGmCmUmAmGmAmAmAmUm AmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUmGmAmAm AmAmAmGmUmGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 440) NLS (bpsv40): mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCU AGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmUsmUsmUsmU-NHC6-CrossL- ac- CKRTADGSEFESPKKKRKV (SEQ ID NOs: 440 and 446) LONGEST: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGUGmG mCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 444) NLS + LONGEST : mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGmUmG mGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU-NHC5-CrossL- CKRTADGSEFESPKKKRKV (SEQ ID NOs: 445 and 446) LONGEST + GOLD: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAmUmCAAmCmUmUGGACUUCGGUCCmAmAm GUGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 447) In embodiments, any of the above guide sequences, the number of N nucleotides (i.e., the spacer sequence) can vary between 15 and 25. In some cases, the number of N nucleotides is 18, 19, 20, 21, 22, or 23. Exemplary guide RNA sequences are provided in the following Tables 1A-1I and 2A-2H. Throughout the tables, the ranges (e.g., 3-9) in the guide polynucleotide names indicate the base editing window for an exemplary base editor suitable for use with the guide ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 polynucleotide (e.g., nucleotides 3 to 9, where location 1 is the first nucleobase complementary to the spacer and adjacent to the protospacer adjacent motif). Table 1A: Representative sequences for guide polynucleotides for use in guiding a base editor to alter a complement factor B splice site.1 1“mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following (i.e., 3′) nucleotide by a phosphorothioate (PS). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 1B: Representative sequences for guide polynucleotides for use in guiding a base editor to introduce a missense mutation to a complement factor B polynucleotide.2 2“mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following (i.e., 3′) nucleotide by a phosphorothioate (PS). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 1C: Representative sequences for guide polynucleotides for use in guiding a base editor to introduce a missense mutation to a complement factor B polynucleotide.3 3“mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following (i.e., 3′) nucleotide by a phosphorothioate (PS). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 1D: Representative sequences for guide polynucleotides for use in guiding a base editor to alter a complement factor B splice site or introduce a new stop codon into a complement factor B polynucleotide using base editing.4 4“mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following (i.e., 3′) nucleotide by a phosphorothioate (PS). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 1E: Representative sequences for guide polynucleotides for use in guiding a base editor to alter a complement factor B splice site or introduce a new stop codon into a complement factor B polynucleotide using base editing.5 5“mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following (i.e., 3′) nucleotide by a phosphorothioate (PS). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024

[0003] ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 1F: Representative sequences for guide polynucleotides for use in guiding a base editor to alter a start codon or TATA box of a complement factor B polynucleotide using base editing.6 6“mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following (i.e., 3′) nucleotide by a phosphorothioate (PS). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 1G: Representative sequences for guide polynucleotides for use in guiding a base editor to alter a start codon or TATA box of a complement factor B polynucleotide using base editing.7 7“mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following (i.e., 3′) nucleotide by a phosphorothioate (PS). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 1H: Representative sequences for guide polynucleotides for use in guiding a base editor to alter a complement factor B splice site.8 8“mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following (i.e., 3′) nucleotide by a phosphorothioate (PS). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 1I: Alternative names for guide polynucleotides. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2A. Representative spacer and target site sequences relating to disruption of a complement factor B splice site using base editing. Table 2A (CONTINUED). 9PAM sequences shown as underlined plain text; target nucleotides are in bold; human sequence nucleotides complementary to a primate (cyno) target sequence but not to a human target sequence are in bold underline. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2B. Representative spacer and target site sequences relating to introduction of a missense mutation to a complement factor B polynucleotide using base editing. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2B (CONTINUED). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2C. Representative spacer and target site sequences relating to introduction of a missense mutation to a complement factor B polynucleotide using base editing. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2C (CONTINUED). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2D. Representative spacer and target site sequences relating to disrupting of a complement factor B splice site or introducing a new stop codon into a complement factor B polynucleotide using base editing. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2E. Representative spacer and target site sequences relating to disrupting of a complement factor B splice site or introducing a new stop codon into a complement factor B polynucleotide using base editing. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2E (CONTINUED). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2F. Representative spacer and target site sequences relating to altering a TATA box or start codon of a complement factor B polynucleotide using base editing. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2G. Representative spacer and target site sequences relating to altering a TATA box or start codon of a complement factor B polynucleotide using base editing. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2G (CONTINUED). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 2H. Representative spacer and target site sequences relating to disruption of a complement factor B splice site using base editing. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 sg23 / sgRNA_088 spacer sequence: CAGGAUCCGCACAGACUCCA (SEQ ID NO: 3794) (target gene: ALAS1). The target sequence corresponding to sg23 is as follows, where the PAM sequence is in bold: CAGGATCCGCACAGACTCCAGGG (SEQ ID NO: 3795). crRNA2 / gRNA2002 spacer sequence:UCCCCGUUCUCGAAGUCGUG (SEQ ID NO: 3796). Target site corresponding to crRNA2 (TSBTx4946): TCCCCGTTCTCGAAGTCGTGTGG (SEQ ID NO: 3797), where the PAM sequence is in bold. NUCLEOBASE EDITORS Useful in the methods and compositions described herein are nucleobase editors that edit, modify or alter a target nucleotide sequence of a polynucleotide. Nucleobase editors described herein typically include a polynucleotide programmable nucleotide binding domain and a nucleobase editing domain (e.g., adenosine deaminase, cytidine deaminase, or a dual deaminase). A polynucleotide programmable nucleotide binding domain, when in conjunction with a bound guide polynucleotide (e.g., gRNA), can specifically bind to a target polynucleotide sequence and thereby localize the base editor to the target nucleic acid sequence desired to be edited. Polynucleotide Programmable Nucleotide Binding Domain Polynucleotide programmable nucleotide binding domains bind polynucleotides (e.g., RNA, DNA). A polynucleotide programmable nucleotide binding domain of a base editor can itself comprise one or more domains (e.g., one or more nuclease domains). In some embodiments, the nuclease domain of a polynucleotide programmable nucleotide binding domain comprises an endonuclease or an exonuclease. Disclosed herein are base editors comprising a polynucleotide programmable nucleotide binding domain comprising all or a portion (e.g., a functional portion) of a CRISPR protein (i.e., a base editor comprising as a domain all or a portion (e.g., a functional portion) of a CRISPR protein (e.g., a Cas protein), also referred to as a “CRISPR protein- ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 derived domain” of the base editor). A CRISPR protein-derived domain incorporated into a base editor can be modified compared to a wild-type or natural version of the CRISPR protein. A CRISPR protein-derived domain can comprise one or more mutations, insertions, deletions, rearrangements and / or recombinations relative to a wild-type or natural version of the CRISPR protein. Cas proteins that can be used herein include class 1 and class 2. Non-limiting examples of Cas proteins include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas9 (also known as Csn1 or Csx12), Cas10, Csy1 , Csy2, Csy3, Csy4, Cse1, Cse2, Cse3, Cse4, Cse5e, Csc1, Csc2, Csa5, Csn1, Csn2, Csm1, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx1S, Csf1, Csf2, CsO, Csf4, Csd1, Csd2, Cst1, Cst2, Csh1, Csh2, Csa1, Csa2, Csa3, Csa4, Csa5, Cas12a / Cpf1, Cas12b / C2c1 (e.g., SEQ ID NO: 232), Cas12c / C2c3, Cas12d / CasY, Cas12e / CasX, Cas12g, Cas12h, Cas12i, and Cas12j / CasΦ, CARF, DinG, Turbo Cas9 (i.e., an SpCas9 with the amino acid alterations Q844R, V842L, F846Y, L847M, and I852F), homologues thereof, or modified versions thereof. A CRISPR enzyme can direct cleavage of one or both strands at a target sequence, such as within a target sequence and / or within a complement of a target sequence. For example, a CRISPR enzyme can direct cleavage of one or both strands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence. A vector that encodes a CRISPR enzyme that is mutated to with respect to a corresponding wild-type enzyme such that the mutated CRISPR enzyme lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence can be used. A Cas protein (e.g., Cas9, Cas12) or a Cas domain (e.g., Cas9, Cas12) can refer to a polypeptide or domain with at least or at least about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity and / or sequence homology to a wild-type exemplary Cas polypeptide or Cas domain. Cas (e.g., Cas9, Cas12) can refer to the wild-type or a modified form of the Cas protein that can comprise an amino acid change such as a deletion, insertion, substitution, variant, mutation, fusion, chimera, or any combination thereof. In some embodiments, a CRISPR protein-derived domain of a base editor can include all or a portion (e.g., a functional portion) of Cas9 from Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 (NCBI Ref: NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC_018010.1); Psychroflexus torquis (NCBI Ref: NC_018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1); Listeria innocua (NCBI Ref: NP_472073.1); Campylobacter jejuni (NCBI Ref: YP_002344900.1); Neisseria meningitidis (NCBI Ref: YP_002342100.1), Streptococcus pyogenes, or Staphylococcus aureus. Some aspects of the disclosure provide high fidelity Cas9 domains. High fidelity Cas9 domains are known in the art and described, for example, in Kleinstiver, B.P., et al. “High- fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects.” Nature 529, 490-495 (2016); and Slaymaker, I.M., et al. “Rationally engineered Cas9 nucleases with improved specificity.” Science 351, 84-88 (2015); the entire contents of each of which are incorporated herein by reference. An Exemplary high fidelity Cas9 domain is provided in the Sequence Listing as SEQ ID NO: 233. In some embodiments, any of the Cas9 fusion proteins or complexes provided herein comprise one or more of a D10A, N497X, a R661X, a Q695X, and / or a Q926X mutation, or a corresponding mutation in any of the amino acid sequences provided herein, wherein X is any amino acid.. Typically, Cas9 proteins, such as Cas9 from S. pyogenes (spCas9), require a “protospacer adjacent motif (PAM)” or PAM-like motif, which is a 2-6 base pair DNA sequence immediately following the DNA sequence targeted by the Cas9 nuclease in the CRISPR bacterial adaptive immune system. The presence of anNGG PAM sequence is required to bind a particular nucleic acid region, where the “N” in “NGG” is adenosine (A), thymidine (T), or cytosine (C), and the G is guanosine. In some embodiments, any of the fusion proteins or complexes provided herein may contain a Cas9 domain that is capable of binding a nucleotide sequence that does not contain a canonical (e.g.,NGG) PAM sequence. Cas9 domains that bind to non-canonical PAM sequences have been described in the art and would be apparent to the skilled artisan. For example, Cas9 domains that bind non-canonical PAM sequences have been described in Kleinstiver, B. P., et al., “Engineered CRISPR-Cas9 nucleases with altered PAM specificities” Nature 523, 481-485 (2015); and Kleinstiver, B. P., et al., “Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition” Nature Biotechnology 33, 1293-1298 (2015); the entire contents of each are hereby incorporated by reference. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 In some embodiments, the napDNAbp is a circular permutant (e.g., SEQ ID NO: 238). In some embodiments, the polynucleotide programmable nucleotide binding domain comprises a nickase domain. Herein the term “nickase” refers to a polynucleotide programmable nucleotide binding domain comprising a nuclease domain that is capable of cleaving only one strand of the two strands in a duplexed nucleic acid molecule (e.g., DNA). For example, where a polynucleotide programmable nucleotide binding domain comprises a nickase domain derived from Cas9, the Cas9-derived nickase domain can include a D10A mutation and a histidine at position 840. In another example, a Cas9-derived nickase domain comprises an H840A mutation, while the amino acid residue at position 10 remains a D. In some embodiments, a Cas9 nuclease has an inactive (e.g., an inactivated) DNA cleavage domain, that is, the Cas9 is a nickase, referred to as an “nCas9” protein (for “nickase” Cas9; SEQ ID No: 201). The Cas9 nickase may be a Cas9 protein that is capable of cleaving only one strand of a duplexed nucleic acid molecule (e.g., a duplexed DNA molecule). In some embodiments the Cas9 nickase comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the Cas9 nickases provided herein. Additional suitable Cas9 nickases will be apparent to those of skill in the art based on this disclosure and knowledge in the field and are within the scope of this disclosure. Also provided herein are base editors comprising a polynucleotide programmable nucleotide binding domain which is catalytically dead (i.e., incapable of cleaving a target polynucleotide sequence). For example, in the case of a base editor comprising a Cas9 domain, the Cas9 can comprise both a D10A mutation and an H840A mutation. In further embodiments, a catalytically dead polynucleotide programmable nucleotide binding domain comprises a point mutation (e.g., D10A or H840A) as well as a deletion of all or a portion (e.g., a functional portion) of a nuclease domain. dCas9 domains are known in the art and described, for example, in Qi et al., “Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression.” Cell.2013; 152(5):1173-83, the entire contents of which are incorporated herein by reference. The term “protospacer adjacent motif (PAM)” or PAM-like motif refers to a 2-6 base pair DNA sequence immediately following the DNA sequence targeted by a nucleic acid programmable DNA binding protein. In some embodiments, the PAM can be a 5′ PAM (i.e., located upstream of the 5′ end of the protospacer). In other embodiments, the PAM can be a ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 3′ PAM (i.e., located downstream of the 5′ end of the protospacer). The PAM sequence can be any PAM sequence known in the art. Suitable PAM sequences include, but are not limited to,NGG,NGA,NGC,NGN,NGT,NGTT,NGCG,NGAG,NGAN,NGNG,NGCN,NGCG,NGTN, NNGRRT,NNNRRT,NNGRR(N),TTTV,TYCV,TYCV,TATV,NNNNGATT,NNAGAAW, or NAAAAC. Y is a pyrimidine; N is any nucleotide base; W is A or T. A base editor provided herein can comprise a CRISPR protein-derived domain that is capable of binding a nucleotide sequence that contains a canonical or non-canonical protospacer adjacent motif (PAM) sequence. In some embodiments, the PAM is an “NRN” PAM where the “N” in “NRN” is adenine (A), thymine (T), guanine (G), or cytosine (C), and the R is adenine (A) or guanine (G); or the PAM is an “NYN” PAM, wherein the “N” inNYN is adenine (A), thymine (T), guanine (G), or cytosine (C), and the Y is cytidine (C) or thymine (T), for example, as described in R.T. Walton et al., 2020, Science, 10.1126 / science.aba8853 (2020), the entire contents of which are incorporated herein by reference. Several PAM variants are described in Table 3 below. Table 3. Cas9 proteins and corresponding PAM sequences. N is A, C, T, or G; and V is A, C, or G. In some embodiments, the PAM is NGC. In some embodiments, the NGC PAM is recognized by a Cas9 variant. In some embodiments, the Cas9 variant contains one or more ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 amino acid substitutions selected from D1135V, G1218R, R1335Q, and T1337R (collectively termed VRQR) of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, the Cas9 variant contains one or more amino acid substitutions selected from D1135V, G1218R, R1335E, and T1337R (collectively termed VRER) of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, the Cas9 variant contains one or more amino acid substitutions selected from E782K, N968K, and R1015H (collectively termed KHH) of saCas9 (SEQ ID NO: 218). In some cases, a Cas9 variant has specificity for the PAM 5′-NGC-3′. In some embodiments, a Cas9 variant includes one or more amino acid substitutions selected from D1135M, S1136Q, G1218K, E1219F, A1322R, D1332A, R1335E, and T1337K of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, a Cas9 variant includes one or more amino acid substitutions selected from D1135M, S1136Y, G1218K, E1219F, A1322R, D1332A, R1335E, and T1337K of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, the a Cas9 variant includes one or more amino acid substitutions selected from D1135L, S1136Y, G1218K, E1219F, A1322R, D1332A, R1335E, and T1337R of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, a Cas9 variant includes one or more amino acid substitutions selected from D1135M, S1136Y, G1218K, E1219F, A1322R, D1332A, R1335E, and T1337K of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, a Cas9 variant includes one or more amino acid substitutions selected from D1135L, S1136Y, G1218K, E1219F, A1283D, A1322R, D1332A, R1335E, and T1337K of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, a Cas9 variant includes one or more amino acid substitutions selected from A61R, L1111R, D1135L, S1136W, G1218K, E1219Q, N1317R, A1322R, R1333P, R1335Q, and T1337R of spCas9 (SEQ ID No: 197) (SpRY), or a corresponding mutation in another Cas9. In some embodiments, a Cas9 variant includes one or more amino acid substitutions selected from D1135L, S1136Q, G1218K, E1219F, E1250K, A1283D, A1322R, D1332A, R1335E, and T1337K of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, a Cas9 variant includes one or more amino acid substitutions selected from D1135M, S1136Y, G1218K, E1219F, E1250K, A1283D, A1322R, D1332A, R1335E, and T1337R of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, a Cas9 variant includes one or more amino acid substitutions selected from R765A, Q768A, D1135L, S1136Y, G1218K, A1283D, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 E1219F, A1322R, D1332A, R1335E, and T1337K of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, any of the Cas9 proteins provided herein, including an SpCas9 comprises any one, two, three, four, five, six, seven, eight, nine, or ten of the following amino acid substitutions in a corresponding residue: R765A, Q768A, W1126R, R1359W, E1250K, A1239T, A1239V, A1283D, R1335D, D1135L, D1135M, D1135R, D1135W, S1136H, S1136Q, S1136Y, G1218D, G1218K, G1218R, G1218E, G1218L, E1219F, E1219K, E1219N, A1322A, A1322R, A1322K, D1332A, R1335V, T1337K, T1337T, D1332A, D1135V and T1337R. In some embodiments, a CRISPR protein-derived domain of a base editor comprises all or a portion (e.g., a functional portion) of a Cas9 protein with a canonical PAM sequence (NGG). In other embodiments, a Cas9-derived domain of a base editor can employ a non- canonical PAM sequence. Such sequences have been described in the art and would be apparent to the skilled artisan. For example, Cas9 domains that bind non-canonical PAM sequences have been described in Kleinstiver, B. P., et al., “Engineered CRISPR-Cas9 nucleases with altered PAM specificities” Nature 523, 481-485 (2015); and Kleinstiver, B. P., et al., “Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition” Nature Biotechnology 33, 1293-1298 (2015); R.T. Walton et al. “Unconstrained genome targeting with near-PAMless engineered CRISPR-Cas9 variants” Science 10.1126 / science.aba8853 (2020); Hu et al. “Evolved Cas9 variants with broad PAM compatibility and high DNA specificity,” Nature, 2018 Apr.5, 556(7699), 57-63; Miller et al., “Continuous evolution of SpCas9 variants compatible with non-G PAMs” Nat. Biotechnol., 2020 Apr;38(4):471-481; the entire contents of each are hereby incorporated by reference. Fusion Proteins or Complexes Comprising a NapDNAbp and a Cytidine Deaminase and / or Adenosine Deaminase Some aspects of the disclosure provide fusion proteins or complexes comprising a Cas9 domain or other nucleic acid programmable DNA binding protein (e.g., Cas12) and one or more cytidine deaminase, adenosine deaminase, or cytidine adenosine deaminase domains. It should be appreciated that the Cas9 domain may be any of the Cas9 domains or Cas9 proteins (e.g., dCas9 or nCas9) provided herein. In some embodiments, any of the Cas9 domains or Cas9 proteins (e.g., dCas9 or nCas9) provided herein may be fused with any of the cytidine deaminases and / or adenosine deaminases provided herein. The domains of the base editors disclosed herein can be arranged in any order. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 In some embodiments, the fusion proteins or complexes comprising a cytidine deaminase or adenosine deaminase and a napDNAbp (e.g., Cas9 or Cas12 domain) do not include a linker sequence. In some embodiments, a linker is present between the cytidine or adenosine deaminase and the napDNAbp. In some embodiments, cytidine or adenosine deaminase and the napDNAbp are fused via any of the linkers provided herein. For example, in some embodiments the cytidine or adenosine deaminase and the napDNAbp are fused via any of the linkers provided herein. It should be appreciated that the fusion proteins or complexes of the present disclosure may comprise one or more additional features. For example, in some embodiments, the fusion protein or complex may comprise inhibitors, cytoplasmic localization sequences, export sequences, such as nuclear export sequences, or other localization sequences, as well as sequence tags that are useful for solubilization, purification, or detection of the fusion proteins or complexes. Suitable protein tags provided herein include, but are not limited to, biotin carboxylase carrier protein (BCCP) tags, myc-tags, calmodulin-tags, FLAG-tags, hemagglutinin (HA)-tags, polyhistidine tags, also referred to as histidine tags or His-tags, maltose binding protein (MBP)-tags, nus-tags, glutathione-S- transferase (GST)-tags, green fluorescent protein (GFP)-tags, thioredoxin-tags, S-tags, Softags (e.g., Softag 1, Softag 3), strep-tags , biotin ligase tags, FlAsH tags, V5 tags, and SBP-tags. Additional suitable sequences will be apparent to those of skill in the art. In some embodiments, the fusion protein or complex comprises one or more His tags. Exemplary, yet nonlimiting, fusion proteins are described in International PCT Application Nos. PCT / US2017 / 045381, PCT / US2019 / 044935, and PCT / US2020 / 016288, each of which is incorporated herein by reference for its entirety. Fusion Proteins or Complexes with Internal Insertions Provided herein are fusion proteins or complexes comprising a heterologous polypeptide fused to a nucleic acid programmable nucleic acid binding protein, for example, a napDNAbp. The heterologous polypeptide can be fused to the napDNAbp at a C-terminal end of the napDNAbp, an N-terminal end of the napDNAbp, or inserted at an internal location of the napDNAbp. In some embodiments, the heterologous polypeptide is a deaminase (e.g., cytidine or adenosine deaminase) or a functional fragment thereof. For example, a fusion protein can comprise a deaminase flanked by an N- terminal fragment and a C-terminal fragment of a Cas9 or Cas12 (e.g., Cas12b / C2c1), polypeptide. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 The deaminase can be a circular permutant deaminase. In some embodiments, the deaminase is a circular permutant TadA, circularly permutated at amino acid residue 116, 136, or 65 as numbered in a TadA reference sequence. The fusion protein or complexes can comprise more than one deaminase. The fusion protein or complex can comprise, for example, 1, 2, 3, 4, 5 or more deaminases. The deaminases in a fusion protein or complex can be adenosine deaminases, cytidine deaminases, or a combination thereof. In some embodiments, the napDNAbp in the fusion protein or complex contains a Cas9 polypeptide or a fragment thereof. The Cas9 polypeptide can be a variant Cas9 polypeptide. The Cas9 polypeptide can be a circularly permuted Cas9 protein. The heterologous polypeptide (e.g., deaminase) can be inserted in the napDNAbp (e.g., Cas9 or Cas12 (e.g., Cas12b / C2c1)) at a suitable location, for example, such that the napDNAbp retains its ability to bind the target polynucleotide and a guide nucleic acid. A deaminase (e.g., adenosine deaminase, cytidine deaminase, or adenosine deaminase and cytidine deaminase (dual deaminase)) can be inserted into a napDNAbp without compromising function of the deaminase (e.g., base editing activity) or the napDNAbp (e.g., ability to bind to target nucleic acid and guide nucleic acid). In some embodiments, the deaminase (e.g., adenosine deaminase, cytidine deaminase, or adenosine deaminase and cytidine deaminase) is inserted in regions of the Cas9 polypeptide comprising higher than average B-factors (e.g., higher B factors compared to the total protein or the protein domain comprising the disordered region). Cas9 polypeptide positions comprising a higher than average B-factor can include, for example, residues 768, 792, 1052, 1015, 1022, 1026, 1029, 1067, 1040, 1054, 1068, 1246, 1247, and 1248 as numbered in SEQ ID NO: 197. Cas9 polypeptide regions comprising a higher than average B-factor can include, for example, residues 792-872, 792-906, and 2-791 as numbered in SEQ ID NO: 197. In some embodiments, a heterologous polypeptide (e.g., deaminase) is inserted in a flexible loop of a Cas9 polypeptide. The flexible loop portions can be selected from the group consisting of 530-537, 569-570, 686-691, 943-947, 1002-1025, 1052-1077, 1232-1247, or 1298-1300 as numbered in SEQ ID NO: 197, or a corresponding amino acid residue in another Cas9 polypeptide. The flexible loop portions can be selected from the group consisting of: 1-529, 538-568, 580-685, 692-942, 948-1001, 1026-1051, 1078-1231, or 1248- 1297 as numbered in SEQ ID NO: 197, or a corresponding amino acid residue in another Cas9 polypeptide. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 A heterologous polypeptide (e.g., adenine deaminase) can be inserted into a Cas9 polypeptide region corresponding to amino acid residues: 1017-1069, 1242-1247, 1052-1056, 1060-1077, 1002 – 1003, 943-947, 530-537, 568-579, 686-691, 1242-1247, 1298 – 1300, 1066-1077, 1052-1056, or 1060-1077 as numbered in SEQ ID NO: 197, or a corresponding amino acid residue in another Cas9 polypeptide. A heterologous polypeptide (e.g., adenine deaminase) can be inserted in place of a deleted region of a Cas9 polypeptide. The deleted region can correspond to an N-terminal or C-terminal portion of the Cas9 polypeptide. Exemplary internal fusions base editors are provided in Table 4A below: Table 4A: Insertion loci in Cas9 proteins A heterologous polypeptide (e.g., deaminase) can be inserted within a structural or functional domain of a Cas9 polypeptide. A heterologous polypeptide (e.g., deaminase) can be inserted between two structural or functional domains of a Cas9 polypeptide. A heterologous polypeptide (e.g., deaminase) can be inserted in place of a structural or functional domain of a Cas9 polypeptide, for example, after deleting the domain from the Cas9 polypeptide. The structural or functional domains of a Cas9 polypeptide can include, for example, RuvC I, RuvC II, RuvC III, Rec1, Rec2, PI, or HNH. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 A fusion protein can comprise a linker between the deaminase and the napDNAbp polypeptide. The linker can be a peptide or a non-peptide linker. For example, the linker can be an XTEN, (GGGS)n(SEQ ID NO: 246),SGGSSGGS (SEQ ID NO: 330), (GGGGS)n(SEQ ID NO: 247), (G)n, (EAAAK)n (SEQ ID NO: 248), (GGS)n,SGSETPGTSESATPES (SEQ ID NO: 249). In some embodiments, the fusion protein comprises a linker between the N- terminal Cas9 fragment and the deaminase. In some embodiments, the fusion protein comprises a linker between the C-terminal Cas9 fragment and the deaminase. In some embodiments, the N-terminal and C-terminal fragments of napDNAbp are connected to the deaminase with a linker. In some embodiments, the N-terminal and C-terminal fragments are joined to the deaminase domain without a linker. In some embodiments, the fusion protein comprises a linker between the N-terminal Cas9 fragment and the deaminase but does not comprise a linker between the C-terminal Cas9 fragment and the deaminase. In some embodiments, the fusion protein comprises a linker between the C-terminal Cas9 fragment and the deaminase but does not comprise a linker between the N-terminal Cas9 fragment and the deaminase. In some embodiments, the napDNAbp in the fusion protein or complex is a Cas12 polypeptide, e.g., Cas12b / C2c1, or a functional fragment thereof capable of associating with a nucleic acid (e.g., a gRNA) that guides the Cas12 to a specific nucleic acid sequence. The Cas12 polypeptide can be a variant Cas12 polypeptide. In other embodiments, the N- or C- terminal fragments of the Cas12 polypeptide comprise a nucleic acid programmable DNA binding domain or a RuvC domain. In other embodiments, the fusion protein contains a linker between the Cas12 polypeptide and the catalytic domain. In other embodiments, the amino acid sequence of the linker isGGSGGS (SEQ ID NO: 250) or GSSGSETPGTSESATPESSG (SEQ ID NO: 251). In other embodiments, the linker is a rigid linker. In other embodiments of the above aspects, the linker is encoded byGGAGGCTCTGGAGGAAGC (SEQ ID NO: 252) orGGCTCTTCTGGATCTGAAACACCTGGCACAAGCGAGAGCGCCACCCCTGAGAGCTCTGGC (SEQ ID NO: 253). In other embodiments, the fusion protein or complex contains a nuclear localization signal (e.g., a bipartite nuclear localization signal). In other embodiments, the amino acid sequence of the nuclear localization signal is MAPKKKRKVGIHGVPAA (SEQ ID NO: 261). In other embodiments of the above aspects, the nuclear localization signal is encoded by the following sequence: ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATGGCCCCAAAGAAGAAGCGGAAGGTCGGTATCCACGGAGTCCCAGCAGCC (SEQ ID NO: 262). In other embodiments, the Cas12b polypeptide contains a mutation that silences the catalytic activity of a RuvC domain. In other embodiments, the Cas12b polypeptide contains D574A, D829A and / or D952A mutations. In some embodiments, the fusion protein or complex comprises a napDNAbp domain (e.g., Cas12-derived domain) with an internally fused nucleobase editing domain (e.g., all or a portion (e.g., a functional portion) of a deaminase domain, e.g., an adenosine deaminase domain). In some embodiments, the napDNAbp is a Cas12b. In some embodiments, the base editor comprises a BhCas12b domain with an internally fused TadA*8 domain inserted at the loci provided in Table 4B below. Table 4B: Insertion loci in Cas12b proteins In some embodiments, the base editing system described herein is an ABE with TadA inserted into a Cas9. Polypeptide sequences of relevant ABEs with TadA inserted into a Cas9 are provided in the attached Sequence Listing as SEQ ID NOs: 263-308. Exemplary, yet nonlimiting, fusion proteins are described in International PCT Application Nos. PCT / US2020 / 016285 and U.S. Provisional Application Nos.62 / 852,228 and 62 / 852,224, the contents of which are incorporated by reference herein in their entireties. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 A to G Editing In some embodiments, a base editor described herein comprises an adenosine deaminase domain. Such an adenosine deaminase domain of a base editor can facilitate the editing of an adenine (A) nucleobase to a guanine (G) nucleobase by deaminating the A to form inosine (I), which exhibits base pairing properties of G. In some embodiments, an A-to- G base editor further comprises an inhibitor of inosine base excision repair, for example, a uracil glycosylase inhibitor (UGI) domain or a catalytically inactive inosine specific nuclease. Without wishing to be bound by any particular theory, the UGI domain or catalytically inactive inosine specific nuclease can inhibit or prevent base excision repair of a deaminated adenosine residue (e.g., inosine), which can improve the activity or efficiency of the base editor. A base editor comprising an adenosine deaminase can act on any polynucleotide, including DNA, RNA and DNA-RNA hybrids. In an embodiment an adenosine deaminase domain of a base editor comprises all or a portion (e.g., a functional portion) of an ADAT comprising one or more mutations which permit the ADAT to deaminate a target A in DNA. For example, the base editor can comprise all or a portion (e.g., a functional portion) of an ADAT from Escherichia coli (EcTadA) comprising one or more of the following mutations: D108N, A106V, D147Y, E155V, L84F, H123Y, I156F, or a corresponding mutation in another adenosine deaminase. Exemplary ADAT homolog polypeptide sequences are provided in the Sequence Listing as SEQ ID NOs: 1 and 309-315. The adenosine deaminase can be derived from any suitable organism (e.g., E. coli). In some embodiments, the adenosine deaminase is from Escherichia coli, Staphylococcus aureus, Salmonella typhi, Shewanella putrefaciens, Haemophilus influenzae, Caulobacter crescentus, or Bacillus subtilis. In some embodiments, the adenine deaminase is a naturally- occurring adenosine deaminase that includes one or more mutations corresponding to any of the mutations provided herein (e.g., mutations in ecTadA). The corresponding residue in any homologous protein can be identified by e.g., sequence alignment and determination of homologous residues. The mutations in any naturally-occurring adenosine deaminase (e.g., having homology to ecTadA) that correspond to any of the mutations described herein (e.g., any of the mutations identified in ecTadA) can be generated accordingly. In some embodiments, the adenosine deaminase comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 99.5% identical to any one of the amino acid sequences set forth in any of the adenosine deaminases provided herein. It should be appreciated that adenosine deaminases provided herein may include one or more mutations (e.g., any of the mutations provided herein). The disclosure provides any deaminase domains with a certain percent identify plus any of the mutations or combinations thereof described herein. In some embodiments, the adenosine deaminase comprises an amino acid sequence that has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more mutations compared to a reference sequence, or any of the adenosine deaminases provided herein. It should be appreciated that any of the mutations provided herein (e.g., based on a TadA reference sequence, such as TadA*7.10 (SEQ ID NO: 1)) can be introduced into other adenosine deaminases, such as E. coli TadA (ecTadA), S. aureus TadA (saTadA), or other adenosine deaminases (e.g., bacterial adenosine deaminases). In some embodiments, the TadA reference sequence is TadA*7.10 (SEQ ID NO: 1). It would be apparent to the skilled artisan that additional deaminases may similarly be aligned to identify homologous amino acid residues that can be mutated as provided herein. Thus, any of the mutations identified in a TadA reference sequence can be made in other adenosine deaminases (e.g., ecTada) that have homologous amino acid residues. It should also be appreciated that any of the mutations provided herein can be made individually or in any combination in a TadA reference sequence or another adenosine deaminase. In some embodiments, the adenosine deaminase comprises an alteration or set of alterations selected from those listed in Tables 5A-5G below: Table 5A. Adenosine Deaminase Variants. Residue positions in the E. coli TadA variant (TadA*) are indicated. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 5B. TadA*8 Adenosine Deaminase Variants. Residue positions in the E. coli TadA variant (TadA*) are indicated. Alterations are referenced to TadA*7.10 (first row). Table 5C. TadA*9 Adenosine Deaminase Variants. Alterations are referenced to TadA*7.10. Additional details of TadA*9 adenosine deaminases are described in International PCT Application No. PCT / US2020 / 049975, which is incorporated herein by reference in its entirety for all purposes. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 In some embodiments, the adenosine deaminase comprises a TadA*8.20 adenosine deaminase variant further comprising an F149Y amino acid alteration. In some embodiments, the adenosine deaminase comprises a TadA*8.20 adenosine deaminase variant further comprising the amino acid alterations R147D, F149Y, T166I, and D167N (TadA*8.10+). In some embodiments, the adenosine deaminase comprises a TadA*8.20 adenosine deaminase variant further comprising the amino acid alterations S82T and F149Y (TadA*9v1). In some embodiments, the adenosine deaminase comprises a TadA*8.20 adenosine deaminase variant further comprising the amino acid alterations Y147D, F149Y, T166I, D167N and S82T (TadA*9v2). In some embodiments, the adenosine deaminase comprises one or more of M1I, M1S, S2A, S2E, S2H, S2R, S2L, E3L, V4D, V4E, V4M, V4K, V4S, V4T, V4A, E5K, F6S, F6G, F6H, F6Y, F6I, F6E, S7K, H8E, H8Y, H8H, H8Q, H8E, H8G, H8S, E9Y, E9K, E9V, E9E, Y10F, Y10W, Y10Y, M12S, M12L, M12R, M12W, R13H, R13I, R13Y, R13R, R13G, R13S, H14N, A15D, A15V, A15L, A15H, T17T, T17A, T17W, T17L, T17F, T17R, T17S, L18A, L18E, L18N, L18L, L18S, A19N, A19H, A19K, A19A, A19D, A19G, A19M, R21N, K20K, K20A, K20R, K20E, K20G, K20C, K20Q R21A, R21R, R21N, R21Y, R21C G22P, A22W, A22R, W23D, R23H, W23G, W23Q, W23L, W23R, W23H W23D W23M, W23W, W23I, D24E, D24G, D24W, D24D, D24R, E25F, E25M, E25D, E25A, E25G, E25R, E25E, E25H E25V, E25S, E25Y, R26D, R26E, R26G, R26N, R26Q, R26C, R26L, R26K, R26W, R26C, R26P, R26R, R26A, R26H, E27E, E27Q, E27H, E27C, E27G, E27K, E27S, E27P, E27R, E27L, E27V, E27D, V28V, V28A, V28C, V28G, V28P, V28S, V28T, P29V, P29P, P29A, P29G, P29K, P29L, V30V, V30I, V30L, V30F, V30G, V30A, V30M, L34S, L34V, L34L, L34M, L34W, L34G, H36E, H36V, L36H, H36L, H36N, N37N, N37H, N37R, N37T, N37S, N38G, N38R, N38N, N38E, V40I, W45A, W45W, W45R, W45L, W45N, N46N, N46M, N46P, N46G, N46L, N46R, N46V, R46W, R46F, R46Q, R46M, R47A, R47Q, R47F, R47K, R47P, R47W, R47M, R47R, R47G, R47S, R47V, R47H, P48T, P48L, P48A, P48I, P48S, P48R, P48K, P48D, P48E, P48H, P48G, P48P, P48N, I49G, I49H, I49V, I49F, I49H, I49I, I49M, I49N, I49K, I49Q, I49T, G50L, G50S, G50R, G50G, R51H, R51L, R51N, L51W, R51Y, R51G, R51V, R51R, H52D, H52Y, H52I, H52H, D53D, D53E, D53G, D53P, P54C, P54T, P54P, P54E, A55H, T55A, T55I, T55V, T55G, T55T, A56A, A56H, A56W, A56E, A56S, H57P, H57A, H57H, H57N, A58G, A58E, A58A, A58R, E59A, E59G, E59I, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 E59Q, E59W, E59E, E59T, E59H, E59P, M61A, M61I, M61L, M61V, M61P, M61G, M61I, L63S, L63V, L63T, L63R, L63H, L63A, R64A, R64Q, R64R, R64D, Q65V, Q65H, Q65G, Q65P, Q65F, Q65Q, Q65R, G66V, G66E, G66T, G66G, G66C, G67G, G67W, G67I, G67A, G67D, G67L, G67V, L68Q, L68M, L68V, L68H, L68L, L68G,V69A, V69M, V69V, M70V, M70L, E70A, M70A, M70M, M70E, M70T, M70v, Q71M, Q71N, Q71L, Q71R, Q71Q, Q71I, N72A, N72K, N72S, N72D, N72Y, N72N, N72H, N72G, N72M, Y73G, Y73I, Y73K, Y73R, Y73S, Y73Y, Y73H, Y73A, R74A, R74Q, R74G, R74K, R74L, R74N, R74G, R74K, R74R, I76H, I76R, I76W, I76Y, I76V, I76Q, I76L, I76D, I76F, I76I, I76N, I76T, I76Y, D77G, D77D, D77A, D77Q, A78Y, A78T, A78G, A78A, A78I, T79M, T79R, T79L, T79T, L80M, L80Y, L80I, L80V, L80L, Y81D, Y81V, Y81Y, Y81M, V82A, V82S, V82G, V82T, V82V, V82Q, V82Y, T83L, T83F, T83T, T83N, L84E, L84F, L84Y, L84I, L84L, L84M, L84A, L84T, L84S, E85K, E85G, E85P, E85S, E85E, E85F, E85V, E85R, P86T, P86C, P86P, P86L, P86N, P86K, P86H, C87M, C87I, C87S, C87N, C87P, S87C, S87L, S87V, V88A, V88M, V88V, V88T, V88E, V88D, V88S, C90S, C90P, C90A, C90T, C90M, A91A, A91G, A91S, A91V, A91T, A91C, A91L, G92T, G92M, G92A, G92Y, G92G, A93I, A93C, A93M, A93V, A93A, M94M, M94T, M94A, M94V, M94L, M94I, M94H, I95S, I95G, I95L, I95H, I95V, H96A, H96L, H96R, H96S, H96H, H96N, H96E, S97C, S97G, S97I, S97M, S97R, S97S, S97P, R98K, R98I, R98N, R98Q, R98G, R98H, R98C, R98L, R98R, G100R, G100V, G100K, G100A, G100S, G100M, G100I, R101V, R101R, R101S, R101C, V102A, V102F, V102I, V102V, D103A, V103A, V103G, V103F, V103V, F104G, D104N, F104V, F104I, F104L, F104A, F104F, F104R, G105V, G105W, G105G, G105M, G105A, A106T, V106Q, V106F, V106W, V106M, A106A, A106Q, A106F, A106G, A106W, A106M, A106V, A106R, A106L, A106S, A106B, A106I, R107C, R107G, R107P, R107K, R107A, R107N, R107W, R107H, R107S, R107R, R107F, D108N, D108F, D108G, D108V, D108A, D108Y, D108H, D108I, D108K, D108L, D108M, D108Q, N108Q, N108F, N108W, N108M, N108K, D108K, D108F, D108M, D108Q, D108R, D108W, D108S, D108E, D108T, D108R, D108D, A109H, A109K, A109R, A109S, A109T, A109V, A109A, A109D, K110G, K110H, K110I, K110R, K110T, K110K, K110A, K110l, T111A, T111G, T111H, T111R, T111T, T111K, G112A, G112G, G112H, G112T, G112R, A113N, A114G, A114H, A114V, A114C, A114S, A114A, G115S, G115G, G115M, G115L, G115A, G115F, L117M, L117L, L117W, L117A, L117S, L117N, L117V, M118D, M118G, M118K, M118N, M118V, M118M, M118L, M118R, D119L, D119N, D119S, D119V, D119D, V120H, V120L, V120V, V120T, V120A, V120E, V120G, V120D, L121D, L121M, L121N, L121K, L121L, H122H, H122N, H122P, H122R, H122S, H122Y, H122G, H122T, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 H122L, H123C, H123G, H123P, H123V, H123Y, Y123H, H123Y, H123H, P124P, P124H, P124A, P124Y, P124D, P124G, P124I, P124L, P124W, G125H, G125I, G125A, G125M, G125K, G125G, G125P, M126D, M126H, M126K, M126I, M126N, M126O, M126S, M126Y, M126M, M126G, N127H, N127S, N127D, N127K, N127R, N127N, N127I, N127P, N127M, H128R, H128N, H128L, H128H, R129H, R129Q, R129V, R129I, R129E, R129V, R129R, R129M, R129P, V130R, V130V, V130E, V130D, E131E, E131I, E131V, E131K, I132I, I132F, I132T, I132L, I132V, I132E, T133V, T133E, T133G, T133K, T133T, T133A, T133H, T133F, T133I, E134A, E134E, E134G, E134I, E134H, E134K, E134T, G135G, G135V, G135I, G135P, G135E, I136G, I136L, I136T, I136I , l137A, l137D, l137E, L137M, l137S, L137L, L137I , A138D, A138E, A138G, S138A, A138N, A138S, A138T, A138V, A138Y, A138A, A138M, A138L, D139E, D139I, D139C, D139L, D139M, D139D, D139G, D139H, D139A, E140A, E140C, E140L, E140R, E140K, E140E, E140D, C141S, C141A, C141C, C141V, C141E, A142N, A142D, A142G, A142A, A142L, A142S, A142T, A142N, A142S, A142V, A142E, A142C, A143D, A143E, A143G, , A143D, A143G, A143E, A143L, A143W, A143M, A143S, A143Q, A143R, A143A, A143I, L144S, L144L, L144T, L144A, L145A, L145F, L145G, L145D, L145L, L145C, L145E, L145s, C146R, S146A, S146C, S146D, S146F, S146R, S146T, S146D, S146G, S146S, S146L, D147D, D147L, D147F, D147G, D147Y, Y147T, Y147R, Y147D, D147R, D147Y, D147A, D147T, D147H, D147F, D147U, D147V, D147I, D147C, F148L, F148F, F148R, F148Y, F148A, F148T, F149C, F149M, F149R, F149Y, F149N, F149F, F149A, F149T, F149V R150R, R150M, R150D, R150F, M151F, M151P, M151R, M151V, M151M, M151E, R152C, R152F, R152H, R152P, R152R, R152P, R152Q, R152M, R152O, R153C, R153Q, R153R, R153V, R153E, R153A, R153P, Q154E, Q154H, Q154M, Q154R, Q154L, Q154S, Q154V, Q154Q, Q154F, Q154I, Q154A, Q154K, E155F, E155G, E155I, E155K, E155P, E155V, E155D, E155E, E155L, E155Q, I156V, I156A, I156I, I156L, I156F, I156D, I156K, I156N, I156R, I156Y, E157A, E157F, E157I, E157P, E157T, E157V, N157K, K157N, K157V, K157P, K157I, K157F, K157F, K157T, K157A, K157S, K157R, A158Q, A158K, A158V, A158A, A158D, A158S, A158T, A158N, Q159S, Q159Q, Q159A, Q159F, Q159K, Q159L, Q159N, K160A, K160S, K160E, K160K, K160N, K160F, K160Q, K161T, K161K, K161R, K161I, K161A, K161N, K161Q, K161S, K161T, A162D, A162Q, R162H, R162P, A162S, A162A, A162N, A162M, A162K, Q163G, Q163S, Q163Q, Q163A, Q163H, Q163N, Q163R, S164F, S164S, S164Q, S164I, S164R, S164Y, S165S, S165P, S165Q, S165A, S165D, S165I, S165T, S165Y, T166T, T166Q, T166E, T166S, T166D, T166K, T166I, T166N, T166P, T166R, D167S D167D, D167I, D167G, D167T, D167A and / or D167N mutation in a TadA reference ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 sequence (e.g., TadA*7.10,ecTadA, or TadA8e), and any alternative mutation at the corresponding position,or one or more corresponding mutations in another adenosine deaminase. Additional mutations are described in U.S. Patent Application Publication No. 2022 / 0307003 A1 U.S. Patent No.11,155,803, and International Patent Application Publications No. WO 2023 / 288304 A2, PCT / CN2022 / 143408, WO 2018 / 027078 A1, WO 2021 / 158921 A1 and WO 2023 / 034959 A2, the disclosures of which are incorporated herein by reference in their entirety for all purposes. In various embodiments, an adenosine deaminase of the disclosure lacks an N- terminal methionine. In some embodiments, the disclosure provides TadA variants comprising an alteration at an amino acid selected from one or more of L36, I76, V82, Y147, Q154, and N157 comapred to TadA*7.10. In some embodiments, the disclosure provides TadA variants comprising one or more of the following alterations relative to TadA*7.10: L36H, I76Y, V82T, Y147T, Q154S, and N157K. In some embodiments, the disclosure provides TadA variants comprising the following alterations relative to TadA*7.10: L36H, I76Y, V82T, Y147T, Q154S, and N157K. In some embodiments, the disclosure provides TadA variants comprising the following alterations relative to TadA*7.10: F84Y, A109L, A109V, A109I, A109F, A109S, A109T, A109N, V155S, V155T, V155N, F156Y, F156W, F156R, F156N, and F156Q. In some embodiments, the disclosure provides TadA variants comprising the following alterations relative to TadA*7.10: E3N, E3K, E3G, F6A, H14D, L18A, W23I, W23R, P29T, P29Y, P29Q, V35Q, L36S, N38D, G42M, N46Y, P48A, G50A, H52L, A62V, L63R, L63F, Q65R, G67N, L68V, M70I, N72Y, T79H, Y81V, V82S, M94R, G100V, V102E, V102S, R107A, A114C, G115E, M118L, D119L, H122T, P124H, P124K, P124Q, H128R, V130F, I132K, I132T, E140L, A142N, A142S, L144Q, L145R, L145N, Y147A, F149A, R152P, F156N, and K160E. In some embodiments, the disclosure provides TadA variants comprising a V82T, Y147T, and / or a Q154S mutation. In some embodiments, the disclosure provides TadA variants comprising a V82T, Y147T, and / or a Q154S mutation. In some embodiments, the disclosure provides TadA*8.8 further comprising a V82T mutation. In some embodiments, the disclosure provides TadA*8.8 further comprising a V82T, a Y147T, and a Q154S mutation. In some embodiments, the disclosure provides TadA*8.17 further comprising a V82T mutation. In some embodiments, the disclosure provides TadA*8.17 further comprising a V82T, a Y147T, and a Q154S mutation. In some embodiments, the disclosure ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 provides TadA*8.20 further comprising a V82T mutation. In some embodiments, the disclosure provides TadA*8.20 further comprising a V82T, a Y147T, and a Q154S mutation. In embodiments, a variant of TadA*7.10 comprises one or more alterations selected from any of those alterations provided herein. In particular embodiments, an adenosine deaminase heterodimer comprises a TadA*8 domain and an adenosine deaminase domain selected from Staphylococcus aureus (S. aureus) TadA, Bacillus subtilis (B. subtilis) TadA, Salmonella typhimurium (S. typhimurium) TadA, Shewanella putrefaciens (S. putrefaciens) TadA, Haemophilus influenzae F3031 (H. influenzae) TadA, Caulobacter crescentus (C. crescentus) TadA, Geobacter sulfurreducens (G. sulfurreducens) TadA, or TadA*7.10. In some embodiments, the TadA*8 is a variant as shown in Table 5D. Table 5D shows certain amino acid position numbers in the TadA amino acid sequence and the amino acids present in those positions in the TadA-7.10 adenosine deaminase. Table 5D also shows amino acid changes in TadA variants relative to TadA-7.10 following phage-assisted non- continuous evolution (PANCE) and phage-assisted continuous evolution (PACE), as described in M. Richter et al., 2020, Nature Biotechnology, doi.org / 10.1038 / s41587-020- 0453-z, the entire contents of which are incorporated by reference herein. In some embodiments, the TadA*8 is TadA*8a, TadA*8b, TadA*8c, TadA*8d, or TadA*8e. In some embodiments, the TadA*8 is TadA*8e. In one embodiment, an adenosine deaminase is a TadA*8 that comprises or consists essentially of SEQ ID NO: 316 or a fragment thereof having adenosine deaminase activity. Table 5D. Select TadA*8 Variants In some embodiments, the TadA variant is a variant as shown in Table 5E. Table 5E shows certain amino acid position numbers in the TadA amino acid sequence and the amino ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 acids present in those positions in the TadA*7.10 adenosine deaminase. In some embodiments, the TadA variant is MSP605, MSP680, MSP823, MSP824, MSP825, MSP827, MSP828, or MSP829. In some embodiments, the TadA variant is MSP828. In some embodiments, the TadA variant is MSP829. Table 5E. TadA Variants Table 5F. TadA Variants ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 5F (CONTINUED). TadA Variants ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 5G. TadA Variants In particular embodiments, the fusion proteins or complexes comprise a single (e.g., provided as a monomer) TadA* (e.g., TadA*8 or TadA*9). Throughout the present disclosure, an adenosine deaminase base editor that comprises a single TadA* domain is indicates using the terminology ABEm or ABE#m, where “#” is an identifying number (e.g., ABE8.20m), where “m” indicates “monomer.” In some embodiments, the TadA* is linked to a Cas9 nickase. In some embodiments, the fusion proteins or complexes of the disclosure ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 comprise as a heterodimer of a wild-type TadA (TadA(wt)) linked to a TadA*. Throughout the present disclosure, an adenosine deaminase base editor that comprises a single TadA* domain and a TadA(wt) domain is indicates using the terminology ABEd or ABE#d, where “#” is an identifying number (e.g., ABE8.20d), where “d” indicates “dimer.” In other embodiments, the fusion proteins or complexes of the disclosure comprise as a heterodimer of a TadA*7.10 linked to a TadA*. In some embodiments, the base editor is ABE8 comprising a TadA* variant monomer. In some embodiments, the base editor is ABE comprising a heterodimer of a TadA* and a TadA(wt). In some embodiments, the base editor is ABE comprising a heterodimer of a TadA* and TadA*7.10. In some embodiments, the base editor is ABE comprising a heterodimer of a TadA*. In some embodiments, the TadA* is selected from Tables 5A-5E. In some embodiments, the adenosine deaminase is expressed as a monomer. In other embodiments, the adenosine deaminase is expressed as a heterodimer. In some embodiments, the deaminase or other polypeptide sequence lacks a methionine, for example when included as a component of a fusion protein. This can alter the numbering of positions. However, the skilled person will understand that such corresponding mutations refer to the same mutation. Any of the mutations provided herein and any additional mutations (e.g., based on the ecTadA amino acid sequence) can be introduced into any other adenosine deaminases. Any of the mutations provided herein can be made individually or in any combination in a TadA reference sequence or another adenosine deaminase (e.g., ecTadA). Details of A to G nucleobase editing proteins are described in International PCT Application No. PCT / US2017 / 045381 (WO2018 / 027078) and Gaudelli, N.M., et al., “Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage” Nature, 551, 464-471 (2017), the entire contents of which are hereby incorporated by reference. C to T Editing In some embodiments, a base editor disclosed herein comprises a fusion protein or complex comprising cytidine deaminase capable of deaminating a target cytidine (C) base of a polynucleotide to produce uridine (U), which has the base pairing properties of thymine. In some embodiments, for example where the polynucleotide is double-stranded (e.g., DNA), the uridine base can then be substituted with a thymidine base (e.g., by cellular repair machinery) to give rise to a C:G to a T:A transition. In other embodiments, deamination of a ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 C to U in a nucleic acid by a base editor cannot be accompanied by substitution of the U to a T. The deamination of a target C in a polynucleotide to give rise to a U is a non-limiting example of a type of base editing that can be executed by a base editor described herein. In another example, a base editor comprising a cytidine deaminase domain can mediate conversion of a cytosine (C) base to a guanine (G) base. For example, a U of a polynucleotide produced by deamination of a cytidine by a cytidine deaminase domain of a base editor can be excised from the polynucleotide by a base excision repair mechanism (e.g., by a uracil DNA glycosylase (UDG) domain), producing an abasic site. The nucleobase opposite the abasic site can then be substituted (e.g., by base repair machinery) with another base, such as a C, by for example a translesion polymerase. Although it is typical for a nucleobase opposite an abasic site to be replaced with a C, other substitutions (e.g., A, G or T) can also occur. Accordingly, in some embodiments a base editor described herein comprises a deamination domain (e.g., cytidine deaminase domain) capable of deaminating a target C to a U in a polynucleotide. Further, as described below, the base editor can comprise additional domains which facilitate conversion of the U resulting from deamination to, in some embodiments, a T or a G. For example, a base editor comprising a cytidine deaminase domain can further comprise a uracil glycosylase inhibitor (UGI) domain to mediate substitution of a U by a T, completing a C-to-T base editing event. In another example, the base editor can comprise a uracil stabilizing protein as described herein. In another example, a base editor can incorporate a translesion polymerase to improve the efficiency of C-to-G base editing, since a translesion polymerase can facilitate incorporation of a C opposite an abasic site (i.e., resulting in incorporation of a G at the abasic site, completing the C-to-G base editing event). A base editor comprising a cytidine deaminase as a domain can deaminate a target C in any polynucleotide, including DNA, RNA and DNA-RNA hybrids. In some embodiments, a cytidine deaminase of a base editor comprises all or a portion (e.g., a functional portion) of an apolipoprotein B mRNA editing complex (APOBEC) family deaminase. APOBEC is a family of evolutionarily conserved cytidine deaminases. Members of this family are C-to-U editing enzymes. The N-terminal domain of APOBEC like proteins is the catalytic domain, while the C-terminal domain is a pseudocatalytic domain. More specifically, the catalytic domain is a zinc dependent cytidine deaminase domain and is important for cytidine deamination. APOBEC family members include APOBEC1, APOBEC2, APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D (“APOBEC3E” now ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 refers to this), APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, and Activation-induced (cytidine) deaminase. Other exemplary deaminases that can be fused to Cas9 according to aspects of this disclosure are provided below. In embodiments, the deaminases are activation-induced deaminases (AID). It should be understood that, in some embodiments, the active domain of the respective sequence can be used, e.g., the domain without a localizing signal (nuclear localization sequence, without nuclear export signal, cytoplasmic localizing signal). Some aspects of the present disclosure are based on the recognition that modulating the deaminase domain catalytic activity of any of the fusion proteins or complexes described herein, for example by making point mutations in the deaminase domain, affect the processivity of the fusion proteins (e.g., base editors) or complexes. For example, mutations that reduce, but do not eliminate, the catalytic activity of a deaminase domain within a base editing fusion protein or complexes can make it less likely that the deaminase domain will catalyze the deamination of a residue adjacent to a target residue, thereby narrowing the deamination window. The ability to narrow the deamination window can prevent unwanted deamination of residues adjacent to specific target residues, which can reduce or prevent off- target effects. In some embodiments, an APOBEC deaminase incorporated into a base editor can comprise one or more mutations selected from the group consisting of R33A, K34A, E63A, H102P, D104N, H121R, H122R, H122L, D124N; R126A, R126E, R118A, W90A, W90Y, and R132E of rAPOBEC1; D316R, D317R, R320A, R320E, R313A, W285A, W285Y, and R326E of hAPOBEC3G; and any alternative mutation at the corresponding position, or one or more corresponding mutations in another APOBEC deaminase. In some embodiments, an APOBEC deaminase incorporated into a base editor can comprise one or more combinations of mutations selected from K34A, H122L, and D124N (AALN); H102P and D104N (evoFERNY derived from FERNY); W90Y and R126E (YE1); W90Y and R132E (YE2); R126E and R132E (EE); W90Y, R126E, and R132E (YEE), or rAPOBEC1; and any alternative mutation at the corresponding positions, or one or more corresponding mutations in another APOBEC deaminase. A number of modified cytidine deaminases are commercially available, including, but not limited to, SaBE3, SaKKH-BE3, VQR-BE3, EQR-BE3, VRER-BE3, YE1-BE3, EE-BE3, YE2-BE3, and YEE-BE3, which are available from Addgene (plasmids 85169, 85170, 85171, 85172, 85173, 85174, 85175, 85176, 85177). In some embodiments, a deaminase ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 incorporated into a base editor comprises all or a portion (e.g., a functional portion) of an APOBEC1 deaminase. In some embodiments, the fusion proteins or complexes of the disclosure comprise one or more cytidine deaminase domains. In some embodiments, the cytidine deaminases provided herein are capable of deaminating cytosine or 5-methylcytosine to uracil or thymine. In some embodiments, the cytidine deaminases provided herein are capable of deaminating cytosine in DNA. The cytidine deaminase may be derived from any suitable organism. In some embodiments, the cytidine deaminase is a naturally-occurring cytidine deaminase that includes one or more mutations corresponding to any of the mutations provided herein. One of skill in the art will be able to identify the corresponding residue in any homologous protein, e.g., by sequence alignment and determination of homologous residues. Accordingly, one of skill in the art would be able to generate mutations in any naturally-occurring cytidine deaminase that corresponds to any of the mutations described herein. In some embodiments, the cytidine deaminase is from a prokaryote. In some embodiments, the cytidine deaminase is from a bacterium. In some embodiments, the cytidine deaminase is from a mammal (e.g., human). In some embodiments, the cytidine deaminase comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the cytidine deaminase amino acid sequences set forth herein. It should be appreciated that cytidine deaminases provided herein may include one or more mutations (e.g., any of the mutations provided herein). Some embodiments provide a polynucleotide molecule encoding the cytidine deaminase nucleobase editor polypeptide of any previous aspect or as delineated herein. In some embodiments, the polynucleotide is codon optimized. In embodiments, a fusion protein of the disclosure comprises two or more nucleic acid editing domains. Details of C to T nucleobase editing proteins are described in International PCT Application No. PCT / US2016 / 058344 (WO2017 / 070632) and Komor, A.C., et al., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage” Nature 533, 420-424 (2016), the entire contents of which are hereby incorporated by reference. Further non-limiting examples of C to T nucleobase editing proteins are described in PCT Applications No. PCT / US2020 / 062428 and PCT / US2019 / 033848, the entire contents of which are hereby incorporated by reference. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Cytidine Adenosine Base Editors (CABEs) In some embodiments, a base editor described herein comprises an adenosine deaminase variant that has increased cytidine deaminase activity. Such base editors may be referred to as “cytidine adenosine base editors (CABEs)” or “cytosine base editors derived from TadA* (CBE-Ts),” and their corresponding deaminase domains may be referred to as “TadA* acting on DNA cytosine (TADC)” domains or TadA-derived cytidine deaminases (TadA-CD). Base editors containing adenosine deaminase variants having both cytidine deaminase and adenosine deaminase activity (i.e., TadA-Dual deaminases) may be referred to as TadA-based dual editors (TadDE). In some instances, an adenosine deaminase variant has both adenine and cytosine deaminase activity (i.e., is a dual deaminase). In some embodiments, the adenosine deaminase variants deaminate adenine and cytosine in DNA. In some embodiments, the adenosine deaminase variants deaminate adenine and cytosine in single-stranded DNA. In some embodiments, the adenosine deaminase variants deaminate adenine and cytosine in RNA. In some embodiments, the adenosine deaminase variant predominantly deaminates cytosine in DNA and / or RNA (e.g., greater than 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of all deaminations catalyzed by the adenosine deaminase variant, or the number of cytosine deaminations catalyzed by the variant is about or at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 25-fold, 50-fold, 75-fold, 100-fold, 500-fold, or 1,000-fold greater than the number adenine deaminations catalyzed by the variant). In some embodiments, the adenosine deaminase variant has approximately equal cytosine and adenosine deaminase activity (e.g., the two activities are within about 10% or 20% of each other). In some embodiments, the adenosine deaminase variant has predominantly cytosine deaminase activity, and little, if any, adenosine deaminase activity. In some embodiments, the adenosine deaminase variant has cytosine deaminase activity, and no significant or no detectable adenosine deaminase activity. In some embodiments, the target polynucleotide is present in a cell in vitro or in vivo. In some embodiments, the cell is a bacteria, yeast, fungi, insect, plant, or mammalian cell. Examples of adenosine deaminase variants having increased cytidine deaminase activity include those described in International Patent Application Publications No. WO 2024 / 040083 and WO 2022 / 204574, the disclosures of which are hereby incorporated by reference in their entireties for all purposes. In some embodiments, the CABE comprises a bacterial TadA deaminase variant (e.g., ecTadA). In some embodiments, the CABE comprises a truncated TadA deaminase variant. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 In some embodiments, the CABE comprises a fragment of a TadA deaminase variant. In some embodiments, the CABE comprises a TadA*8.20 variant. In some embodiments, an adenosine deaminase variant of the disclosure is a TadA adenosine deaminase comprising one or more alterations that increase cytosine deaminase activity (e.g., at least about 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold or more increase) while maintaining adenosine deaminase activity (e.g., at least about 30%, 40%, 50% or more of the activity of a reference adenosine deaminase (e.g., TadA*8.20 or TadA*8.19)). In some instances, the adenosine deaminase variant comprises one or more alterations that increase cytosine deaminase activity (e.g., at least about 10-fold, 20-fold, 30- fold, 40-fold, 50-fold, 60-fold, 70-fold or more increase) relative to the activity of a reference adenosine deaminase and comprise undetectable adenosine deaminase activity or adenosine deaminase activity that is less than 30%, 20%, 10%, or 5% of that of a reference adenosine deaminase. In some embodiments, the reference adenosine deaminase is TadA*8.20 or TadA*8.19. In some embodiments, the adenosine deaminase variant is an adenosine deaminase comprising two or more alterations at an amino acid position selected from the group consisting of 2, 4, 6, 8, 13, 17, 23, 27, 29, 30, 47, 48, 49, 67, 76, 77, 82, 84, 96, 100, 107, 112, 114, 115, 118, 119, 122, 127, 142, 143, 147, 149, 158, 159, 162165, 166, and 167, of an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or greater identity to SEQ ID NO: 1, or a corresponding alteration in another deaminase. I In some embodiments, the adenosine deaminase variant is an adenosine deaminase comprising one or more alterations selected from the group consisting of S2H, V4K, V4S, V4T, V4Y, F6G, F6H, F6Y, H8Q, R13G, T17A, T17W, R23Q, E27C, E27G, E27H, E27K, E27Q, E27S, E27G, P29A, P29G, P29K, V30F, V30I, R47G, R47S, A48G, I49K, I49M, I49N, I49Q, I49T, G67W, I76H, I76R, I76W, Y76H, Y76R, Y76W, F84A, F84M, H96N, G100A, G100K, T111H, G112H, A114C, G115M, M118L, H122G, H122R, H122T, N127I, N127K, N127P, A142E, R147H, A158V, Q159S, A162C, A162N, A162Q, and S165P of an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or greater identity to SEQ ID NO: 1, or a corresponding alteration in another deaminase. In some embodiments, the adenosine deaminase variant is an adenosine deaminase comprising an amino acid alteration or combination of amino acid alterations selected from those listed in any of Tables 6A-6F. The residue identity of exemplary adenosine deaminase variants that are capable of deaminating adenine and / or cytidine in a target polynucleotide (e.g., DNA) is provided in ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Tables 6A-6F below. Further examples of adenosine deaminase variants include the following variants of 1.17 (see Table 6A): 1.17+E27H; 1.17+E27K; 1.17+E27S; 1.17+E27S+I49K; 1.17+E27G; 1.17+I49N; 1.17+E27G+I49N; and 1.17+E27Q. In some embodiments, any of the amino acid alterations provided herein are substituted with a conservative amino acid. Additional mutations known in the art can be further added to any of the adenosine deaminase variants provided herein. In some embodiments, the base editor systems comprising a CABE provided herein have at least about a 30%, 40%, 50%, 60%, 70% or more C to T editing activity in a target polynucleotide (e.g., DNA). In some embodiments, a base editor system comprising a CABE as provided herein has an increased C to T base editing activity (e.g., increased at least about 30-fold, 40-fold, 50-fold, 60-fold, 70-fold or more) relative to a reference base editor system comprising a reference adenosine deaminase (e.g., TadA*8.20 or TadA*8.19). Table 6A. Adenosine Deaminase Variants. Mutations are indicated with reference to TadA*8.20. “S” indicates “Surface,” and “NAS” indicates “Near Active Site.” ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 6A (continued). Adenosine Deaminase Variants. Mutations are indicated with reference to TadA*8.20. “I” indicates “Internal,” “S” indicates “Surface,” and “NAS” indicates “Near Active Site.” Table 6B. Adenosine deaminase variants. Mutations are indicated with reference to TadA*8.20. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 6C. Adenosine deaminase variants. Mutations are indicated with reference to variant 1.2 (Table 6A) . ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 6C. (CONTINUED) ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 6D. Adenosine deaminase variants. Mutations are indicated with reference to TadA*8.20. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 Table 6E. Hybrid constructs. Mutations are indicated with reference to TadA*7.10. Table 6F. Base editor variants. Mutations are indicated with reference to TadA*8.19 / 8.20. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 A TadA-derived cytidine deaminase (e.g., TadA-CD), according to certain embodiments, comprises an amino acid sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 98% identical, at least 99% identical, and at least 99.5% identical to the amino acid sequence of SEQ ID NO: 3594, wherein residue 27 of SEQ ID NO: 3594 is any amino acid expect for E (glutamic acid). TadA-CDs with other sequence homologies are also possible. For example, in certain embodiments, the TadA-derived cytidine deaminase (e.g., TadA-CD) comprises an amino acid sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 98% identical, at least 99% identical, and at least 99.5% identical to the amino acid sequence of SEQ ID NO: 3594, wherein residue 28 of SEQ ID NO: 3594 is any amino acid expect for V (valine). In another exemplary embodiment, the TadA-derived cytidine deaminase is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 98% identical, at least 99% identical, and at least 99.5% identical to the amino acid sequence of SEQ ID NO: 3594, wherein residue 96 of SEQ ID NO: 3594 is any amino acid expect for H (histidine). In another exemplary embodiment, the TadA-derived cytidine deaminase is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 98% identical, at least 99% identical, and at least 99.5% identical to the amino acid sequence of SEQ ID NO: 3594, wherein residue 26 of SEQ ID NO: 3594 is any amino acid expect for R (arginine). In various embodiments, the TadA-derived cytidine deaminase comprises an alteration at one or more of positions 26, 27, 28, 48, 73, or 96 compared to SEQ ID NO: 3594. As will be appreciated by those of skill in the art, TadA-derived cytidine deaminases (e.g., TadA-CD) may comprise a plurality of mutations relative to the parent adenosine deaminase (e.g., TadA-8e). In some embodiments, the deaminase of the instant application (e.g., TadA-CD) comprises mutations at residues E27, V28, and H96. In some embodiments, ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 the disclosed deaminase further comprises at least one mutation at a residue selected from R26, M61, Y73, I76, M151, Q154, and A158, in the amino acid sequence of SEQ ID NO: 3594, or corresponding mutations in a homologous adenosine deaminase. In some embodiments, the deaminase comprises at least one mutation selected from E27A, E27K, V28G, V28A, and H96N, and further comprises at least one mutation at a residue selected from R26G, M61I, Y73H, Y73S, Y73C, I76F, M151I, Q154R, Q154H, and A158S, in the amino acid sequence of SEQ ID NO: 3594, or a corresponding mutation in a homologous adenosine deaminase. Other mutations are also possible. For example, in certain embodiments, the TadA-CD enzyme comprises mutations selected from E27A, V28G, and H96N, and further comprises at least one mutation selected from R26G, M61I, Y73H, Y73S, Y73C, I76F, M151I, Q154R, Q154H, and A158S, in the amino acid sequence of SEQ ID NO: 3594, or corresponding mutations in a homologous adenosine deaminase. Other exemplary embodiments may include (1) deaminases comprising mutations E27K, V28G, and H96N, and further comprising at least one mutation selected from R26G, M61I, Y73H, Y73S, Y73C, I76F, M151I, Q154R, Q154H, and A158S, in the amino acid sequence of SEQ ID NO: 3594 or corresponding mutations in a homologous adenosine deaminase; (2) deaminases comprising mutations E27A, V28A, and H96N, and further comprising at least one mutation selected from R26G, M61I, Y73H, Y73S, Y73C, I76F, M151I, Q154R, Q154H, and A158S, in the amino acid sequence of SEQ ID NO: 3594, or corresponding mutations in a homologous adenosine deaminase; (3) deaminases comprising mutations E27K, V28A, and H96N, and further comprising at least one mutation selected from R26G, M61I, Y73H, Y73S, Y73C, I76F, M151I, Q154R, Q154H, and A158S, in the amino acid sequence of SEQ ID NO: 3594, or corresponding mutations in a homologous adenosine deaminase. In some embodiments, the TadA-derived cytidine deaminases (TadA-CD) comprise at least two mutations at residues selected from R26, M61, Y73, I76, M151, Q154, and A158 (relative to a reference adenosine deaminase). In other embodiments, the TadA-CD comprises at least two mutations at residues selected from R26G, M61I, Y73H, I76F, M151I, Q154H, Q154R, and A158S. In some embodiments, the addition of a V106W mutation improves the selectivity by suppressing A deamination to a greater extent than C deamination. In some embodiments, a TadA-based dual editor comprises an adenosine deaminase variant comprising one, two, three, four, or five mutations selected from R26G, V28A, A48R, Y73S, and H96N (e.g., SEQ ID NO: 3600). ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 As such, in some embodiments, provided herein are deaminases that comprise mutations at residues R26, V28, A48, and Y73 in the amino acid sequence of SEQ ID NO: 3594, or corresponding mutations in a homologous adenosine deaminase. Further provided herein are deaminases that comprise mutations at residues R26, E27, V28, A48, and Y73 (e.g., further comprise a mutation at E27) in the amino acid sequence of SEQ ID NO: 3594. In particular embodiments, these deaminases comprise the mutations R26G, V28A, A48R, Y73S, and H96N. In some embodiments, these deaminases comprise the mutations R26G, V28G, A48R, and Y73C. TadA-CD variants may comprise at least one mutation selected from R26G, E27A, V28G, I76F, H96N, and M151I (e.g, TadA-CDa, SEQ ID NO: 3595); R26G, E27A, V28G, I76F, H96N, and A158S (e.g, TadA-CDb, SEQ ID NO: 3596); R26G, E27A, V28G, I76F, H96N, Q154R, and A158S (e.g, TadA-CDc, SEQ ID NO: 3597); E27A, V28G, Y73H, H96N, Q154H, and A158S (e.g., TadA-CDd, SEQ ID NO: 3598); R26G, V28A, A48R, Y73S, and H96N (e.g., TadA-CDe, SEQ ID NO: 3599); V28A, A48R, and Y73S (e.g, TadA- CDf, SEQ ID NO: 3600), and R26G, V28G, A48R, and Y73C (e.g, TadA-CDg, SEQ ID NO: 3601). In some preferred embodiments, the deaminase comprises the mutations R26G, E27A, V28G, I76F, H96N, and A158S (e.g., TadA-CDa, SEQ ID NO: 3595), R26G, E27A, V28G, I76F, H96N, Q154R, and A158S (e.g., TadA-CDb, SEQ ID NO: 3596), R26G, E27A, V28G, I76F, H96N, and M151I (e.g., TadA-CDc, SEQ ID NO: 3597), E27K, V28A, M61I, and H96N (e.g., TadA-CDd, SEQ ID NO: 3598), E27A, V28G, Y73H, H96N, Q154H, and A158S (e.g., TadA-CDe, SEQ ID NO: 3599), R26G, V28A, A48R, Y73S, and H96N (e.g., TadA-CDf, SEQ ID NO: 3600), and R26G, V28G, A48R, and Y73C (e.g., TadA-CDg, SEQ ID NO: 3601). In some embodiments, the TadA-CD variants described above and herein may also comprises a V106W mutation. In some embodiments, the TadA-CD variants comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% to any of the amino acid sequences of SEQ ID NOs: 3594-3601. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46I, A48R, Y73P, and H96N (TadA-CD-1, SEQ ID NO: 3602) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46T, A48R, Y73P, and H96N (TadA- CD-2, SEQ ID NO: 3603) relative to the amino acid sequence of SEQ ID NO: 3594. In some ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 embodiments, the evolved TadA- Dual deaminase comprises the mutations R26G, V28A, N46T, A48R, Y73S, and H96N (TadA-CD-3, SEQ ID NO: 3604) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73S, and H96N (TadA-CD-4, SEQ ID NO:3605) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73P, and H96N (TadA-CD-5, SEQ ID NO: 3606) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46L, A48R, Y73P, and H96N (TadA-CD-6, SEQ ID NO: 3607) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations V28A, N46L, A48P, and Y73P (TadA-CD-7, SEQ ID NO: 3608) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations V28A, N46C, A48P, and Y73P (TadA-CD-8, SEQ ID NO: 3609) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73P, and H96N (TadA- CD-9, SEQ ID NO: 3610) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Q71H, Y73P, and H96N (TadA-CD- 10, SEQ ID NO: 3611) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46L, A48R, Y73P, and H96N (TadA- CD-11, SEQ ID NO: 3612) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46C, A48R, Y73P, and H96N (TadA-CD-12, SEQ ID NO: 3613) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46C, A48R, Y73P, H96N, and A162V (TadA-CD- 13, SEQ ID NO: 3614) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46I, A48R, Y73S, and H96N (TadA-CD-14, SEQ ID NO: 3615) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA- Dual deaminase comprises the mutations R26G, V28A, A48R, Q71S, Y73S, and H96N (TadA-CD-15, SEQ ID NO: 3616) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46L, A48R, and Y73P (TadA-CD-16, SEQ ID NO: 3617) relative to the amino acid ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46L, A48R, Y73P, and H96N (TadA-CD-17, SEQ ID NO: 3618) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, Y73P, and H96N (TadA-CD-18, SEQ ID NO: 3619) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73S, and H96N (TadA-CD-19, SEQ ID NO: 3620) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73P, and H96N (TadA-CD-20, SEQ ID NO: 3621) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G and N46L (TadA-CD-21, SEQ ID NO: 3622) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46I, A48R, Y73P, and H96N (TadA-CD-22, SEQ ID NO: 3623) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73P, and H96N (TadA-CD-23, SEQ ID NO: 3624) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, A48P, Y73H, T79P, and H96N (TadA-CD-24, SEQ ID NO: 3625) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA- Dual deaminase comprises the mutations R26G, N46I, and H96N (TadA-CD-25, SEQ ID NO: 3626) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73P, and H96N (TadA-CD-26, SEQ ID NO: 3627) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA- Dual deaminase comprises the mutations R26G, V28A, N46L, A48R, Y73S, and H96N (TadA-CD-27, SEQ ID NO: 3628) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46C, A48R, H96N, and A162V (TadA-CD-28, SEQ ID NO: 3629) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Q71H, Y73P, and H96N (TadA-CD- 29, SEQ ID NO: 3630) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46C, A48R, Y73P, and H96N (TadA-CD-30, SEQ ID NO: 3631) relative to the ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46C, A48R, Y73P, H96N, and A162V (TadA-CD-31, SEQ ID NO: 3632) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73P, and H96N (TadA-CD-32, SEQ ID NO: 3633) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA- Dual deaminase comprises the mutations R26G, V28A, N46V, A48R, Y73S, and H96N (TadA-CD-33, SEQ ID NO: 3634) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46V, A48P, Y73S, and H96N (TadA-CD-34, SEQ ID NO: 3635) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46C, A48R, Y73P, and H96N (TadA- CD-35, SEQ ID NO: 3636) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, L34M, N46L, A48R, Y73P, and H96N (TadA-CD-36, SEQ ID NO: 3637) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA- Dual deaminase comprises the mutations R26G, V28A, N46L, A48R, Y73P, and H96N (TadA-CD-37, SEQ ID NO: 3638) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R26G, V28A, N46L, A48P, R64K, Y73P, and H96N (TadA-CD- 38, SEQ ID NO: 3639) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46I, S73P, and H154Q (TadA-CD-1, SEQ ID NO: 3602) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46T (TadA-CD-2, SEQ ID NO: 3603) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46T and H154Q (TadA-CD-3, SEQ ID NO: 3604) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V and H154Q (TadA-CD-4, SEQ ID NO: 3605) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V, S73P, G105S, and H154Q (TadA- CD-5, SEQ ID NO: 3606) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA- Dual deaminase comprises the mutations N46L, S73P, and H154Q (TadA-CD-6, SEQ ID NO: 3607) relative to the amino acid sequence of SEQ ID NO: ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations G26R N46L, R48P, S73P, N96H, and H154Q (TadA-CD-7, SEQ ID NO: 3608) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA- Dual deaminase comprises the mutations N46C, N96H, and H154Q (TadA-CD-8, SEQ ID NO: 3609) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V, S73P, and H154Q (TadA- CD-9, SEQ ID NO: 3610) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V, Q71H, S73P, and H154Q (TadA-CD-10, SEQ ID NO: 3611) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46L and H154Q (TadA-CD-11, SEQ ID NO: 3612) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46C, S73P, and H154Q (TadA- CD-12, SEQ ID NO: 3613) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46C, S73P, H154Q, and A162V (TadA- CD-13, SEQ ID NO: 3614) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46I and H154Q (TadA-CD-14, SEQ ID NO: 3615) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations Q71S and H154Q (TadA-CD-15, SEQ ID NO: 3616) relative to the amino acid sequence of SEQ ID NO: 3594. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46L, S73P, N79T, and N96H (TadA-CD-16, SEQ ID NO: 3617) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46L, S73P, N79T (TadA-CD-17, SEQ ID NO: 3618) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R48A, S73P, and N79T (TadA- CD-18, SEQ ID NO: 3619) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V and N79T (TadA-CD-19, SEQ ID NO: 3620) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V, S73P, and N79T (TadA-CD-20, SEQ ID NO: 3621) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations A28V, N46L, R48A, S73Y, N79T, and N96H (TadA-CD-21, SEQ ID NO: 3622) relative to the amino acid sequence of SEQ ID NO: 3600. In some ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 embodiments, the evolved TadA-Dual deaminase comprises the mutations N46I, S73P, and N79T (TadA-CD-22, SEQ ID NO: 3623) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V, S73P, N79T, and G106S (TadA-CD-23, SEQ ID NO: 3624) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations R48P, S73H, and N79P (TadA-CD-24, SEQ ID NO: 3625) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA- Dual deaminase comprises the mutations A28V, N46I, R48A, S73Y, and N79T (TadA-CD- 25, SEQ ID NO: 3626) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V and S73P (TadA-CD-26, SEQ ID NO: 3627) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutation N46L (TadA-CD-27, SEQ ID NO: 3628) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46C, S73Y, and A162V (TadA- CD-28, SEQ ID NO: 3629) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V, Q71H, and S73P (TadA-CD-29, SEQ ID NO: 3630) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46C and S73P (TadA-CD-30, SEQ ID NO: 3631) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46C, S73P, and A162V (TadA-CD-31, SEQ ID NO: 3632) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V and S73P (TadA-CD-32, SEQ ID NO: 3633) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutation N46V (TadA-CD-33, SEQ ID NO: 3634) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46V and R48P(TadA-CD-34, SEQ ID NO: 3635) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46CV and S73P (TadA-CD-35, SEQ ID NO: 3636) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations L34M, N46L and S73P (TadA-CD- 36, SEQ ID NO: 3637) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46L and S73P ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 (TadA-CD-37, SEQ ID NO: 3638) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the evolved TadA-Dual deaminase comprises the mutations N46L, r48P, R64K and S73P (TadA-CD-38, SEQ ID NO: 3639) relative to the amino acid sequence of SEQ ID NO: 3600. In some embodiments, the TadA-CDs evolved from TadA-dual comprise at least 80%, 85%, 90%, 95%, 98%, 99%, or 99.5% identical to any of the amino acid sequences of SEQ ID NOs: 39, 41-54, and 359-383. Exemplary TadA-derived cytosine base editor amino acid sequences include: TadA- CDa base editor (SpCas9n napDNAbp domain) (TadCBEa) (SEQ ID NO: 3640), TadA-CDb base editor (SpCas9n napDNAbp domain) (TadCBEb) (SEQ ID NO: 3641), TadA-CDc base editor (SpCas9n napDNAbp domain) (TadCBEc) (SEQ ID NO: 3642), TadA-CDd base editor (SpCas9n napDNAbp domain) (TadCBEd) (SEQ ID NO: 3643), TadA-CDe base editor (SpCas9n napDNAbp domain) (TadCBEe) (SEQ ID NO: 3644), TadA-CDa(V106W) base editor (SpCas9n napDNAbp domain) (TadCBEa(V106W)) (SEQ ID NO: 3645), TadA- CDd(V106W) base editor (SpCas9n napDNAbp domain) (TadCBEd(V106W)) (SEQ ID NO: 3646), TadA-CDf base editor (SpCas9n napDNAbp domain) (TadCBEf) (SEQ ID NO: 3647), TadA-CDg base editor (SpCas9n napDNAbp domain) (TadCBEg) (SEQ ID NO: 3648), TadA-CDa:eNme2Cas9 base editor (SEQ ID NO: 3649), TadA-CDa:SaCas9 base editor (SEQ ID NO: 3650), TadA-CDa:SpCas9-NG base editor (SEQ ID NO: 3651), TadA- CDa:enCjCas9 base editor (SEQ ID NO: 3652). Exemplary polynucleotides encoding TadA-derived cytosine base editors of the disclosure include: TadCBEa-eNme2-C-BE4max vector (SEQ ID NO: 3653), TadCBEa- enCjCas9-BE4max vector (SEQ ID NO: 3654), TadCBEa-SpCas9-BE4max vector (SEQ ID NO: 3655), TadCBEa-SaCas9-BE4max vector (SEQ ID NO: 3656), TadCBEa-SpCas9-NG- BE4max vector (SEQ ID NO: 3657). Guide Polynucleotides A polynucleotide programmable nucleotide binding domain, when in conjunction with a bound guide polynucleotide (e.g., gRNA), can specifically bind to a target polynucleotide sequence (i.e., via complementary base pairing between bases of the bound guide nucleic acid and bases of the target polynucleotide sequence) and thereby localize the base editor to the target nucleic acid sequence desired to be edited. In some embodiments, the target polynucleotide sequence comprises single-stranded DNA or double-stranded DNA. In ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 some embodiments, the target polynucleotide sequence comprises RNA. In some embodiments, the target polynucleotide sequence comprises a DNA-RNA hybrid. In an embodiment, a guide polynucleotide described herein can be RNA or DNA. In one embodiment, the guide polynucleotide is a gRNA. In some embodiments, the guide polynucleotide is at least one single guide RNA (“sgRNA” or “gRNA”). In some embodiments, a guide polynucleotide comprises two or more individual polynucleotides, which can interact with one another via for example complementary base pairing (e.g., a dual guide polynucleotide, dual gRNA). For example, a guide polynucleotide can comprise a CRISPR RNA (crRNA) and a trans-activating CRISPR RNA (tracrRNA) or can comprise one or more trans-activating CRISPR RNA (tracrRNA). A guide polynucleotide may include natural or non-natural (or unnatural) nucleotides (e.g., peptide nucleic acid or nucleotide analogs). In some cases, the targeting region of a guide nucleic acid sequence (e.g., a spacer) can be at least 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the methods described herein can utilize an engineered Cas protein. A guide RNA (gRNA) is a short synthetic RNA composed of a scaffold sequence necessary for Cas-binding and a user-defined ∼20 nucleotide spacer that defines the genomic target to be modified. Exemplary gRNA scaffold sequences are provided in the sequence listing as SEQ ID NOs: 317-327 and 425. Thus, a skilled artisan can change the genomic target of the Cas protein specificity is partially determined by how specific the gRNA targeting sequence is for the genomic target compared to the rest of the genome. In embodiments, the spacer is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, or more nucleotides in length. The spacer of a gRNA can be or can be about 19, 20, or 21 nucleotides in length. A gRNA or a guide polynucleotide can target any exon or intron of a gene target. In some embodiments, a composition comprises multiple gRNAs that all target the same exon or multiple gRNAs that target different exons. An exon and / or an intron of a gene can be targeted. A gRNA or a guide polynucleotide can target a nucleic acid sequence of about 20 nucleotides or less than about 20 nucleotides (e.g., at least about 5, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30 nucleotides), or anywhere between about 1-100 nucleotides (e.g., 5, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90, 100). A target nucleic acid sequence can be or can be about 20 bases immediately 5′ of the first nucleotide of the PAM. A gRNA can target a nucleic acid sequence. A target nucleic acid can be at least or at least about 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, or 1-100 nucleotides. ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 The guide polynucleotides can comprise standard ribonucleotides, modified ribonucleotides (e.g., pseudouridine), ribonucleotide isomers, and / or ribonucleotide analogs. In some embodiments, a base editor system may comprise multiple guide polynucleotides, e.g., gRNAs. For example, the gRNAs may target to one or more target loci (e.g., at least 1 gRNA, at least 2 gRNA, at least 5 gRNA, at least 10 gRNA, at least 20 gRNA, at least 30 g RNA, at least 50 gRNA) comprised in a base editor system. The multiple gRNA sequences can be tandemly arranged and may be separated by a direct repeat. Modified Polynucleotides To enhance expression, stability, and / or genomic / base editing efficiency, and / or reduce possible toxicity, the base editor-coding sequence (e.g., mRNA) and / or the guide polynucleotide (e.g., gRNA) can be modified to include one or more modified nucleotides and / or chemical modifications, e.g. using pseudo-uridine, 5-Methyl-cytosine, 2′-O-methyl-3′- phosphonoacetate, 2′-O-methyl thioPACE (MSP), 2′-O-methyl-PACE (MP), 2′-fluoro RNA (2′-F-RNA), =constrained ethyl (S-cEt), 2′-O-methyl (‘M’), 2′-O-methyl-3′-phosphorothioate (‘MS’), 2′-O-methyl-3′-thiophosphonoacetate (‘MSP’), 5-methoxyuridine, phosphorothioate, and N1-Methylpseudouridine. Chemically protected gRNAs can enhance stability and editing efficiency in vivo and ex vivo. Methods for using chemically modified mRNAs and guide RNAs are known in the art and described, for example, by Jiang et al., Chemical modifications of adenine base editor mRNA and guide RNA expand its application scope. Nat Commun 11, 1979 (2020). doi.org / 10.1038 / s41467-020-15892-8, Callum et al., N1- Methylpseudouridine substitution enhances the performance of synthetic mRNA switches in cells, Nucleic Acids Research, Volume 48, Issue 6, 06 April 2020, Page e35, and Andries et al., Journal of Controlled Release, Volume 217, 10 November 2015, Pages 337-344, each of which is incorporated herein by reference in its entirety. In some embodiments, the guide polynucleotide comprises one or more modified nucleotides at the 5′ end and / or the 3′ end of the guide. In some embodiments, the guide polynucleotide comprises two, three, four or more modified nucleosides at the 5′ end and / or the 3′ end of the guide. In some embodiments, the guide polynucleotide comprises two, three, four or more modified nucleosides at the 5′ end and / or the 3′ end of the guide. In some embodiments, the guide comprises at least about 50%-75% modified nucleotides. In some embodiments, the guide comprises at least about 85% or more modified nucleotides. In some embodiments, at least about 1-5 nucleotides at the 5′ end of the gRNA are modified and at least about 1-5 nucleotides at the 3′ end of the gRNA are modified. In ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 some embodiments, at least about 3-5 contiguous nucleotides at each of the 5′ and 3′ termini of the gRNA are modified. In some embodiments, at least about 20% of the nucleotides present in a direct repeat or anti-direct repeat are modified. In some embodiments, at least about 50% of the nucleotides present in a direct repeat or anti-direct repeat are modified. In some embodiments, at least about 50-75% of the nucleotides present in a direct repeat or anti- direct repeat are modified. In some embodiments, at least about 100 of the nucleotides present in a direct repeat or anti-direct repeat are modified. In some embodiments, at least about 20% or more of the nucleotides present in a hairpin present in the gRNA scaffold are modified. In some embodiments, at least about 50% or more of the nucleotides present in a hairpin present in the gRNA scaffold are modified. In some embodiments, the guide comprises a variable length spacer. In some embodiments, the guide comprises a 20-40 nucleotide spacer. In some embodiments, the guide comprises a spacer comprising at least about 20-25 nucleotides or at least about 30-35 nucleotides. In some embodiments, the spacer comprises modified nucleotides. In some embodiments, the guide comprises two or more of the following: • at least about 1-5 nucleotides at the 5′ end of the gRNA are modified and at least about 1-5 nucleotides at the 3′ end of the gRNA are modified; • at least about 20% of the nucleotides present in a direct repeat or anti-direct repeat are modified; • at least about 50-75% of the nucleotides present in a direct repeat or anti-direct repeat are modified; • at least about 20% or more of the nucleotides present in a hairpin present in the gRNA scaffold are modified; • a variable length spacer; and • a spacer comprising modified nucleotides. In embodiments, the gRNA contains numerous modified nucleotides and / or chemical modifications. Such modifications can increase base editing ~2 fold in vivo or in vitro. In embodiments, the gRNA comprises 2′-O-methyl or phosphorothioate modifications. In an embodiment, the gRNA comprises 2′-O-methyl and phosphorothioate modifications. In an embodiment, the modifications increase base editing by at least about 2 fold. A guide polynucleotide can comprise one or more modifications to provide a nucleic acid with a new or enhanced feature. A guide polynucleotide can comprise a nucleic acid ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 affinity tag. A guide polynucleotide can comprise synthetic nucleotide, synthetic nucleotide analog, nucleotide derivatives, and / or modified nucleotides. A gRNA or a guide polynucleotide can also be modified by 5′ adenylate, 5′ guanosine-triphosphate cap, 5′ N7-Methylguanosine-triphosphate cap, 5′ triphosphate cap, 3′ phosphate, 3′ thiophosphate, 5′ phosphate, 5′ thiophosphate, Cis-Syn thymidine dimer, trimers, C12 spacer, C3 spacer, C6 spacer, dSpacer, PC spacer, rSpacer, Spacer 18, Spacer 9, 3′-3′ modifications, 2′-O-methyl thioPACE (MSP), 2′-O-methyl-PACE (MP), and constrained ethyl (S-cEt), 5′-5′ modifications, abasic, acridine, azobenzene, biotin, biotin BB, biotin TEG, cholesteryl TEG, desthiobiotin TEG, DNP TEG, DNP-X, DOTA, dT-Biotin, dual biotin, PC biotin, psoralen C2, psoralen C6, TINA, 3′ DABCYL, black hole quencher 1, black hole quencher 2, DABCYL SE, dT-DABCYL, IRDye QC-1, QSY-21, QSY-35, QSY- 7, QSY-9, carboxyl linker, thiol linkers, 2′-deoxyribonucleoside analog purine, 2′- deoxyribonucleoside analog pyrimidine, ribonucleoside analog, 2′-O-methyl ribonucleoside analog, sugar modified analogs, wobble / universal bases, fluorescent dye label, 2′-fluoro RNA, 2′-O-methyl RNA, methylphosphonate, phosphodiester DNA, phosphodiester RNA, phosphothioate DNA, phosphorothioate RNA, UNA, pseudouridine-5′-triphosphate, 5′- methylcytidine-5′-triphosphate, or any combination thereof. In some cases, a phosphorothioate enhanced RNA gRNA can inhibit RNase A, RNase T1, calf serum nucleases, or any combinations thereof. These properties can allow the use of PS-RNA gRNAs to be used in applications where exposure to nucleases is of high probability in vivo or in vitro. For example, phosphorothioate (PS) bonds can be introduced between the last 3-5 nucleotides at the 5′- or 3′-end of a gRNA which can inhibit exonuclease degradation. In some cases, phosphorothioate bonds can be added throughout an entire gRNA to reduce attack by endonucleases. Fusion Proteins or Complexes Comprising a Nuclear Localization Sequence (NLS) In some embodiments, the fusion proteins or complexes provided herein further comprise one or more (e.g., 2, 3, 4, 5) nuclear targeting sequences, for example a nuclear localization sequence (NLS). In one embodiment, a bipartite NLS is used. In some embodiments, a NLS comprises an amino acid sequence that facilitates the importation of a protein, that comprises an NLS, into the cell nucleus (e.g., by nuclear transport). In some embodiments, the NLS is fused to the N-terminus or the C-terminus of the fusion protein. In some embodiments, the NLS is fused to the C-terminus or N-terminus of an nCas9 domain or a dCas9 domain. In some embodiments, the NLS is fused to the N-terminus or C-terminus of ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 the Cas12 domain. In some embodiments, the NLS is fused to the N-terminus or C-terminus of the cytidine or adenosine deaminase. In some embodiments, the NLS is fused to the fusion protein via one or more linkers. In some embodiments, the NLS is fused to the fusion protein without a linker. In some embodiments, the NLS comprises an amino acid sequence of any one of the NLS sequences provided or referenced herein. Additional nuclear localization sequences are known in the art and would be apparent to the skilled artisan. For example, NLS sequences are described in Plank et al., PCT / EP2000 / 011690, the contents of which are incorporated herein by reference for their disclosure of exemplary nuclear localization sequences. In some embodiments, the NLS is present in a linker or the NLS is flanked by linkers, for example described herein. A bipartite NLS comprises two basic amino acid clusters, which are separated by a relatively short spacer sequence (hence bipartite - 2 parts, while monopartite NLSs are not). The NLS of nucleoplasmin,KR[PAATKKAGQA]KKKK (SEQ ID NO: 191), is the prototype of the ubiquitous bipartite signal: two clusters of basic amino acids, separated by a spacer of about 10 amino acids. The sequence of an exemplary bipartite NLS follows: PKKKRKVEGADKRTADGSEFESPKKKRKV (SEQ ID NO: 328). In some embodiments, any of the fusion proteins or complexes provided herein comprise an NLS comprising the amino acid sequence EGADKRTADGSEFESPKKKRKV (amino acids 8 to 29 of SEQ ID NO 328). In some embodiments, any of the adenosine base editors provided herein comprise an NLS comprising the amino acid sequence EGADKRTADGSEFESPKKKRKV (amino acids 8 to 29 of SEQ ID NO: 328). In some embodiments, the NLS is at a C-terminal portion of the adenosine base editor. In some embodiments, the NLS is at the C-terminus of the adenosine base editor. Additional Domains A base editor described herein can include any domain which helps to facilitate the nucleobase editing, modification or altering of a nucleobase of a polynucleotide. In some embodiments, a base editor comprises a polynucleotide programmable nucleotide binding domain (e.g., Cas9), a nucleobase editing domain (e.g., deaminase domain), and one or more additional domains. In some embodiments, the additional domain can facilitate enzymatic or catalytic functions of the base editor, binding functions of the base editor, or be inhibitors of cellular machinery (e.g., enzymes) that could interfere with the desired base editing result. In ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 some embodiments, a base editor comprises a nuclease, a nickase, a recombinase, a deaminase, a methyltransferase, a methylase, an acetylase, an acetyltransferase, a transcriptional activator, or a transcriptional repressor domain. In some embodiments, a base editor comprises an uracil glycosylase inhibitor (UGI) domain. In some cases, a base editor is expressed in a cell in trans with a UGI polypeptide. In some embodiments, cellular DNA repair response to the presence of U: G heteroduplex DNA can be responsible for a reduction in nucleobase editing efficiency in cells. In such embodiments, uracil DNA glycosylase (UDG) can catalyze removal of U from DNA in cells, which can initiate base excision repair (BER), mostly resulting in reversion of the U:G pair to a C:G pair. In such embodiments, BER can be inhibited in base editors comprising one or more domains that bind the single strand, block the edited base, inhibit UGI, inhibit BER, protect the edited base, and / or promote repairing of the non-edited strand. Thus, this disclosure contemplates a base editor fusion protein or complex comprising a UGI domain and / or a uracil stabilizing protein (USP) domain. BASE EDITOR SYSTEM Provided herein are systems, compositions, and methods for editing a nucleobase using a base editor system. In some embodiments, the base editor system comprises (1) a base editor (BE) comprising a polynucleotide programmable nucleotide binding domain and a nucleobase editing domain (e.g., a deaminase domain) for editing the nucleobase; and (2) a guide polynucleotide (e.g., guide RNA) in conjunction with the polynucleotide programmable nucleotide binding domain. In some embodiments, the base editor system is a cytidine base editor (CBE) or an adenosine base editor (ABE). In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA or RNA binding domain. In some embodiments, the nucleobase editing domain is a deaminase domain. In some embodiments, a deaminase domain can be a cytidine deaminase or an cytosine deaminase. In some embodiments, a deaminase domain can be an adenine deaminase or an adenosine deaminase. In some embodiments, the adenosine base editor can deaminate adenine in DNA. In some embodiments, the base editor is capable of deaminating a cytidine in DNA. Use of the base editor system provided herein comprises the steps of: (a) contacting a target nucleotide sequence of a polynucleotide (e.g., double- or single stranded DNA or RNA) of a subject with a base editor system comprising a nucleobase editor (e.g., an adenosine base editor or a cytidine base editor) and a guide polynucleotide (e.g., gRNA), ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 wherein the target nucleotide sequence comprises a targeted nucleobase pair; (b) inducing strand separation of said target region; (c) converting a first nucleobase of said target nucleobase pair in a single strand of the target region to a second nucleobase; and (d) cutting no more than one strand of said target region, where a third nucleobase complementary to the first nucleobase base is replaced by a fourth nucleobase complementary to the second nucleobase. It should be appreciated that in some embodiments, step (b) is omitted. In some embodiments, said targeted nucleobase pair is a plurality of nucleobase pairs in one or more genes. In some embodiments, the base editor system provided herein is capable of multiplex editing of a plurality of nucleobase pairs in one or more genes. In some embodiments, the plurality of nucleobase pairs is located in the same gene. In some embodiments, the plurality of nucleobase pairs is located in one or more genes, wherein at least one gene is located in a different locus. The components of a base editor system (e.g., a deaminase domain, a guide RNA, and / or a polynucleotide programmable nucleotide binding domain) may be associated with each other covalently or non-covalently. For example, in some embodiments, the deaminase domain can be targeted to a target nucleotide sequence by a polynucleotide programmable nucleotide binding domain, optionally where the polynucleotide programmable nucleotide binding domain is complexed with a polynucleotide (e.g., a guide RNA). In some embodiments, a polynucleotide programmable nucleotide binding domain can be fused or linked to a deaminase domain. In some embodiments, a polynucleotide programmable nucleotide binding domain can target a deaminase domain to a target nucleotide sequence by non-covalently interacting with or associating with the deaminase domain. For example, in some embodiments, the nucleobase editing component (e.g., the deaminase component) comprises an additional heterologous portion or domain that is capable of interacting with, associating with, or capable of forming a complex with a corresponding heterologous portion, antigen, or domain that is part of a polynucleotide programmable nucleotide binding domain and / or a guide polynucleotide (e.g., a guide RNA) complexed therewith. In some embodiments, the polynucleotide programmable nucleotide binding domain, and / or a guide polynucleotide (e.g., a guide RNA) complexed therewith, comprises an additional heterologous portion or domain that is capable of interacting with, associating with, or capable of forming a complex with a corresponding heterologous portion, antigen, or domain that is part of a nucleobase editing domain (e.g., the deaminase component). In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polypeptide. In some embodiments, the ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a guide polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a polypeptide linker. In some embodiments, the additional heterologous portion is capable of binding to a polynucleotide linker. An additional heterologous portion may be a protein domain. In some embodiments, an additional heterologous portion comprises a polypeptide, such as a 22 amino acid RNA-binding domain of the lambda bacteriophage antiterminator protein N (N22p), a 2G12 IgG homodimer domain, an ABI, an antibody (e.g. an antibody that binds a component of the base editor system or a heterologous portion thereof) or fragment thereof (e.g. heavy chain domain 2 (CH2) of IgM (MHD2) or IgE (EHD2), an immunoglobulin Fc region, a heavy chain domain 3 (CH3) of IgG or IgA, a heavy chain domain 4 (CH4) of IgM or IgE, an Fab, an Fab2, miniantibodies, and / or ZIP antibodies), a barnase-barstar dimer domain, a Bcl-xL domain, a Calcineurin A (CAN) domain, a Cardiac phospholamban transmembrane pentamer domain, a collagen domain, a Com RNA binding protein domain (e.g. SfMu Com coat protein domain, and SfMu Com binding protein domain), a Cyclophilin-Fas fusion protein (CyP-Fas) domain, a Fab domain, an Fe domain, a fibritin foldon domain, an FK506 binding protein (FKBP) domain, an FKBP binding domain (FRB) domain of mTOR, a foldon domain, a fragment X domain, a GAI domain, a GID1 domain, a Glycophorin A transmembrane domain, a GyrB domain, a Halo tag, an HIV Gp41 trimerisation domain, an HPV45 oncoprotein E7 C-terminal dimer domain, a hydrophobic polypeptide, a K Homology (KH) domain, a Ku protein domain (e.g., a Ku heterodimer), a leucine zipper, a LO...

Claims

ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 CLAIMS What is claimed:

1. A method of treating a disease or disorder associated with inappropriate activation of the complement system in a subject in need thereof, the method comprising altering a nucleobase of a complement factor B (CFB) polynucleotide in the subject by administering to the subject one or more guide polynucleotides, or one or more polynucleotides encoding the one or more guide polynucleotides, and a base editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a deaminase domain, or one or more polynucleotides encoding the base editor, wherein (a) said one or more guide polynucleotides targets said base editor to effect an alteration of a nucleobase of the CFB polynucleotide that: i. disrupts a splice site in the CFB polynucleotide, ii. alters a start codon in the CFB polynucleotide, iii. alters a TATA box in the CFB polynucleotide, iv. introduces a new stop codon in the CFB polynucleotide, and / or v. alters a nucleobase in a codon encoding an amino acid residue within a region of the CFB polypeptide encoded by the CFB polynucleotide selected from the group consisting of: serine protease (SP) active site, Mg2+binding loop, cleavage site, salt bridge, and oxyanion-hole; (b) the deaminase domain comprises a TadA variant (TadA*) comprising an amino acid sequence having at least 90% sequence identity to the following TadA*7.10 amino acid sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), or a fragment thereof lacking only the N-terminal methionine, wherein the TadA* further comprises a combination of amino acid alterations compared to the TadA*7.10 amino acid sequence selected from the group consisting of: i. I76Y, V82T, Y123H, Y147T, and Q154S, ii. Y123H, Y147R, and Q154R, iii. I76Y, Y133H, Y147R, and Q154R, iv. V82S, and Q164R, v. I76Y, V82S, Y123H, Y147R, and Q154R, andATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 vi. I76Y, V82T, Y123H, Y147R, and Q154; (c) the one or more guide polynucleotides comprises a nucleic acid sequence selected fromCCUCAGAUGUCUAUGUGUUU (SEQ ID NO: 1524), UGCUUACAAUGACUGAGAUCU (SEQ ID NO: 1535),UUGCUCCCCAUGGCGUUGGA (SEQ ID NO: 3476), CCCCAUGGCGUUGGAAGGCA (SEQ ID NO: 3443), andUGCUCCCCAUGGCGUUGGAA (SEQ ID NO: 3467) and / or comprising at least 10-23 contiguous nucleotides of a spacer nucleic acid sequence listed in any one of Tables 2A to 2H; and / or (d) said one or more guide polynucleotides targets said base editor to effect an alteration of a nucleobase in one or more codons encoding an amino acid residue selected from the group consisting of amino acid residue 1, 171, 175, 176, 177, 202, 203, 229, 230, 231, 232, 233, 254, 255, 256, 257, 258, 259, 260, 275, 276, 277, 278, 279, 280, 281, 351, 353, 354, 389, 470, 471, 472, 525, 526, 529, 574, 575, 576, 696, 697, and 699 relative to the following reference sequence: Complement factor B amino acid sequence MGSNLSPQLCLMPFILGLLSGGVTTTPWSLAQPQGSCSLEGVEIKGGSFRLLQEGQALEYVC PSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVS DEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDS VTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAE DGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYG LVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDV PPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLV NQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQ AKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPN YNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKE ELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLC TGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHIN LFQVLPWLKEKLQDEDLGFL (SEQ ID NO: 426), or a corresponding position in another CFB polypeptide sequence; thereby altering the nucleobase of the CFB polynucleotide.

2. A method of treating a disease or disorder associated with inappropriate activation of the complement system in a subject in need thereof, the method comprising altering a nucleobase of a complement factor B (CFB) polynucleotide in the subject by administering to the subject one or more guide polynucleotides, or one or more polynucleotides encoding theATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 guide polynucleotides, and a base editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a deaminase domain, or one or more polynucleotides encoding the base editor, wherein (a) the deaminase domain comprises a cytidine deaminase or a TadA variant (TadA*) comprising an amino acid sequence having at least 90% sequence identity to the following TadA*7.10 amino acid sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), wherein the TadA* further comprises a combination of amino acid alterations compared to the TadA*7.10 amino acid sequence selected from the group consisting of: i. I76Y, V82T, Y123H, Y147T, and Q154S, ii. Y123H, Y147R, and Q154R, iii. I76Y, Y133H, Y147R, and Q154R, iv. V82S, and Q164R, v. I76Y, V82S, Y123H, Y147R, and Q154R, and vi. I76Y, V82T, Y123H, Y147R, and Q154R; and (b) the one or more guide polynucleotides comprise a spacer comprising a nucleotide sequence selected from the group consisting of:CCUCAGAUGUCUAUGUGUUU (SEQ ID NO: 1524; TSBTx3826),AGGUGAUUCUGGCGGCCCCU (SEQ ID NO: 1719; gRNA1536), CGCCAGAAUCACCUGCAAGG (SEQ ID NO: 1715; gRNA1532), CUAUGACGUUGCCCUGAUCA (SEQ ID NO: 1723; gRNA1540), UGCUCCCCAUGGCGUUGGAA (SEQ ID NO: 3467; gRNA3657), UUGCUCCCCAUGGCGUUGGA (SEQ ID NO: 3476; gRNA3658), CCCCAUGGCGUUGGAAGGCA (SEQ ID NO: 3443; gRNA3660), GCUUACAAUGACUGAGAUCU (SEQ ID NO: 1534; TSBTx3837), UGCUUACAAUGACUGAGAUCU (SEQ ID NO: 1535; TSBTx3837), and UCUCACCUCUGCAAGUAUUG (SEQ ID NO: 1529; TSBTx3835); thereby treating the disease or disorder associated with inappropriate activation of the complement system in the subject.ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 3. The method of claim 1 or claim 2, wherein the one or more guide polynucleotides target said base editor to effect an alteration of the nucleobase of the CFB polynucleotide that disrupts a splice site in the CFB polynucleotide.

4. The method of claim 1 or claim 2, wherein the napDNAbp is a nickase.

5. The method of claim 1 or claim 2, wherein the napDNAbp binds a protospacer adjacent motif (PAM) selected from the group consisting ofNGA,NGC,NGG, andNNNRRT, wherein “N” is any nucleotide and “R” is A or G.

6. The method of claim 5, wherein the napDNAbp is a Cas9 polypeptide.

7. The method of claim 1 or claim 2, wherein the one or more guide polynucleotides comprises a modified nucleotide.

8. The method of claim 7, wherein the one or more guide polynucleotides comprises a sequence selected from the group consisting of: End-mod SpCas9 guide polynucleotide mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCU AGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU (SEQ ID NO: 440); End-mod SaCas9 guide polynucleotide mNsmNsmNsNNNNNNNNNNNNNNNNNNGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUA CUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU (SEQ ID NO: 441); HM01: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmUmAmGmAmAmAmUmAmGmCAAGU UAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGmUmGmGmCmAmCmCmG mAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 440); HM07: mNsmNsmNsmNmNmNmNmNmNmNNNNNNNNNNNmGUUUUAGmAmGmCmUmAmGmAmAmAmUm AmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUmGmAmAmATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 AmAmAmGmUmGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 440); NLS (bpsv40): mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCU AGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmUsmUsmUsmU-NHC6-CrossL- ac- CKRTADGSEFESPKKKRKV (SEQ ID NOs: 440 and 446); LONGEST: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGUGmG mCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 445); NLS + LONGEST : mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAmAmAmGmUmG mGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU-NHC5-CrossL- CKRTADGSEFESPKKKRKV (SEQ ID NOs: 445 and 446); and LONGEST + GOLD: mNsmNsmNsNNNNNNNNNNNNNNNNNGUUUUAGAmGmCmCmGmGmCmGmGmAmAmAmCmGmC mCmGmGmCAAGUUAAAAUAAGGCUAGUCCGUUAmUmCAAmCmUmUGGACUUCGGUCCmAmAm GUGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 447); wherein “N” represents any nucleotide, “mN” indicates a 2′-OMe modification of the nucleotide “N”, and “Ns” indicates that the nucleotide “N” is linked to the following nucleotide by a phosphorothioate (PS), and wherein the number of N nucleotides is between 15 and 25.

9. The method of claim 1 or claim 2, wherein the nucleobase alteration results in disruption of Mg2+binding to the CFB polypeptide encoded by the CFB polynucleotide.

10. The method of claim 1 or claim 2, wherein the nucleobase alteration results in a reduction or elimination of serine protease activity of the CFB polypeptide encoded by the CFB polynucleotide.

11. The method of claim 1 or claim 2, wherein the nucleobase alteration eliminates a salt bridge of the CFB polypeptide encoded by the CFB polynucleotide.ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 12. The method of claim 1 or claim 2, wherein the base editor effects a nucleobase alteration to the CFB polynucleotide that reduces cleavage of the CFB polypeptide encoded by the CFB polynucleotide by a factor D polypeptide.

13. The method of claim 1 or claim 2, wherein the deaminase domain is an adenosine deaminase comprising the TadA*7.10 amino acid sequence further comprising a combination of amino acid alterations selected from the group consisting of: i . I76Y, V82T, Y123H, Y147T, and Q154S, ii. Y123H, Y147R, and Q154R, iii. I76Y, Y133H, Y147R, and Q154R, iv. V82S, and Q164R, v. I76Y, V82S, Y123H, Y147R, and Q154R, and vi. I76Y, V82T, Y123H, Y147R, and Q154R.

14. The method of claim 1, wherein said one or more guide polynucleotides target said base editor to effect an alteration of a nucleobase in a codon encoding an amino acid residue selected from the group consisting of M1, P171, V177, R203, E232, E255, K258, R259, K260, D276, S278, S280, T353, D389, E471, H526, Y575, D576, G697, and S699 relative to the following reference sequence: Complement factor B amino acid sequence MGSNLSPQLCLMPFILGLLSGGVTTTPWSLAQPQGSCSLEGVEIKGGSFRLLQEGQALEYVC PSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPYYNVS DEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQYRLEDS VTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTETIEGVDAE DGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKVASYGVKPRYG LVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQAVYSMMSWPDDV PPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPREDYLDVYVFGVGPLV NQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGMVWEHRKGTDYHKQPWQ AKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVSVGGEKRDLEIEVVLFHPN YNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCTEGTTRALRLPPTTTCQQQKE ELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDAQYAPGYDKVKDISEVVTPRFLC TGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWGVVDVCKNQKRQKQVPAHARDFHIN LFQVLPWLKEKLQDEDLGFL (SEQ ID NO: 426).ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 15. The method of claim 1 or claim 2, wherein CFB activity, protein concentration, and / or mRNA concentration is reduced by at least about 15% as compared to a control subject without the alteration.

16. The method of claim 1 or claim 2, wherein the inappropriate activation of the complement system is associated with increased levels of one or more of inflammation, the presence of autoantibodies, neural degeneration, and microthrombosis.

17. The method of claim 1 or claim 2, wherein the inappropriate activation of the complement system is associated with damage to the central nervous system (CNS), the eyes, the gastrointestinal system, the pulmonary system, the musculoskeletal system, the circulatory system, the integumentary system, blood cells, thyroid, kidney, joints, gastrointestinal system, or transplanted organs.

18. The method of claim 1 or claim 2, wherein the disease or disorder is selected from the group consisting of acute antibody-mediated rejection, age-related macular degeneration, allergic bronchopulmonary aspergillosis, allergic neuritis, allergic rhinitis, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), anaphylaxis, scleritis, atopic dermatitis, atypical hemolytic syndrome (aHUS), autoimmune hemolytic anemia, Bechet’s disease, bronchiolitis, IC-MPGN / C3 glomerulopathy, central nervous system (CNS) inflammatory disorders, choroidal neovascularization (CNV), choroiditis, chronic allograft vasculopathy, chronic hepatitis, chronic muscle inflammation, chronic pain, chronic pancreatitis, chronic urticaria, Churg-Strauss syndrome, conjunctivitis, cyclitis, demyelinating disease, dermatitis, dermatomyositis, diabetic retinopathy, encephalitis, eosinophilic pneumonia, geographic atrophy, giant cell arteritis, glaucoma, glomerulonephritis, graft or transplant rejection or failure, HELLP syndrome, Henoch-Schonlein purpura, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), IgA nephropathy (IgAN), inflammatory bowel diseases, inflammatory joint conditions, inflammatory skin diseases, infusion reactions, interstitial pneumonia, iridocyclitis, iritis, ischemia / reperfusion injury, Kawasaki disease, keratitis, lupus nephritis, membranoproliferative glomerulonephritis (MPGN), meningitis, microscopic polyangiitis, myasthenia gravis, myocarditis, nasal polyposis, neuromyelitis optica, neuropathic pain, ocular inflammation, osteoarthritis, pancreatitis, panniculitis, paroxysmal nocturnal hemoglobinuria (PNH), pars planitis, pemphigoid, pemphigus, polyarteritis nodosa,ATTORNEY DOCKET NO.180802-055803 / PCT ELECTRONIC DEPOSIT DATE: November 20, 2024 polymyositis, primary membranous nephropathy, proliferative vitreoretinopathy, proteinuria, psoriasis, pulmonary fibrosis, renal disease, respiratory distress syndrome, retinal neovascularization (RNV), retinopathy of prematurity, rheumatoid arthritis (RA), rhinosinusitis, sarcoid, sarcoidosis, scleritis, scleroderma, sclerodermatomyositis, sclerosis, Sjögren syndrome, systemic lupus erythematosus, systemic scleroderma, Takayasu's arteritis, Tautopathies, thyroiditis, thyroidoisis, ulcerative colitis, uveitis, vasculitis, and Wegener’s granulomatosis.

19. The method of claim 1 or claim 2, wherein the administration is local administration to an eye, to spinal fluid, or to the liver.

20. The method of claim 1 or claim 2, wherein the CFB polynucleotide is contacted with two or more guide polynucleotides, and wherein each guide polynucleotide binds a different location within the CFB polynucleotide.

21. The method of claim 1 or claim 2, wherein the subject is a mammal.

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