Modified proteins and associated methods of treatment

Abstract

To provide a modified human protein having improved in vivo stability.SOLUTION: There is provided a modified protein having an amino acid sequence derived from the amino acid sequence of a human wild-type protein, wherein the amino acid sequence of the human wild-type protein is modified to remove one or more ubiquitination sites identified as being present in the amino acid sequence of the human wild-type protein but absent in the homologous non-human animal wild-type protein.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 776,322, filed December 6, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated by reference herein in its entirety. The ASCII copy, created on December 4, 2019, is titled 049386_522001WO_SL.txt and is 363 kilobytes in size.

[0003] The present invention relates to the fields of molecular biology and genetics and to biopharmaceuticals and therapeutics generated from translatable molecules. More particularly, the present invention relates to methods, structures and compositions for molecules capable of being translated into active polypeptides or proteins for use in vivo and as therapeutic agents. [Background technology]

[0004] New approaches and therapies are still needed for the treatment of diseases associated with proteins that are genetically deficient in quantity or function.For example, strategies are needed to overcome the challenges and limitations associated with gene therapy.The insufficient stability of therapeutic proteins, the insufficient delivery of certain therapeutic proteins that are required for normal cell function, and efficient delivery to target cells remain problems. Summary of the Invention

[0005] The present disclosure provides modified human therapeutic protein sequences that have been altered from their wild-type sequences to remove one or more predicted ubiquitination sites. The present disclosure also provides human therapeutic proteins designed to include a stabilized signal peptide to ensure delivery of the protein to a targeted organelle. Removal of predicted ubiquitination sites preferably involves replacing N-terminal residues known to support ubiquitination, such as asparagine, arginine, leucine, lysine, or phenylalanine, with residues known to stabilize against ubiquitination, such as alanine, glycine, methionine, serine, threonine, valine, or proline. For example, stabilizing the modified ornithine transcarbamylase (OTC) protein of SEQ ID NO: 4 in this manner is particularly advantageous for maintaining the stability of the modified OTC protein during transport from the cytosol to mitochondria, where it exerts its enzymatic activity.

[0006] In some embodiments, modified proteins are provided having an amino acid sequence derived from the amino acid sequence of a human wild-type protein, where the amino acid sequence of the human wild-type protein has been modified to remove one or more ubiquitination sites identified as being present in the amino acid sequence of the human wild-type protein but not in the homologous non-human animal wild-type protein.

[0007] In other embodiments, modified proteins are provided having an amino acid sequence derived from that of a wild-type protein having a signal peptide located at its terminal end, where the amino acid sequence of the signal peptide has been modified by changing the amino acid at position +1 or +2 or by adding an amino acid at position +1 or +2. In some embodiments, an amino acid residue at position +1 or +2 is changed to or added as a stabilizing amino acid. Stabilizing amino acids include valine, methionine, glycine, proline, threonine, alanine, and serine.

[0008] In yet another embodiment, a modified protein is provided having an amino acid sequence derived from the amino acid sequence of a human wild-type protein, wherein the human wild-type protein has a signal peptide located at its terminal end, and wherein i) the amino acid sequence of the signal peptide has been modified by changing an amino acid at the +1 or +2 position or by adding an amino acid at the +1 or +2 position; and ii) the amino acid sequence of the human wild-type protein has been modified to remove one or more ubiquitination sites identified to be present in the amino acid sequence of the human wild-type protein but not in the wild-type protein of a homologous non-human animal.

[0009] In still other embodiments, a polynucleotide comprising a sequence encoding any of the modified peptides described herein is provided. In some embodiments, a composition comprising a polynucleotide described herein and a pharmaceutically acceptable carrier is provided. In some embodiments, the pharmaceutically acceptable carrier comprises a transfection reagent, a lipid nanoparticle, or a liposome. In some embodiments, a method is provided for ameliorating, preventing, delaying the onset of, or treating a disease or condition associated with a deficiency in a human wild-type protein in a subject identified as suffering from the deficiency, the method comprising administering to the subject a composition described herein.

[0010] In yet another embodiment, a method is provided for modifying a protein of interest, wherein the protein of interest is a human wild-type protein, comprising the steps of: i) identifying ubiquitination sites in the amino acid sequence of the human wild-type protein that are not present in the amino acid sequence of a homologous non-human animal wild-type protein; and ii) removing at least one of the ubiquitination sites identified in step (i) from the amino acid sequence of the human wild-type protein to provide a modified protein of interest.

[0011] Preferably, the protein of SEQ ID NO: 4 described herein is produced from a nucleic acid encoding the protein of SEQ ID NO: 4. The nucleic acid can be RNA or DNA encoding the protein of SEQ ID NO: 4. Preferably, the nucleic acid is a heterologous mRNA construct comprising an open reading frame encoding the modified protein of SEQ ID NO: 4. Preferably, the open reading frame is a codon-optimized open reading frame. Preferably, the open reading frame sequence is optimized to have the theoretical minimum number of uridines capable of encoding the modified protein. Preferably, the heterologous mRNA construct comprises a 5' cap, a 5' UTR, a 3' UTR, an open reading frame encoding the modified protein of SEQ ID NO: 4, and a 3' polyA tail. Preferably, the 5' UTR is derived from a gene expressed by Arabidopsis thaliana. Preferably, 5' UTRs derived from genes expressed by Arabidopsis thaliana are identified in Table 2.

[0012] The mRNA constructs described herein provide for highly efficient expression of the proteins described herein. Expression can be in vitro, ex vivo, or in vivo.

[0013] The present disclosure also provides pharmaceutical compositions comprising the mRNA sequences described herein, and methods of treating diseases associated with protein deficiency by administering to a patient in need thereof a pharmaceutical composition comprising the mRNA sequences described herein, whereby the defective protein is expressed in the patient. [Brief explanation of the drawings]

[0014] [Figure 1] 1A-B are scatter plots showing protein expression of exemplary modified proteins described herein in the hepatic cell lines Hepa1,6 (mouse) and Hep3B (human) at 24 hours (FIG. 1A) and 48 hours (FIG. 1B) using an In-Cell Western (ICW) assay. [Figure 2A] Figure 2A-B shows scatter plots illustrating the correlation of protein stability compounds screened in Hepa1,6 cells (Figure 2A) and Hep3B cells (Figure 2B) at 24 h in round 1. [Figure 2B] Figure 2A-B shows scatter plots illustrating the correlation of protein stability compounds screened in Hepa1,6 cells (Figure 2A) and Hep3B cells (Figure 2B) at 24 h in round 1. [Figure 3A] Figures 3A-B show scatter plots illustrating the correlation of protein stability compounds (newly optimized compounds based on round 1) screened in human primary hepatocytes at 24 and 48 hours in round 2, as shown in Figures 3A and 3B. [Figure 3B] Figures 3A-B show scatter plots illustrating the correlation of protein stability compounds (newly optimized compounds based on round 1) screened in human primary hepatocytes at 24 and 48 hours in round 2, as shown in Figures 3A and 3B. [Figure 4A] Figures 4A-B show scatter plots illustrating the correlation of protein stability compounds (newly optimized compounds based on rounds 1 and 2) screened in human primary hepatocytes at 24 and 48 hours in round 3, as shown in Figures 4A and 4B. [Figure 4B] Figures 4A-B show scatter plots illustrating the correlation of protein stability compounds (newly optimized compounds based on rounds 1 and 2) screened in human primary hepatocytes at 24 and 48 hours in round 3, as shown in Figures 4A and 4B. [Figure 5] 5 is a plot showing protein expression levels of exemplary modified proteins described herein in human primary hepatocytes transfected with mRNA encoding the modified proteins. 1799.1 is an mRNA having the sequence of SEQ ID NO: 175, in which 100% of the uridines in SEQ ID NO: 175 are N1-methylpseudouridine (N1MPU). [Figure 6A]Figures 6A-B show bar graphs depicting the expression levels of exemplary modified proteins over time in spf / ash mice administered 10 mg / kg of human-specific protein mRNA epitopes (Figure 6A) or mouse-specific protein mRNA epitopes (Figure 6B). [Figure 6B] Figures 6A-B show bar graphs depicting the expression levels of exemplary modified proteins over time in spf / ash mice administered 10 mg / kg of human-specific protein mRNA epitopes (Figure 6A) or mouse-specific protein mRNA epitopes (Figure 6B). [Figure 7] FIG. 7 is a bar graph showing the expression levels of exemplary modified proteins described herein in spf / ash mice administered mRNA at 3 mg / kg using two different chemistries: 100% N1-methylpseudouridine (N1MPU) and 100% uridine is 5-methoxyuridine (5MeOU). [Figure 8] FIG. 8 is a graph showing the expression levels of exemplary modified proteins described herein in Balb / c mice administered three different doses of mRNA using two different chemicals (N1MPU and 5MeOU). [Figure 9] FIG. 9 is a Western blot showing the expression levels of exemplary modified proteins described herein in spf / ash mice administered mRNA at 1 mg / kg and 3 mg / kg. [Figure 10] FIG. 10 is a Western blot showing the expression levels of exemplary modified proteins described herein in the mitochondrial versus cytosolic fractions of spf / ash mice treated with mRNA. [Figure 11] FIG. 11 is a plot showing the expression levels of modified proteins described herein in male C57BL / 6 mice administered mRNA(2262) with different modifications. [Figure 12]FIG. 12 is a Western blot showing protein expression levels in mitochondrial versus cytosolic fractions of spf / ash mice treated with mRNA encoding exemplary proteins. DETAILED DESCRIPTION OF THE INVENTION

[0015] Definition: The term "mitochondrial protein" refers to a protein that has been identified as being located within the mitochondria.

[0016] As used herein, the term "nuclear-expressed mitochondrial protein" refers to a protein identified as being transcribed from nuclear DNA. A database listing these proteins is MitoCarta, described in: Sarah E. Calvo, Karl R. Clauser, Vamsi K. Mootha; MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins, Nucleic Acids Research, Volume 44, Issue D1, 4 January 2016, Pages D1251-D1257.

[0017] The term "ornithine transcarbamylase," used interchangeably herein with "OTC" or "hOTC" or "OTC_HUMAN," generally refers to a human protein related to UniPRotKB-P00480. The amino acid sequence of the wild-type human OTC protein is represented herein by SEQ ID NO:3.

[0018] As used herein, the term "therapeutic protein" means a protein that can be used to replace a protein in a patient in which such protein is deficient, or in which such protein does not retain an activity required for normal function in the patient.

[0019] The term "nucleic acid," in its broadest sense, includes any compound and / or substance comprising a polymer of nucleotides. These polymers are often referred to as polynucleotides. Exemplary nucleic acids or polynucleotides described herein include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), threose nucleic acid (TNA), glycol nucleic acid (GNA), peptide nucleic acid (PNA), locked nucleic acid (LNA, including LNA with a β-D-ribo configuration, α-LNA (a diastereomer of LNA) with an α-L-ribo configuration, 2′-amino LNA with a 2′-amino functionalization, and 2′-amino-α-LNA with a 2′-amino functionalization), or hybrids thereof.

[0020] As used herein, the term "polynucleotide" is generally used to refer to nucleic acids (e.g., DNA or RNA). When RNA, such as mRNA, is specifically referred to, the term polyribonucleotide may be used. The terms polynucleotide, polyribonucleotide, nucleic acid, ribonucleic acid, DNA, RNA, mRNA, etc., include such molecules, which may be composed of standard or unmodified residues; non-standard or modified residues (e.g., analogs); and mixtures of standard and non-standard (e.g., analog) residues. In certain embodiments, the polynucleotide or polyribonucleotide is a modified polynucleotide or modified polyribonucleotide. In the context of the present disclosure, for each RNA (polyribonucleotide) sequence listed herein, the corresponding DNA (polydeoxyribonucleotide or polynucleotide) sequence is contemplated, and vice versa. "Polynucleotide" may be used interchangeably with "oligomer." Polynucleotide sequences set forth herein are from left to right, 5' to 3', unless otherwise specified.

[0021] As used herein, the term "messenger RNA" (mRNA) refers to any polynucleotide that encodes a protein or polypeptide of interest and that can be translated to produce the encoded protein or polypeptide of interest in vitro, in vivo, in situ, or ex vivo.

[0022] As used herein, the term "translation" refers to the process by which ribosomes make polypeptides. In translation, messenger RNA (mRNA) is decoded by transfer RNA (tRNA) in the ribosomal complex to produce a specific amino acid chain, or polypeptide. The coding region of a polynucleotide sequence (DNA or RNA), also known as a coding sequence or CDS, can be converted into a protein or a fragment thereof by the process of translation.

[0023] As used herein, the term "codon optimization" refers to a redesigned natural (or intentionally designed natural variant) coding sequence by selecting different codons without changing the amino acid sequence of the encoded protein. Codon-optimized sequences can increase the protein expression level of the encoded protein, among other benefits (Gustafsson et al., Codon bias and heterologous protein expression. 2004, Trends Biotechnol 22: 346-53). Variables such as high codon adaptation index (CAI), low U method, mRNA secondary structure, cis-regulatory sequences, GC content, and many other similar variables have been shown to correlate to some degree with protein expression levels (Villalobos et al., Gene Designer: a synthetic biology tool for constructing artificial DNA segments. 2006, BMC Bioinformatics 7:285). The high CAI (codon adaptation index) method selects the most frequently used synonymous codons across the entire protein-coding sequence. The most frequently used codons for each amino acid are predicted from 74,218 protein-coding genes from the human genome. The LowU method targets only U-containing codons that can be replaced with synonymous codons with fewer U moieties. When there are several options for substitution, the most frequently used codon is selected. The remaining codons in the sequence are left unchanged by the LowU method. This method can be used in conjunction with the disclosed mRNAs to generate codons containing, for example, 5-methoxyuridine or N. 1 The coding sequence can be designed to be synthesized using -methylpseudouridine.

[0024] As used herein, "modified" refers to a change in the state or structure of a molecule disclosed herein. Molecules can be changed in many ways, such as chemically, structurally, or functionally. Preferably, the polynucleotide or polypeptide of the present disclosure is modified compared to the natural form of the polynucleotide or polypeptide, or compared to a reference polynucleotide sequence or polynucleotide sequence. For example, the mRNA disclosed herein can be modified by codon optimization or by inserting non-natural nucleosides or nucleotides. Polypeptides can be modified, for example, by site-specific amino acid deletion or substitution, to change the properties of the polypeptide.

[0025] As used herein, the term "homology" refers to the overall relatedness between polymer molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polymer molecules are considered to be "homologous" to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical or similar. The term "homologous" necessarily refers to a comparison between at least two sequences (polynucleotide sequences or polypeptide sequences). According to the present disclosure, two polynucleotide sequences are considered to be homologous if the polypeptides they encode are at least about 50%, 60%, 70%, 80%, 90%, 95%, or even 99% identical over at least one stretch of at least about 20 amino acids. In some embodiments, homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. According to the present disclosure, two protein sequences are considered to be homologous if the proteins are at least about 50%, 60%, 70%, 80%, or 90% identical over at least one stretch of at least about 20 amino acids.

[0026] As used herein, the term "identity" refers to the overall relatedness between polymer molecules, for example, between oligonucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. For example, calculating the percent identity of two polynucleotide sequences can be performed by aligning the two sequences for optimal comparison purposes. In certain embodiments, the length of the aligned sequence for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. Nucleotides at corresponding nucleotide positions are then compared. If a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. Sequence comparison and determination of the percent identity between two sequences can be achieved using a mathematical algorithm. Commonly used methods for determining percent identity between sequences include, but are not limited to, those disclosed in Carillo, H., and Lipman, D., SIAM J Applied Math., 48:1073 (1988), which is incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software for determining the homology between two sequences includes, but is not limited to, the GCG program package; Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984); BLASTP, BLASTN, and FASTA; Altschul, SF et al., J. Molec. Biol., 215, 403 (1990).

[0027] An "effective amount" of an mRNA sequence encoding an open reading frame (ORF) protein or its corresponding composition is generally an amount of mRNA that provides efficient production of the ORF protein in a cell. Preferably, protein production using the mRNA compositions described herein is more efficient than a composition containing the corresponding wild-type mRNA encoding the ORF protein. Improved efficiency can be demonstrated by increased cell transfection (i.e., the percentage of cells transfected with the nucleic acid), increased protein translation from the nucleic acid, decreased nucleic acid degradation (e.g., as indicated by an increased duration of protein translation from the modified nucleic acid), or a reduced innate immune response of the host cell. When referring to the ORF proteins described herein, an effective amount is an amount of ORF protein that overcomes an ORF protein deficiency in a cell.

[0028] As used herein, the term "in vitro" refers to events that take place not within a living organism (e.g., an animal, plant, or microorganism), but in an artificial environment, e.g., a test tube or reaction vessel, cell culture, Petri dish, etc.

[0029] As used herein, the term "in vivo" refers to events that take place within an organism (e.g., an animal, plant, or microorganism, or cells or tissues thereof).

[0030] As used herein, the term "isolated" refers to a substance or entity that has been separated from at least some of the components with which it was associated (whether in nature or in an experimental environment). Isolated substances can have various levels of purity compared to the substance with which it was associated. Isolated substances and / or entities can be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were originally associated. In some embodiments, isolated agents have a purity of about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99%. As used herein, a substance is "pure" if it is substantially free of other components. Substantially Isolated: "Substantially isolated" means that the compound has been substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in a compound described herein. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound described herein or a salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0031] As used herein, the term "subject" or "patient" refers to any living organism to which a composition according to the present disclosure can be administered, for example, for experimental, diagnostic, preventative, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals, such as mice, rats, rabbits, non-human primates, and humans) and / or plants. Preferably, "patient" refers to a human subject who may be seeking or in need of treatment, in need of treatment, undergoing treatment, or to be undergoing treatment, or a subject receiving care from a trained professional for a particular disease or condition.

[0032] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0033] As used herein, the term "prevent" refers to partially or completely delaying the onset of an infection, disease, disorder, and / or condition; partially or completely delaying the onset of one or more symptoms, characteristics, or clinical signs of a particular infection, disease, disorder, and / or condition; partially or completely delaying the onset of one or more symptoms, characteristics, or signs of a particular infection, disease, disorder, and / or condition; partially or completely delaying the progression from an infection, a particular disease, disorder, and / or condition; and / or reducing the risk of developing pathology associated with an infection, disease, disorder, and / or condition.

[0034] As used herein, the term "substantially" refers to a qualitative state of exhibiting a complete or nearly complete extent or degree of a characteristic or property of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely go to completion and / or proceed perfectly, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to express the possibility of an inherent lack of completeness in many biological and chemical phenomena.

[0035] As used herein, the term "therapeutically effective amount" means the amount of an agent (e.g., nucleic acid, protein or peptide, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) delivered that, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and / or condition, is sufficient to treat, ameliorate symptoms of, diagnose, prevent, and / or delay the onset of the infection, disease, disorder, and / or condition.

[0036] As used herein, a "total daily dose" is the amount administered or prescribed in a 24-hour period. It may be administered as a single unit dose.

[0037] As used herein, the term "treat" refers to the partial or complete alleviation, reversal, improvement, relief, delay in onset, inhibition of progression, reduction in severity, and / or reduction in occurrence of one or more symptoms or characteristics of a protein deficiency. Treatment can be administered to subjects who do not exhibit signs of said protein deficiency and / or who exhibit only early signs of a protein deficiency, for the purpose of reducing the risk of developing pathologies associated with the disease, disorder, and / or condition.

[0038] As used herein, the term "transfect" or "transfection" refers to the intracellular introduction of a nucleic acid into a cell, preferably into a target cell. The introduced nucleic acid can be stably or transiently maintained in the target cell. The term "transfection efficiency" refers to the relative amount of nucleic acid taken up by the target cell subjected to transfection. In practice, transfection efficiency is estimated by the amount of reporter nucleic acid product expressed by the target cell after transfection. Compositions with high transfection efficiency are preferred, especially those that minimize side effects mediated by transfection of non-target cells and tissues.

[0039] As used herein, the term "target cell" refers to a cell or tissue to which a composition of the present disclosure is directed or targeted. In some embodiments, the target cell is deficient in a protein or enzyme of interest. For example, if it is desired to deliver a nucleic acid to a hepatocyte, the hepatocyte represents the target cell. In some embodiments, the nucleic acids and compositions of the present disclosure transfect target cells on a differential basis (i.e., do not transfect non-target cells). The compositions and methods of the present disclosure can be prepared to preferentially target a variety of target cells, including, but not limited to, hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, lung cells, bone cells, stem cells, mesenchymal cells, neural cells (e.g., meningeal, astrocytes, motor neurons, cells of the dorsal root ganglion and anterior horn motor neurons), photoreceptor cells (e.g., rods and cones), retinal pigment epithelial cells, secretory cells, cardiac cells, adipocytes, vascular smooth muscle cells, cardiac myocytes, skeletal muscle cells, beta cells, pituitary cells, synovial lining cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, granulocytes, and tumor cells.

[0040] After transfection of one or more target cells with the compositions and nucleic acids described herein, expression of the protein encoded by such nucleic acids can be preferably stimulated, enhancing the ability of such target cells to express the protein of interest. For example, transfection of target cells with mRNA can result in expression of a modified protein product after translation of the nucleic acid. The nucleic acids of the compositions and / or methods provided herein preferably encode a product (e.g., a protein, enzyme, polypeptide, peptide, functional RNA, and / or antisense molecule), preferably a product whose in vivo production is desired.

[0041] As used herein, "OTC protein enzyme activity" refers to the enzyme activity that catalyzes the reaction between carbamoyl phosphate and ornithine to form citrulline as part of the urea cycle in mammals.

[0042] As used herein, the term "about" or "approximately" as applied to one or more values ​​of interest refers to a value similar to a stated reference value. In certain embodiments, the term "about" or "approximately" refers to a range of values ​​that falls within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or lesser) of the stated reference value, unless otherwise stated or apparent from the context (except where such number exceeds 100% of possible values).

[0043] Polynucleotide sequence The present disclosure provides improved methods and compositions for treating diseases associated with protein deficiencies, such as ornithine transcarbamylase (OTC) deficiency, using, for example, mRNA therapy to express modified proteins of the present disclosure. The present disclosure provides a method for treating a protein deficiency, comprising administering to a subject in need of treatment a composition comprising an mRNA sequence described herein that encodes a stabilized modified human protein or an active fragment of such a stabilized modified human protein, in an effective amount and at an interval such that at least one symptom or characteristic of the protein deficiency is reduced in intensity, severity, or frequency, or the onset is delayed. The present disclosure also provides modified proteins encoded by the mRNA sequence that have improved properties, such as increased stability and resistance to proteolysis and half-life, compared to wild-type human proteins.

[0044] Preferably, administration of the mRNA compositions described herein results in an increase in the expression or activity of a therapeutic protein in a subject compared to a control level. Preferably, the control level is a baseline serum therapeutic protein expression or activity level in the subject before treatment and / or the control level represents the average serum protein expression or activity level in untreated patients.

[0045] Preferably, the proteins encoded by the mRNAs described herein are produced from heterologous mRNA constructs comprising an open reading frame (ORF), also referred to herein as a "coding sequence" (CDS), encoding a therapeutic protein. Preferably, the coding sequence is codon-optimized. Preferably, the coding sequence is optimized to have the theoretical minimum number of uridines capable of encoding a therapeutic protein. Preferably, the mRNA constructs described herein comprise one or more of the following features: a 5' cap; a 5' UTR, a 5' UTR enhancer sequence, a Kozak sequence or a partial Kozak sequence, a 3' UTR, an open reading frame encoding a therapeutic protein, and a polyA tail. Preferably, the mRNA constructs described herein can provide highly efficient expression of modified proteins. Expression can be in vitro, ex vivo, or in vivo.

[0046] Exemplary human modified proteins encoded by the mRNAs described herein include the modified human OTC protein of SEQ ID NO: 4 shown in Table 1. SEQ ID NO: 4 has been modified from the wild-type OTC of SEQ ID NO: 3 (Table 1) to remove one or more predicted ubiquitination sites, resulting in a protein that is less susceptible to ubiquitination and degradation by ubiquitin ligases. Removal of predicted ubiquitination sites preferably involves replacing N-terminal residues that have been identified to support ubiquitination, such as asparagine, arginine, leucine, lysine, or phenylalanine, with residues that have been identified to stabilize against ubiquitination, such as alanine, glycine, methionine, serine, threonine, valine, or proline. Stabilizing the modified OTC protein of SEQ ID NO: 4 in this manner is particularly advantageous for maintaining stability during transport of the modified OTC protein from the cytosol to mitochondria, where it exerts its enzymatic activity.

[0047] Preferably, the modified proteins encoded by the mRNAs described herein comprise a protein sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the corresponding human wild-type protein, while retaining the biological and chemical activity, e.g., catalytic activity, of the protein.

[0048] Table 1: Selected OTC nucleotide and peptide sequences [Table 1-1] [Table 1-2] [Table 1-3] *The OTC protein contains a signal peptide that is translated and involved in translocation to mitochondria. This signal peptide is represented by the first 32 underlined amino acids in SEQ ID NO:3 and SEQ ID NO:4. The signal sequence of SEQ ID NO:4 is also modified compared to SEQ ID NO:3. An amino acid valine is inserted at position 3 of SEQ ID NO:4. This modification provides better mitochondrial localization of the modified OTC of SEQ ID NO:4 compared to the wild-type human OTC of SEQ ID NO:3.

[0049] Preferably, the open reading frame (ORF) or coding sequence (CDS) of the mRNA sequences described herein encodes an amino acid sequence that is substantially identical to that of the corresponding human wild-type protein.

[0050] Preferably, the mRNAs described herein further comprise a sequence immediately downstream of the CDS (i.e., in the 3' direction from the CDS) that creates a triple stop codon. The triple stop codon may be incorporated to enhance translation efficiency. In some embodiments, the translatable oligomer may comprise the sequence AUAAGUGAA (SEQ ID NO: 25) immediately downstream of the CDS of the mRNA sequences described herein.

[0051] Preferably, the mRNA described herein further comprises a 5' untranslated region (UTR) sequence. As is understood in the art, the 5' UTR and / or 3' UTR can affect the stability or translation efficiency of the mRNA. The 5' UTR can be derived from an mRNA molecule known in the art to be relatively stable (e.g., histone, tubulin, globin, glyceraldehyde 1-phosphate dehydrogenase (GAPDH), actin, or a citric acid cycle enzyme) to enhance the stability of the translatable oligomer. In other embodiments, the 5' UTR sequence may comprise a partial sequence of the cytomegalovirus (CMV) immediate-early 1 (IE1) gene.

[0052] Preferably, the 5'UTR comprises a sequence selected from the 5'UTRs of human IL-6, alanine aminotransferase 1, human apolipoprotein E, human fibrinogen alpha chain, human transthyretin, human haptoglobin, human alpha-1-antichymotrypsin, human antithrombin, human alpha-1-antitrypsin, human albumin, human beta globin, human complement C3, human complement C5, SynK (a thylakoid potassium channel protein from the cyanobacterium Synechocystis sp.), mouse beta globin, mouse albumin, and tobacco etch virus, or a fragment of any of the foregoing. Preferably, the 5'UTR is derived from tobacco etch virus (TEV). Preferably, the mRNA described herein comprises a 5'UTR sequence derived from a gene expressed by Arabidopsis thaliana. Preferably, the 5'UTR sequence of the gene expressed by Arabidopsis thaliana is AT1G58420. Preferred 5'UTR sequences include SEQ ID NOs: 5-10, 125-127, and 227-247 as shown in Table 2.

[0053] Table 2 5'UTR sequence [Table 2-1] [Table 2-2] [Table 2-3]

[0054] Preferably, the 5'UTR sequence comprises SEQ ID NO: 6 (AT1G58420).

[0055] Preferably, the mRNAs described herein contain a translational enhancer sequence. The translational enhancer sequence increases the translation efficiency of the mRNAs described herein, thereby providing increased production of the protein encoded by the mRNA. The translational enhancer region can be located in the 5'UTR or 3'UTR of the mRNA sequence. Examples of translational enhancer regions include naturally occurring enhancer regions from the TEV 5'UTR and Xenopus beta-globin 3'UTR. Preferred 5'UTR enhancer sequences include sequences derived from mRNAs encoding human heat shock proteins (HSPs), including, but not limited to, HSP70-P2, HSP70-M1, HSP72-M2, HSP17.9, and HSP70-P1. Preferred translational enhancer sequences used by embodiments of the present disclosure are represented by SEQ ID NOs: 11-15 in Table 3.

[0056] Table 3 5'UTR enhancer [Table 3]

[0057] Preferably, the mRNA described herein comprises a Kozak sequence. As understood in the art, a Kozak sequence is a short consensus sequence centered around the translation start site of eukaryotic mRNA, which allows efficient initiation of mRNA translation. The ribosomal translation machinery recognizes the AUG start codon in the context of the Kozak sequence. The Kozak sequence can be inserted upstream of the coding sequence of a therapeutic protein of interest and downstream of the 5'UTR, or can be inserted upstream of the coding sequence of a therapeutic protein of interest and downstream of the 5'UTR. Preferably, the mRNA described herein comprises a Kozak sequence having the amino acid sequence GCCACC (SEQ ID NO: 23). Preferably, the mRNA described herein comprises a partial Kozak sequence "p" having the amino acid sequence GCCA (SEQ ID NO: 24).

[0058] Preferably, the mRNA described herein comprises a 3'UTR. Preferably, the 3'UTR comprises a sequence selected from the 3'UTRs of alanine aminotransferase 1, human apolipoprotein E, human fibrinogen alpha chain, human haptoglobin, human antithrombin, human alpha globin, human beta globin, human complement C3, human growth factor, human hepcidin, MALAT-1, mouse beta globin, mouse albumin, Xenopus beta globin, or a fragment of any of the foregoing. Preferably, the 3'UTR is derived from Xenopus beta globin. Preferred 3'UTR sequences include SEQ ID NOs: 16 to 22 shown in Table 4.

[0059] Table 4 3'UTR sequence [Table 4]

[0060] Preferably, the mRNA described herein includes a 3' tail region, which may be useful for protecting the mRNA from exonuclease degradation. The tail region may be a 3' poly(A) region and / or a 3' poly(C) region. Preferably, the tail region is a 3' poly(A) tail. As used herein, a "3' poly(A) tail" is a polymer of consecutive adenine nucleotides, and may range in size from 10 to 250 consecutive adenine nucleotides; 60 to 125 consecutive adenine nucleotides; 90 to 125 consecutive adenine nucleotides; 95 to 125 consecutive adenine nucleotides; 95 to 121 consecutive adenine nucleotides; 100 to 121 consecutive adenine nucleotides; 110 to 121 consecutive adenine nucleotides; 112 to 121 consecutive adenine nucleotides; 114 to 121 consecutive adenine nucleotides; and 115 to 121 consecutive adenine nucleotides. Preferably, the 3' poly-A tails described herein comprise 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, or 125 consecutive adenine nucleotides. 3' poly(A) tails can be added using a variety of methods known in the art, for example, using poly(A) polymerase to add tails to synthetic or in vitro transcribed RNA. Other methods include the use of transcription vectors to encode poly(A) tails, or the use of ligases (e.g., via splint ligation using T4 RNA ligase and / or T4 DNA ligase), whereby poly(A) can be linked to the 3' end of the sense RNA. Preferably, a combination of any of the above methods is used.

[0061] Preferably, the mRNA described herein includes a 5' cap. 5'-ends capped with various groups and their analogs are known in the art. The 5' cap can be selected from m7GpppA, m7GpppC; unmethylated cap analogs (e.g., GpppG); dimethylated cap analogs (e.g., m2,7GpppG), trimethylated cap analogs (e.g., m2,2,7GpppG), dimethylated symmetric cap analogs (e.g., m7Gpppm7G), or anti-reverse cap analogs (e.g., ARCA; m7,2'OmeGpppG, m72'dGpppG, m7,3'OmeGpppG, m7,3'dGpppG, and their tetraphosphate derivatives) [see, e.g., Jemielity, J. et al., RNA 9: 1108-1122 (2003)]. The 5' cap can be an ARCA cap (3'-OMe-m7G(5')pppG). The 5' cap can be mCAP [m7G(5')ppp(5')G,N 7 -methyl-guanosine-5'-triphosphate-5'-guanosine]. The 5' cap can be resistant to hydrolysis. A preferred 5' cap, referred to herein as an "m7GpppGm cap," also referred to herein as "Cap1," has the following core structure:

[0062] [ka]

[0063] Preferably, the mRNA described herein comprises one or more chemically modified nucleotides. Examples of nucleic acid monomers include unnatural, modified, and chemically modified nucleotides, including any such nucleotides known in the art. mRNA sequences comprising chemically modified nucleotides have been shown to improve mRNA expression, expression rate, half-life, and / or expressed protein concentration. mRNA sequences comprising chemically modified nucleotides have also been useful for optimizing protein localization, thereby avoiding adverse biological responses, such as immune responses and / or degradation pathways.

[0064] Examples of modified or chemically modified nucleotides include 5-hydroxycytidine, 5-alkylcytidine, 5-hydroxyalkylcytidine, 5-carboxycytidine, 5-formylcytidine, 5-alkoxycytidine, 5-alkynylcytidine, 5-halocytidine, 2-thiocytidine, N 4 -Alkylcytidine, N 4 -aminocytidine, N 4 -acetylcytidine, and N 4 ,N 4 -Dialkylcytidines.

[0065] Examples of modified or chemically modified nucleotides include 5-hydroxycytidine, 5-methylcytidine, 5-hydroxymethylcytidine, 5-carboxycytidine, 5-formylcytidine, 5-methoxycytidine, 5-propynylcytidine, 5-bromocytidine, 5-iodocytidine, and 2-thiocytidine; 4 -methylcytidine, N 4 -aminocytidine, N 4 -acetylcytidine, and N 4 ,N 4 -Dimethylcytidine.

[0066] Examples of modified or chemically modified nucleotides include 5-hydroxyuridine, 5-alkyluridine, 5-hydroxyalkyluridine, 5-carboxyuridine, 5-carboxyalkylester uridine, 5-formyluridine, 5-alkoxyuridine, 5-alkynyluridine, 5-halouridine, 2-thiouridine, and 6-alkyluridine.

[0067] Examples of modified or chemically modified nucleotides include 5-hydroxyuridine, 5-methyluridine, 5-hydroxymethyluridine, 5-carboxyuridine, 5-carboxymethylesteruridine, 5-formyluridine, 5-methoxyuridine (also referred to herein as "5MeOU"), 5-propynyluridine, 5-bromouridine, 5-fluorouridine, 5-iodouridine, 2-thiouridine, and 6-methyluridine.

[0068] Examples of modified or chemically modified nucleotides include 5-methoxycarbonylmethyl-2-thiouridine, 5-methylaminomethyl-2-thiouridine, 5-carbamoylmethyluridine, 5-carbamoylmethyl-2'-O-methyluridine, 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine, 5-methylaminomethyl-2-selenouridine, 5-carboxymethyluridine, 5-methyldihydrouridine, 5-taurinomethyluridine, 5-taurinomethyl-2-thiouridine, 5-(isopentenylaminomethyl)uridine, 2'-O-methylpseudouridine, 2-thio-2'O-methyluridine, and 3,2'-O-dimethyluridine.

[0069] Examples of modified or chemically modified nucleotides include N 6 -methyladenosine, 2-aminoadenosine, 3-methyladenosine, 8-azaadenosine, 7-deazaadenosine, 8-oxoadenosine, 8-bromoadenosine, 2-methylthio-N 6 -methyladenosine, N 6 -Isopentenyl adenosine, 2-methylthio-N 6-Isopentenyl adenosine, N 6 -(cis-Hydroxyisopentenyl)adenosine, 2-methylthio-N 6 -(cis-hydroxyisopentenyl)adenosine, N 6 -Glycinylcarbamoyl adenosine, N 6 -Threonylcarbamoyl-adenosine, N 6 -methyl-N 6 -Threonylcarbamoyl-adenosine, 2-methylthio-N 6 -Threonylcarbamoyl-adenosine, N 6 ,N 6 -Dimethyladenosine, N 6 -Hydroxynorvalylcarbamoyladenosine, 2-methylthio-N 6 -hydroxynorvalylcarbamoyl-adenosine, N 6 -acetyl-adenosine, 7-methyl-adenine, 2-methylthio-adenine, 2-methoxy-adenine, alpha-thio-adenosine, 2'-O-methyl-adenosine, N 6 ,2'-O-dimethyl-adenosine,N 6 ,N 6 ,2'-O-trimethyl-adenosine, 1,2'-O-dimethyl-adenosine, 2'-O-ribosyladenosine, 2-amino-N 6 -methyl-purine, 1-thio-adenosine, 2'-F-ara-adenosine, 2'-F-adenosine, 2'-OH-ara-adenosine, and N 6 -(19-amino-pentaoxanonadecyl)-adenosine.

[0070] Examples of modified or chemically modified nucleotides include N 1 -Alkylguanosine, N 2 -Alkylguanosine, thienoguanosine, 7-deazaguanosine, 8-oxoguanosine, 8-bromoguanosine, O 6 -Alkylguanosine, xanthosine, inosine, and N 1 -Alkinosine is one example.

[0071] Examples of modified or chemically modified nucleotides include N 1 -methylguanosine, N 2 -methylguanosine, thienoguanosine, 7-deazaguanosine, 8-oxoguanosine, 8-bromoguanosine, O 6 -methylguanosine, xanthosine, inosine, and N 1 -methylinosine.

[0072] Examples of modified or chemically modified nucleotides include pseudouridine. 1 -Alkylpseudouridine, N 1 -Cycloalkylpseudouridine, N 1 -Hydroxypseudouridine, N 1 -Hydroxyalkylpseudouridine, N 1 -phenylpseudouridine, N 1 -phenylalkylpseudouridine, N 1 -aminoalkylpseudouridine, N 3 -Alkylpseudouridine, N 6 -Alkylpseudouridine, N 6 -Alkoxypseudouridine, N 6 -Hydroxypseudouridine, N 6 -Hydroxyalkylpseudouridine, N 6 -Morpholinopseudouridine, N 6 -phenylpseudouridine, and N 6 Examples of pseudouridines include N-halopseudouridine. 1 -Alkyl-N 6 -Alkylpseudouridine, N 1 -Alkyl-N 6 -Alkoxypseudouridine, N 1 -Alkyl-N 6 -Hydroxypseudouridine, N 1 -Alkyl-N 6 -Hydroxyalkylpseudouridine, N 1 -Alkyl-N 6 -Morpholinopseudouridine, N1 -Alkyl-N 6 -phenylpseudouridine, and N 1 -Alkyl-N 6 In these examples, the alkyl, cycloalkyl, and phenyl substituents may be unsubstituted or further substituted with alkyl, halo, haloalkyl, amino, or nitro substituents.

[0073] Examples of pseudouridines include N 1 -methylpseudouridine (also referred to herein as "N1MPU"), N 1 -Ethylpseudouridine, N 1 -Propylpseudouridine, N 1 -Cyclopropylpseudouridine, N 1 -phenylpseudouridine, N 1 -aminomethylpseudouridine, N 3 -methylpseudouridine, N 1 -hydroxypseudouridine, and N 1 -hydroxymethylpseudouridine.

[0074] Examples of nucleic acid monomers include modified and chemically modified nucleotides, including any such nucleotides known in the art.

[0075] Examples of modified and chemically modified nucleotide monomers include any such nucleotides known in the art, such as 2'-O-methylribonucleotides, 2'-O-methylpurine nucleotides, 2'-deoxy-2'-fluororibonucleotides, 2'-deoxy-2'-fluoropyrimidine nucleotides, 2'-deoxyribonucleotides, 2'-deoxypurine nucleotides, universal base nucleotides, 5-C-methyl-nucleotides, and inverted deoxyabasic monomer residues.

[0076] Examples of modified and chemically modified nucleotide monomers include 3'-terminal stabilized nucleotides, 3'-glyceryl nucleotides, 3'-inverted abasic nucleotides, and 3'-inverted thymidines.

[0077] Examples of modified and chemically modified nucleotide monomers include locked nucleic acid nucleotides (LNA), 2'-O,4'-C-methylene-(D-ribofuranosyl) nucleotides, 2'-methoxyethoxy (MOE) nucleotides, 2'-methyl-thio-ethyl, 2'-deoxy-2'-fluoronucleotides, and 2'-O-methyl nucleotides. In an exemplary embodiment, the modified monomer is a locked nucleic acid nucleotide (LNA).

[0078] Examples of modified and chemically modified nucleotide monomers include 2',4'-constrained 2'-O-methoxyethyl (cMOE) and 2'-O-ethyl (cEt) modified DNA.

[0079] Examples of modified and chemically modified nucleotide monomers include 2'-amino nucleotides, 2'-O-amino nucleotides, 2'-C-allyl nucleotides, and 2'-O-allyl nucleotides.

[0080] Examples of modified and chemically modified nucleotide monomers include N 6 -methyl adenosine nucleotides.

[0081] Examples of modified and chemically modified nucleotide monomers include nucleotide monomers having the modified bases 5-(3-amino)propyluridine, 5-(2-mercapto)ethyluridine, 5-bromouridine; 8-bromoguanosine, or 7-deazaadenosine.

[0082] Examples of modified and chemically modified nucleotide monomers include 2'-O-aminopropyl substituted nucleotides.

[0083] Examples of modifications and chemically modified nucleotide monomers include replacing the 2'-OH group of the nucleotide with 2'-R, 2'-OR, 2'-halogen, 2'-SR, or 2'-amino, where R can be H, alkyl, alkenyl, or alkynyl.

[0084] The above examples of base modifications can be combined with further modifications of the nucleoside or nucleotide structure, including sugar modifications and linkage modifications. Certain modified or chemically modified nucleotide monomers can be found in nature.

[0085] Preferred nucleotide modifications include N 1 -methylpseudouridine and 5-methoxyuridine. Preferred mRNA sequence constructs are shown in Table 5.

[0086] Table 5: Exemplary mRNA constructs [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] * The Kozak sequence is defined as GCCACC (SEQ ID NO: 23). The partial (P) Kozak is defined as GCCA (SEQ ID NO: 24). ** The construct encodes the modified human OTC protein of SEQ ID NO:4.

[0087] Preferred mRNA sequences include all of the mRNA sequences listed in Table 5. Preferred mRNA sequences include all of the mRNA sequences listed in which 0%-100%, preferably 1%-100%, preferably 25%-100%, preferably 50%-100%, preferably 75%-100% of the uracil nucleotides of the mRNA sequence are modified. Preferably, 1%-100% of the uracil nucleotides are N 1 uridine or 5-methylpseudouridine. Preferably, 100% of the uracil nucleotides are N 1 -methylpseudouridine. Preferably, 100% of the uracil nucleotides are 5-methoxyuridine.

[0088] A preferred mRNA sequence comprises a 5' cap, a 5' UTR derived from a gene expressed by Arabidopsis thaliana, an optional translational enhancer sequence, an optional Kozak sequence or partial Kozak sequence, a codon-optimized coding sequence (CDS / ORF) encoding a human protein of interest, a 3' UTR, and a poly(A) tail. Preferably, the 5' UTR derived from a gene expressed by Arabidopsis thaliana is selected from those identified in Table 5. Preferably, the 5' UTR derived from a gene expressed by Arabidopsis thaliana is selected from the group consisting of SEQ ID NO: 6, SEQ ID NOs: 125-127, and SEQ ID NOs: 227-247. Preferably, the 5' UTR sequence is AT1G58420, having the sequence of SEQ ID NO: 6. Preferably, the uracil content of the codon-optimized sequence is reduced relative to the percentage of uracil content of SEQ ID NO: 1. Preferably, 0% to 100% of the uracil nucleotides of the mRNA sequence are modified. Preferably, 0% to 100% of the uracil nucleotides are N 1 -methylpseudouridine or 5-methoxyuridine. Preferably, 100% of the uracil nucleotides are N 1 -methylpseudouridine. Preferably, 100% of the uracil nucleotides are 5-methoxyuridine.

[0089] Preferred mRNA constructs comprise a codon-optimized coding sequence and a 5'UTR derived from a gene expressed by Arabidopsis thaliana and are selected from SEQ ID NOs: 62, 67, 68, 69, 73, 113-119, 121-127.

[0090] Exemplary mRNA sequences include mRNA constructs with a codon-optimized ORF encoding the modified OTC of SEQ ID NO:4.

[0091] Preferably, 100% of the uridine nucleotides in mRNA constructs 1799 (SEQ ID NO: 73) and 1921 (SEQ ID NO: 119) are N 1-methylpseudouridine. Preferably, 100% of the uracil nucleotides in mRNA constructs 1799 (SEQ ID NO: 73) and 1921 (SEQ ID NO: 119) are 5-methoxyuridine.

[0092] Design and synthesis of mRNA sequences mRNA for use according to the present disclosure can be prepared by any available technique, including but not limited to chemical synthesis, in vitro transcription (IVT), or enzymatic or chemical cleavage of a longer precursor, etc. Methods for synthesizing RNA are known in the art.

[0093] In some embodiments, mRNA is produced from a primary complementary DNA (cDNA) construct. The process of designing and synthesizing a primary cDNA construct described herein generally includes the steps of gene construction, mRNA production (with or without modification), and purification. In the IVT method, a target polynucleotide sequence encoding a modified therapeutic protein of interest is first selected for incorporation into a vector, which is then amplified to produce a cDNA template. The target polynucleotide sequence and / or any flanking sequences may be codon-optimized. The cDNA template is then used to produce mRNA via in vitro transcription (IVT). After production, the mRNA can undergo purification and cleanup processes, which are described in more detail below.

[0094] Gene construction steps include, but are not limited to, gene synthesis, vector amplification, plasmid purification, plasmid linearization and cleanup, and cDNA template synthesis and cleanup. Once a modified protein (e.g., SEQ ID NO: 4) is selected for production, a primary construct is designed. Within the primary construct, a first region of linked nucleosides encoding a polypeptide of interest can be constructed using the open reading frame (ORF) of a selected nucleic acid (DNA or RNA) transcript. The ORF can include a wild-type ORF, its isoform, mutant, or fragment thereof. As used herein, "open reading frame" or "ORF" refers to a nucleic acid sequence (DNA or RNA) capable of encoding a polypeptide of interest. An ORF often begins with an ATG start codon and ends with a nonsense or stop codon or signal.

[0095] Furthermore, the nucleotide sequence of any region of an mRNA or DNA template can be codon-optimized. Codon optimization methods are known in the art and can be useful in efforts to achieve one or more of several goals. These goals include matching codon frequencies in the target and host organisms to ensure proper folding, biasing GC content to increase mRNA stability or reduce secondary structure, minimizing tandem repeat codons or base runs that can impair gene assembly or expression, customizing transcriptional and translational control regions, inserting or removing protein transport sequences, removing / adding post-translational modification sites (e.g., glycosylation sites) within the encoded protein, adding, removing, or shuffling protein domains, inserting or deleting restriction sites, modifying ribosome binding sites and mRNA degradation sites, adjusting the translation rate so that various domains of a protein can fold properly, or reducing or eliminating problematic secondary structures within the mRNA. Suitable codon optimization tools, algorithms, and services are known in the art.

[0096] Preferably, primary cDNA template can comprise reducing the presence or frequency of specific nucleotide in template strand.For example, the presence of nucleotide in template can be reduced to a level of less than 25% of the nucleotide in template.In another example, the presence of nucleotide in template can be reduced to a level of less than 20% of the nucleotide in template.In some examples, the presence of nucleotide in template can be reduced to a level of less than 16% of the nucleotide in template.Preferably, the presence of nucleotide in template can be reduced to a level of less than 15% of the nucleotide in template, preferably to a level of less than 12%.

[0097] For example, the present disclosure provides nucleic acids in which the uracil content has been altered, such that at least one codon in the wild-type sequence is replaced with an alternative codon to produce a uracil-altered sequence. The altered uracil sequence can have at least one of the following properties: (i) an increase or decrease in overall uracil content (i.e., the percentage of uracil of the total nucleotide content in a section of nucleic acid, e.g., an open reading frame nucleic acid); or (ii) a localized increase or decrease in uracil content (i.e., the change in uracil content is limited to a specific subsequence); or (iii) a change in uracil distribution without a change in overall uracil content; or (iv) changes in uracil cluster formation (e.g., number of clusters, location of clusters, or distance between clusters); or (v) combinations thereof.

[0098] Preferably, the percentage of uracil nucleobases in nucleic acid sequence is reduced relative to the percentage of uracil nucleobases in wild-type nucleic acid sequence.For example, 30% of nucleobases can be uracil in wild-type sequence, but the nucleobases that are uracil are preferably less than 15%, preferably less than 12%, preferably less than 10% of the nucleobases in the nucleic acid sequence disclosed.The percentage of uracil content can be determined by dividing the number of uracils in sequence by the total number of nucleotides and multiplying by 100.

[0099] Preferably, the percentage of uracil nucleobases in a subsequence of a nucleic acid sequence is reduced relative to the percentage of uracil nucleobases in the corresponding subsequence of a wild-type sequence.For example, a wild-type sequence may have a 5'-end region (e.g., 30 codons) with a local uracil content of 30%, and the uracil content in the same region may be reduced to preferably 15% or less, preferably 12% or less, preferably 10% or less in the nucleic acid sequence of the present disclosure.

[0100] Preferably, the codons in the nucleic acid sequences of the present invention reduce or alter the number, size, location, or distribution of uracil clusters, which may, for example, adversely affect protein translation. While a lower uracil content is desirable, in certain embodiments, the uracil content, particularly local uracil content, of some subsequences of the wild-type sequence can be greater than the wild-type sequence and still maintain beneficial characteristics (e.g., increased expression).

[0101] Preferably, the uracil-modified sequence induces a lower Toll-like receptor (TLR) response compared to the wild-type sequence. Some TLRs recognize and respond to nucleic acids. Double-stranded (ds) RNA, a frequent viral component, has been shown to activate TLR3. Single-stranded (ss) RNA activates TLR7. RNA oligonucleotides, such as RNA with phosphorothioate internucleotide linkages, are ligands for human TLR8. DNA containing unmethylated CpG motifs, characteristic of bacterial and viral DNA, activates TLR9.

[0102] As used herein, the term "TLR response" is defined as the recognition of single-stranded RNA by the TLR7 receptor, and preferably includes physiological responses resulting from RNA degradation and / or receptor recognition of single-stranded RNA. Methods for determining and quantifying RNA binding to TLR7 are known in the art. Similarly, methods for determining whether RNA triggers a TLR7-mediated physiological response (e.g., cytokine secretion) are well known in the art. Preferably, the TLR response may be mediated by TLR3, TLR8, or TLR9 instead of TLR7. Inhibition of TLR7-mediated responses may be achieved through nucleoside modifications. RNA naturally undergoes over 100 different nucleoside modifications. Human rRNA, for example, has 10 times more pseudouracil ('R) and 25 times more 2'-O-methylated nucleosides than bacterial rRNA. While bacterial mRNA does not contain nucleoside modifications, mammalian mRNAs have nucleoside modifications, such as N-methylated nucleosides. 7In addition to -methylguanosine (m7G), 5-methylcytidine (m5C), N 6 -methyladenosine (m6A), inosine, and many 2'-O-methylated nucleosides.

[0103] Preferably, the uracil content of the polynucleotides disclosed herein, preferably those encoding a modified therapeutic protein of interest, is less than 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 90%, 80%, 70%, 60%, 5%, 4%, 3%, 2%, or 1% of the total nucleobases in the sequence of a reference sequence. Preferably, the uracil content of the polynucleotides disclosed herein is about 5% to about 25%. Preferably, the uracil content of the polynucleotides disclosed herein is about 15% to about 25%.

[0104] The cDNA template can be transcribed to produce the mRNA sequences described herein using an in vitro transcription (IVT) system. This system typically includes a transcription buffer, nucleotide triphosphates (NTPs), an RNase inhibitor, and a polymerase. The NTPs can be selected from those described herein, including, but not limited to, natural and unnatural (modified) NTPs. The polymerase can be selected from, but not limited to, T7 RNA polymerase, T3 RNA polymerase, and mutant polymerases, including, but not limited to, polymerases capable of incorporating modified nucleic acids.

[0105] The primary cDNA template or transcribed mRNA sequence may also undergo a capping and / or tailing reaction. The capping reaction can be carried out by methods known in the art for adding a 5' cap to the 5' end of the primary construct. Capping methods include, but are not limited to, the use of vaccinia capping enzyme (New England Biolabs, Ipswich, Massachusetts) or CLEANCAP® technology (TriLink Biotechnologies). The poly-A tailing reaction can be carried out by methods known in the art, such as, but not limited to, 2'O-methyltransferase and the methods described herein. If the primary construct generated from cDNA does not contain poly-T, it may be beneficial to carry out a poly-A tailing reaction before cleaning the primary construct.

[0106] Codon-optimized cDNA constructs encoding modified therapeutic proteins of interest are particularly suitable for generating the mRNA sequences described herein. For example, such cDNA constructs can be used as a basis for in vitro transcription of polyribonucleotides encoding the modified proteins of interest. Table 6 provides a list of exemplary cDNA ORF templates used for in vitro transcription of the mRNA sequences listed in Table 5.

[0107] Table 6: Exemplary cDNA templates [Table 6] ** SEQ ID NO: 4 is the amino acid sequence of modified human OTC. *** The entire plasmid sequence is not included.

[0108] The present disclosure also provides a polynucleotide (e.g., DNA, RNA, cDNA, mRNA) encoding a modified human protein of interest, which can be operably linked to one or more regulatory nucleotide sequences in an expression construct, such as a vector or plasmid. In certain embodiments, such a construct is a DNA construct. The regulatory nucleotide sequence is generally suitable for the host cell used for expression. Many types of suitable expression vectors and suitable regulatory sequences are known in the art for various host cells.

[0109] Typically, the one or more regulatory nucleotide sequences may include, but are not limited to, promoter sequences, leader or signal sequences, ribosome binding sites, transcription initiation and termination sequences, translation initiation and termination sequences, and enhancer or activator sequences.Constitutive promoters or inducible promoters known in the art are considered in the embodiments of the present disclosure.Promoters can be either naturally occurring promoters or hybrid promoters that combine elements of multiple promoters.

[0110] The expression construct may be present in the cell on an episome, such as a plasmid, or the expression construct may be inserted into a chromosome. Preferably, the expression vector contains a selectable marker gene that allows the selection of transformed host cells. Selectable marker genes are well known in the art and vary depending on the host cell used.

[0111] The present disclosure also provides expression vectors comprising a nucleotide sequence encoding a modified protein of interest preferably operably linked to at least one regulatory sequence, which regulatory sequences are art-recognized and selected to direct expression of the encoded polypeptide.

[0112] Thus, the term control sequence includes promoters, enhancers, and other expression control elements. The design of the expression vector may depend on such factors as the choice of the host cell to be transformed and / or the type of protein desired to be expressed.

[0113] The present disclosure also provides a host cell transfected with the mRNA or DNA described herein encoding the modified polypeptide described herein. For example, the modified polypeptide has the sequence of SEQ ID NO: 4. The host cell can be any prokaryotic or eukaryotic cell. For example, the modified polypeptide described herein can be expressed in bacterial cells, such as E. coli, insect cells (e.g., using a baculovirus expression system), yeast cells, or mammalian cells. Other suitable host cells are known to those skilled in the art.

[0114] The present disclosure also provides a host cell comprising a vector comprising a polynucleotide encoding the mRNA sequence of any one of SEQ ID NOs: 26-229.

[0115] The present disclosure also provides a method for producing a modified therapeutic human protein of interest. For example, host cells transfected with an expression vector encoding the modified therapeutic protein of interest can be cultured under appropriate conditions to allow expression of the polypeptide. The polypeptide can be secreted and isolated from a mixture of cells and polypeptide-containing medium. Alternatively, the polypeptide can be retained in the cytoplasm or membrane fraction, and the cells can be harvested, lysed, and the protein isolated. A cell culture includes host cells, medium, and other by-products. Suitable media for cell culture are well known in the art.

[0116] The expressed modified therapeutic proteins described herein can be isolated from the cell culture medium, the host cells, or both using techniques known in the art for purifying proteins, including ion exchange chromatography, gel filtration chromatography, ultrafiltration, electrophoresis, and immunoaffinity purification with antibodies specific for particular epitopes of the modified polypeptide.

[0117] Therapeutic Proteins The modified proteins described herein can be modified therapeutic proteins. Therapeutic human wild-type proteins of interest are suitable for the modifications described herein. In some embodiments, the therapeutic protein can be an intracellular antibody. Exemplary therapeutic proteins include, but are not limited to, modified therapeutic proteins of the present disclosure that have the activity of the following human wild-type proteins: AIBG; AICF; A2M; A2MLI: A4GNT; AAAS; AACS: AADAC; AAGAB; AAKI; AANAT; AARD; AARS2; AARS; AASDH; AASDHPPT; AASS; AATF; AATK; ABAT; ABCAI2; ABCAI3; ABCAI; ABCA2; ABCA3; ABCA5; ABCAB; ABCA7; ABCA9; ABCBII; ABCBI; ABCB4; ABCB5; ABCB6; ABCB7; ABCB8; ABCB9; ABCCIO; ABCCII; ABCCI2; ABCCI; ABCC2; ABCC3; ABCC4; ABCC5; ABCC6; ABCC8; ABCC9; ABCDI; ABCD2; ABCD3; ABCD4; ABCEI; ABCFI; ABCF2; ABCGI; ABCG2; ABCG4; ABCG5; ABCG8; ABHDI2B; ABHDI2; ABHDIBA; ABHDI7B; ABHD2; ABHD5; ABHDB; ABII; ABI2; ABI3BP; ABI3; ABU; ABL2; ABLIM: ABLIM2; ABO; ABRA; ABR; ABTI; ACAAI; ACAA2; ACACA; ACACB5; ACADIO; ACAD8; ACAD9: ACADL; ACADSB; ACADS; ACADVL; ACAN; ACATI; ACAT2; ACBD3; ACBD4; ACBD5; ACBDB; ACCS; ACD; ACE2; ACE; ACER2; ACER3; ACHE; ORANGE; ACKRI; ACKR2; ACKR3; ACKR4; ACLY; ACMSD; ACDI: AC02; AC0TI3; ACOTI; ACDT2; AC0T9; ACDXI; AC0X2; AC0X3; AC0XL; ACPI; ACP2; ACP5; ACP6; ACPP; ACRBP; ACRC; ACR; ACVI; ACSBGI; ACSBG2; ACSF3; ACSLI; ACSL3; ACSL5; ACSLB; ACSMI; ACSM2B; ACS3; ACSSI; ACSS2; ACSS3; ACTAI; ACTA2; ACTB; ACTBL2; ACTCI; ACTGI; ACTG2; ACTLBA; ACTLBB; ACTL8; ACTL9; ACTNI; ACTN2; ACTN3; ACTN4; ACTRIA; ACTRIB; ACTR2; ACTR3B; ACTR3; ACTR5; ACTRTI; ACVRIB; ACVRIC; ACVRIO; ACVR2A; ACVR2B; ACVRLI; ACYI; ACY3; ACYP2; TRUE; YES; ADAMIO; HUMANS; MAN2; MAN5; MAN7; ADAMI9; ADAM20; ADAM2I; ADAM22; ADAM23; ADAM28; ADAM29; ADAM2; ADAM33; ADAM7; ADAM8; ADAM9; MAN: ADAMCIO; ADAMSI2; ADAMSI3; ADAMTSI4; ADAMTSI5; ADAMTSIB; ADAMTSI7; ADAMTSI8; ADAMTSI9; ADAMTSI; ADAMTSI20; ADAMTSI2; ADAMTSI3; ADANTS4; ADAMTS5; ADAMTSB; ADAMTS7; ADAMTSB; ADAMTS9; ADAMTSLI; ADAMTSL2; ADAMTSL3; ADAMTSL4; ADAMTSL5; ADAPI; ADAP2; ADARBI; ADARB2; ADAR; ADAT2; ADAT3; ADCK3; ADCK4; ADCYIO; AOCYSI; ADCY2; ADCY3; ADCY5; ADCYB; ADCY7; ADCY8; ADCY9; ADJAPI; YOUNGER; ADD1; ADD2; ADD3; ADGB; ADGRAI; ADGRA2; ADGRA3; ADGRBI; ADGRB2; ADGRB3; ADGRDI; ADGRD2; ADBREI; ADGREZ; ADGRE5; ADGRF5; ADGRGI; ADGRGZ; ADGRG3; ADGRGB; ADGRG7; ADGRL1; ADGRL3; ADGRVI; AOHIA; ADHIB; ADH4; ADH5; ADHB; ADH7; ADHFEI; AOIt; AOIG; ADIPBD; ADIPBRI; ADIPDR2; ADIRF; ADK; ADM2; ADM; ADNP; ADO; ADDRAI; AD0RA2A; AD0RA2B; ADPGK; ADPRH; ADPRHL1; ADPRHL2; ADRIA; ADRAIB; ADRAID; ADRA2A; ADRA2B; ADRA2C; ADRBI; ADRB2; ADRB3; AORB1; ADRBK2; SLEEP; ADSL; ADSS; ADSSLI; ADTRP; AEBP2; AEN; AES; AFAPI; AFAPEL; AFAPIL2; AFFI; AFF2; AFF3; AFF4; AFG3L2; OF; AFP; AGA; AGAPt; AGAP2; AGAP3; AGAP4; AGBLI; AGBL2; AGBL3; AGBL4; IF; AGFGI; AGFG2; AGGFI; AG; AGMD; AGD2; KING: FOUR2; AGPAT3; AGPAT4; AGPAT9; AGPS; AGR2; AGR3; ABRN; AGRP; AGT; AGTPBPI; AGTRI; AGTR2; AGXT2; AGXT; AHCY; AHCYL2; FIRE; QUESTIONS; AHR; AHRR; ACHIEVEMENT; AHSA2; AHSG; AICDA; AIDA; AIR: AIFMI: AIFM2; AIFM3; AIGI: AIM1: AIM2; AIP1; AIMP2; AIP: AIPLI; AIR; AJAPI; AJUBA; AI; A3; AB; AK7; AK8; AK9; COMPANION; AKAPI2; AKAPI3; CHAPTER7A; AKAPI; AKAP2; AKAP3; AKAP4; AKAP5; AKAPB; AAP7; AKAPB; AIPI: END2; HONOR; ACRIBID; ACRIVI; AICI: AKRIC2; AKRIC3; AKRIC4; CREDIT; ACREE2; AKR7A3; ACT; ACTION; ID AKT2; AKT3; ACTIVE; ALAD; STEEL; AT2; ALB; ALCAM; ALDHIBAI: ALDHI8AI: ALDHIAI: ALDHIA2; ALDHIA3; ALDHIBI; ALDHIU; ALDH2; ALDH3AI; ALDH3A2; ALDH3BI: ALDH4AI; ALDH5AI: ALDHBAI: ALDH7AI: ALDH9AI: ALDDA; ALDDB; ALDDC; ALGIOB; ALGIQ; ALGII; ALGI2; ALGI3; ALGI; ALGIL; ALG2; ALG3; ALG8; ALG9; ALKBHI; ALKBH2; ALKBH3; ALKBH7; ALKBH8; ALK; ALLC; ALMSI; ALDXI2B; ALDXI2; AL0XI5B; ALDXI5; ALDX5AP; AL0X5; ALDXE3; ALPI: ALPKI; ALPK2; ALPK3; ALPP; ALPPL2; ALS2CL; ALS2CRI2; ALS2; ALXI; ALX4; ALYREF; AMACR; AMBN; AMBP; AMBRAI; AMDI; AMELX; AMELY; AMERI; AMER2; AMER3; AMFR; AMH; AMHR2; AMICAI; AMIGD2; 15 AMMECRI; AMN; AMOT; AMDTLI: AMPD2; AMPD3; AMPH; AMT; AMZI; ANAPCIO; ANAPCII; ANAPCI3; ANAPCl; ANAPC2; ANAPC4; ANAPC5; ANAPC7; ANG; ANGPTI; ANGPT2; ANGPT4; ANGPTLI:ANGPTL2; ANGPTL4; ANGPTLG; ANKI; ANK2; ANK3; AN FNI: ANKFYI: ANKHDI-EIF4EBP3; ANKHD1; ANKH; ANKKt; ANKLEI; ANKLE2; ANKMYI; ANKRDIO; ANKRDII; ANKRDI2; ANKRDI8A; ANKRDI; ANKRD23; ANKRD2B; ANKRD28; ANKRD2; ANKRD3DA; ANKRD3BB; ANKRD3B; ANKRD37; ANKRD44; ANKRD45; ANKRD4B; ANK D5D; ANKRD55; ANKRDB; ANKRD7; ANXIETY; ANXIB; ANKS4B; ANKSB; ANLN; ANDID; ANDI; AN02; AN03; AND4; AND5; AN06; AND7; ANP32A; ANP32B; ANP32D;0 ANPEP; ANTXRI; ANTXR2; ANXIETY; ANXIETY; ANXAI3; ANXAI: ANXA2; ANXA2R; ANXA3; ANXA4; ANXA5; ANXAB; ANXA7; ANXA8; ANXABLE; ADAH; AOCI; AOC2; AOC3; ADXI: FIRE; FIRE; PIGI; FIRE; APIM2; FIRE; APIS2; APIS3; AP2AI; APZBI; AP2MI; AP2SI; AP3BI; AP3DI; AP3M2; AP3SI; AP3S2; AP4BI; AP4EI; AP4MI; AP4SI: AP5MI: AP5ZI; APAFI; APBAI; APBA2; APBA3; APBBI; APBIBIP; APBB2; APBB3; APC2; APCDDI; APCDDIL; APC; APCS; WHAT; APPENDIX; APEX2; APHIB; APIS; APIP; APLN; APLNR; APPLE; APLP2; APDAIBP; AP0A2; AP0A4; APDA5; APDBECI; APDBEC2; APDBEC3AJ; AP0BEC3B; APDBEC3C; APDBEC3F; APDBEC3G; AP0BEC3H; APDB; POOR; APOC5; APDC2; AP0C3; AP0C4; APDD; APDE; APDF; APDH; APDLI: APDL2; APDL3; AP0L4; APOLB; APOLDI: APDM; APDD; APOPTI: APPBP2; APP; APPLI; APPL2; APRT; APTX; AflPID; ADPI; A0P2; ADP3; ADP4; ADP5; ADPB; ADP7; ADP8; ADP9; ARAF; ARAPI; ARAP3; ARC; ARCNI; AREG; ARFI; ARF3; ARF4; ARFB; AFGAPI; ARFGAP2; ARFGAP3; ARFGEFI; ARFGEF2; ARFGEF3; AFiPf; ARFRPI:ARB1; ARGLUI; ARHGAPID; ARHGAPIIA; ARHGAPIIB; ARHGAPI5; ARHGAPI8; ARHGAPI; ARHGAP2D; ARHGAP2I; ARHGAP22; ARHGAP23; ARHGAP24; ARHGAP25; ARHGAP2B; ARHGAP27; ARHGAP28; ARHGAP30; ARHGAP3I; ARHGAP32; ARHGAP35; ARHGAP42; ARHGAP4; ARHGAP5;D ARHGAPB; ARHGAP9; ARHGDIA; ARHGDIB; ARHGEFIO; ARHGEFIDL; ARHGEFII:ARHGEFI2; ARHGEFI5; ARHGEFIB; ARHGEFI7; ARHGEFI: ARHGEF25; ARHGEF2B; ARHGEF28; ARHGEF2; ARHGEF38; ARHGEF3; ARHGEF4; ARHGEF5; ARHGEFB; ARHGEF7; ARHGEF9; AR; ARIDIB; ARID2; ARID3A; ARID3B; ARID4A; ARID4B; ARID5B; ARIHI; ARUI; ARLI3A; ARLI3B; ARLI4EP; ARLI4; ARLI5; ARLI; ARL2BP; ARL2; ARL3; ARL4A; ARL4C; ARL4D; ARL5A; ARL5B; ARLB; ARLBIPI; ARLBIP5; ARMCIO; ARMCI:ARMC2; ARMC3; ARMC4; ARMC5; ARMC8; ARMC9; ARMCXI; ARMS2; ARMTI: ARNT2; ARNT; ARNTL2; ARNTL; HARP; ARPCIB; ARPC2; ARPC3; ARPC5; ARPIN; ARPP2I; ARR3; ARRBI;5 ARRBI; ARRDC2; ARRDC3; ARRDC4; DOG; ARSB; ARSD; ASS; ARSF; ARSG; ARSH; ARSI: ARSJ; ARSK; ART; ART3; ART4; ARVCF; ARX; AS3MT; ASAHI; ASAH2; SMOKE; ASAP2; ASBID; ASBI3; ASBI5; ASBIS; ASBI; ASB2; ASBB; ASB7; ASCCI; ASCC2; ASCC3; ASCLI; ASCL2; ASCL4; ASFIA; ASFIB; ASHIL; ASH2L; ASICI; ASIC2; ASIC3; ASIC4; ASICS; ASIP; ASL; ASMT; ASMTL; ASNAI; ASMS; ASPA; ASPG; ASPH; ASPM; ASPN; ASPRVI; ASPSCRI; ASRBLI; ASSI: ASTN2; DOG; ASXLI; ASXL2; ASXL3; ASZI; ATAD2; ATAD3B; ATAD3C; ATAD5; FATHER; ATCAY; LIVER; ATFI; ATF2; ATF3; ATF4; ATF5; ATFBB; ATFB; ATF7; ATF7IP; ATBIO; ATGI2; APPLICABLE: ATG2B; ATG3; ATG4A; ATG4B; ATG4C; ATG5; ATG7; ATG9A; ATIC; WATER; ATL2; ATL3; ATM; WOMEN; ATDHI; ATDH7; ATOXIC; ATPIDA; ATPIOB; ATPIOD; ATPIIA; APPEARANCE; ATPIIB; ATPI2A; ATPI3A3; ATPI3A4; ATPIA2; ATPIA3; ATPIA4; ATPIBI; ATPIB2; ATP2AI; ATP2A2; ATP2A3; ATP2BI; ATP2B2; ATP2B3; ATP2B4; ATP2CI; ATP2C2; ATP4A; ATP4B; ATP5AI; ATP5B; ATP5CI; ATP5D; ATP5E; ATP5GI; ATP5G2; ATP5G3; ATP5H; ATP5J2; ATP5J; ATP5L; ATP5D; ATPBAPI; ATPBAPIL; ATPBAP2; ATP6V0AI; ATPBV0A2; ATPBV0A4; ATPBVOC; ATPBVDDI; ATPBVOEI; ATPGV0E2; ATPBVIBI; ATPGVIB2; ATPBVICI; ATPBVIO; ATPBVIEI; ATPBVIF; ATPBVIGI; ATPBVIG2; ATPBVIG3; ATP7A; ATP7B; ATP8AI; ATP8A2; ATP8BI; ATP8B3; ATP8B4; ATP9B; ATPAF2; ATRAID; ATR; ATRIP; ATRN; ATRNLI; ATRX; ATXNIO; ATXNI; ATXNIL; ATXN2; ATXN2L; ATXN 3; ATXN7; ATXN7L3B; AUH; AURKA; AU KB; AURKC; AUTS2; AVEN; AVP; AVPII; AVPRIA; AVPRIB; AVPR2; AWATI; AXDNDI; AXINI: AXIN2; AXL; AZGPI; AZI2; AZINI; AZIN2; AZUI; B2M; B3GALNTI; B3GALNT2; B3GALT2; B3GALT4; B3GALT5; B3GALTL; B3GATI; B3GAT2; B3GAT3; B3HNT2; B3HNT3; B3HNT5; B3GNTB; B3HNT8; B3GNTLI; B4GALNTI; B4GALNT2; B4GALNT3; B4WRONG; B4GALT3; B4GALT4; B4GALT5; B4GALTB; B4GALT7; B4GATI; B9DI: B9D2; BAALC; BAT; WOMEN; BACEI; BACE2; BACHI; BACH2; BAD; BAG); BAG3; BAG4; BAGS; BAGB; BAIAP2LI; BAIAP3; BAKU BAMBI: OWNERS: BANKS; BANP; BAPI; BARDI; BARHLI; BARX: BARX2; BASPI; BATF2; BATF; BOX; BASIC; BASIS; BAZ2A; BAZ2B; BBC3; BBIPI; LAND; BBSID; BBSI2; BBS1; BBS2; BBS4; BBSS; BBS7; BBSS; BBX; BCAM; BCAN; BCAP29; BCAP3I; BCARI; BCASI; BCAS3; BCAS4; BCATI; BCAT2; BCCIP; BCDIN3D; BCHE; BC DHA; BC DHB; BC DK; BCLIO; BCLIIA; BCLIIB; BCL2AI; BCL2; BCL2LI0; BCL2LII; BCL2LI2; BCL2LI3; BCL2LI4; BCL2LI; BCL2L2; BCL2L2-PABPNI; BCL3; BCLBB; BCLB; BCL7A; BCL7B; BCL7C; BCL9L; BCLAFI; BCDI; BC02; BCDR; BCORLI; BCR; BCSIL; BDHI; BDH2; BDKRBI; BDKRB2; BDNF; BDPI; BEANI; BEGAIN; BENDS; BEND4; BESTI; BEST2; BETI; BETIL; BEXI; BEX2; BEX4; BFAR; BFSPI; BFSP2; BGLAP; BGN; BHLHAI5; BHLHA9; BHLHB9; BHLHE22; BHLHE23; BHLHE40; BHLHE4I; BHMT2; BHMT; BICCI; BICDI; BICD2; BID; BIN: BIN2; BINS; BIRC2; BIRC3; BIRC5; BIRCB; BIRC7; BIVM; BLCAP; BUD; BLK; BLMH; BLM; BLNK; BLOCIS2; BLDCIS3; BLOCIS4; BLOCIS5; BLDCISB; BLVRA; BLVRB; BLZFI: BMF; BMII: BMPIO; BMPI5; BMPI; BMP2; BMP2K; BMP3; BMP4; BMP5; BMPG:BMP7; BMP8B; BMPER; BMPRIA; BMPRIB; BMPR2; BMSI; BMX; BNCI; BNC2; BNIPI; BNIP2; BNIP3; BNIP3L; BNIPL; BDC; BODIL2; BO; BOLA3; BDLL; BDPI:BORA; BPGM; BPIFAI; BPIFA2; BPIFA3; BPIFBI:BPIFB2; BPIFC; BPI; BPNTI; BPTF; BPY2; BRAF; BRAP; BRATI; BRCAI; BRCA2:BRCC3; BRDI; BRD2; BRD3; BRD4; BRD7; BRD8; BRE; BRFI; BRF2; BRI3BP; BRI3; BRINK; BRINP2; BRINP3; BRIP; BRKI; BRMSI; BRMSIL; BRS3; BRSI; BRSK2; BRWDI: BRWD3; BSCL2; BSG; BSN; BSPHI; BSPRY; BSTI; BST2; BSX; BTBDID; BTBDII; BTBDIB; BTBDI; BTBD2; BTBD3; BTBD9; BTC; BTD; BTF3; BTGI; BTG2; BTG3; BTG4; BTK; BTLA; BTNIAI; BTN2AI; BTN2A2; BTN3AI; BTN3A2; BTN3A3; BTNL2; BTRC; BUBBLE; EVIL; BUB3; WORD3; BUD3I; BVES; BYSL; BZRAPI; VOICE; CID; CIGALTICS; CIGARETTES; IOC; CIDBP; CIQLI; CIDL3; CIQTNFI; CIQTNF3; C1QTNF5: CIOTNFB; CIOTNF7; CIDTNF9B-ASI; CIR: CIRCLE; CIS; C2CO3; C2CD4A; C2CD4B; C2CD5; C2; C4A; C4B2; C4B; C4BPA; C4BPB; C5KING: C5AR2; C5; CB; CAIO; CAM; CAI2; CAI3; CAI; CA2; CA3; CA4; CA5A; CAB; CA8; CAB39; CAB39L; CABIN; CABLE!; CABP2; CABP4; CABSY; CABYR; HUNTER; CACNAIB; CACNAIC; CACNAID; HUNTING; CACNAiF: CACNAIG; LOVE; HUNT: HUNT; CACNA2DI; CACNA2D2; CACNA2D3; CACNA2D4; CACNBI; CACNB2; CACNB3; CACNB4; CACNG2; CACNG3; GACNG4; CACNG5; CACNGB; CACULI; CACYBP; CAD; CADMI ID; CADM2; CADM3; CADM4; CADPS2; CADPS; GAGEI; CALBI; CALB2; HUMBLE; CALCB; CALCOCDI; CALCDCD2; CALCR; CALCRL; HOT; CALHMI; CALHM2; CALHM3; CALM2; CALML3; CALML5; CALNI: CALR3; CALR; CALU; CALY; CAMKID; CAMKIG; CAMKI; CAMK2A; CAMK2B; CAMK2D; CAMK2G; CAMK4; CAM KI: CAMKK2; CAMKMT; CAMLG; CAMP; CAMSAPI; CAMSAP2; CA TAI; CANOES: CAND2; SONGS: CANX; CHIEFS; CAP2; CAPG; CAPNID; CAPNI3; CAPNI4; CAPNI: CAPN2; CAPN3; CAPN5; CAPNB; CAPN7; CAPN9; CAPNSI: GOATS; CAPRIN2; CAPS2; CAPS; CAPSL; CAPZA2; CAPZA3; CARDID; CARDII; CARDI4; CARDIB; CARDB; CARDS: CARD9; CARF; CARKD; CARMI; 15 CARS; CARTPT; CASCI; CASC3; CASC4; CASC5; CASDI; CASK; CASPIAN; CASPI4; CASPI; CASP2; CASP3; CASP4; CASP5; CASPB; CASP7; CASP8AP2; CASPB; CASPB; CASDI: CASR; CASS4; CAST: CASZI: CAT; CATSPERI; CATSPER2; CABLES; CAV2; CAV3; CBFA2T2; CBFA2T3; CBFB; CBLB; CBL; CBLLI; CBLNI; CBLN2; CBLN4; CBRI; CBR3; CBR4; CBS; CBXI; CBX2; CBX3; CBX4; CBX5; CBXB; CBX7; CBX8; CBYI; 200 days; CC2DIB; CC2D2A; CCAR; CCAR2; CCBEI; CCBLI; 500 CCDCI02B; CCDCID3; CCDCID5; CCDCID8; CCDCII4; CCDCII5; CCDCI2I; CCDCI22; CCDCI29; CCDCI3D; CCDCI34; CCDCI3B; CCDCI40; CCDCI4I; CCDCI48; CCDCI5I; CCDCIB7; CCDCIB9-D S0HLH2; CCDCI70; CCDCI7I; CCDCI75; CCDCI7B; CCDCI78; CCDCI8D; CCDCI8I: CCDCI85; CCDC22; CCDC28A; CCDC39; CCDC3; CCDC4D; CCDC42B; CCDC42; CCDC5D; CCDC54; CCCBD; CCDCB2; CCDCB3; CCDCG5; CCDCBB; CCDCB7; CCDCB8; CCDCB; CCDC78; CCDC8D; CCDC83; CCDC85A; CCDCBB; CCDC88A; CCDC88C; CCDC8; CCDC9I; CCDC94; CCDC97; CCHCRI; CCKAR; CCKBR; CCK; CGLII; CCLI3; CCLI4; CCLI5; CCLIB; CCLI7; CCLI8; CCLI9; CCD; CCL2D; 251: 222; 2323; 2524; 2525; CCL2G; CCL27; CCL28; CCL2; CCL3; CCL3L3; CCL4; CCL4LI; CCL4L2; CCL5; CCL7; CCL8; CCM2; CCNAI; CCNA2; CCNBI; CCNB2; CCNB3; CCNC; CCNDt:5 CCND2; CCND3; CCNDBPI: CCNEI; CCNE2; CCNF; CCNBI: CCNG2; CCNH; CCNI; CCNJ; CCNJL; CCNK; CCNL1; CCNL2; CCNO; CCNTI; CCNY; CCPIID; CCRID; CCRI; CCR2; CCR3; CGR4; CCR5; CCRB; CCR7; CCR8; CCR9; CCRL2; CCRN4L; CCSERI; CCS; CCT2; CCT3; CCT4; CCT5; CCTGA; CCTBB; CCT7; CDI09; CDI4; CDI5I; CDIB3; CDIB3LI; CDIB4; CDI77; CDI8D; CDI9; CDIA; CDIB; CDIC; CDID; CDIE; CD20D; CD2DDRI; CD2D7; CD2D9; CD22B; CD22; CD244; CD247; CD248; CD24; CD274; CD27B; CD27; CD28; CD2AP; CD3DDA; CD3D0C; CD3D0LF; CD302; CD320; CD33; CD34; CD3B; CD37; CD38; CD3D; CD3EAP; CD3E; CD3G; CD40; CD4DLG; CD44; CD4B; CD47; CD48;D CD4; CD55; CD59; CD5; CD5L; CDB3; CDG8; CDB9: CDB; CD72; CD74; CD79A; CD79B; CD7; CD8D; CD8I; CD82; CD83; CD84; CD8B; CD8A; CD8B; CD93; CD9B; CD99; CBD; CDADCI: CDANI; CDCI23; CDCI4A; CDCI4B; CDCIG; CDC2DB; CDC23; CDC25A; CDC25B; CDC25C; CDC27; CDC34; CDC37; CDC37LI; CDC42BPA; CDC42BPB; CDC42BPG; CDC4ZEPI: CDC42EP3; CDC42SE2; CDC45; CDC5L; CDCB; CDC73; CDC7; CDCA2; CDCA3; CDCA5; CDCA7; CDCA7L; CDCPI; CDHID; CDH11: CDHI3; CDHI5; CDHIB; CDHI7; CDHI8; CDHI9; CDHI; CDH2D; CDH22; CDH23; CDH2B; CDH2; CDH3; CDH4; CDH5; CDHB; CDH7; CDH8; CDH9; CDHRI; CDHR2; CDHR3; CDHR5; CDIPT;5 CDKID; CDKIIB; CDKI2; CDKI3; CDKI4; CDKI5; CDKIB; CDKI7; CDKI8; CDKI9; CDKI; CDK2D; CDK2API; CDK2AP2; CDK2; CDK3; CDK4; C0K5; CDK5 I: CDK5R2; CDK5RAPI: CDK5RAP2; CDK5 AP3; CDKB; CDK7; CDK8; CDK9; CDKALI; CDKLI: CDKL2; C0KL3; CDKL4; CDKL5; CDKNIA; CDKNIB; CDKNIC; CDKN2A; C0KN2A1P: CDKN2B; CDKN2C; CDKN2D; CDKN3; CDNF; COOI; CDON; CDRI; CDR2; CDS2; CDTI: CDV3; 141: 142; CDX4; GDYIB; CDY2B; CDYL2; CDYL; CEACAMIB; CEACAMIB; CEACAMI; CEACAM2I; CEACAM3; CEACAM4; CEACAM5; CEACAMB; CEACAM7; CEACAM8; CEBPA; CEBPB; CEBPD; CEBPE; CEBPG; CEBPZ; CECRI; CECR2; CELAI: CELA3B; CELFI; CELF2; CELF4; CELF5; CELFB; GEL; CELSRI; CELSR3; CEMIP; CEMPI; CENDI; CENPA; CENPB; CENPC; CENPE; CENPF; CENPH; CENPJ; CENPK; CENPN; CENPO; CENPO; CENPU; CENPV; CENPW; CEPII2; CEPI2D; CEPI28; CEPI3I; CEPI35; CEPI52; CEPIB2; CEPIB4; CEPI7D; CEPI92; CEPIB; CEP25D; CEP29D; CEP4I; CEP55; CEP57; CEPB3; CEPG8; CEP72; CEP7B; CEP83; CEP85L; CEP83; CERI; CERK; CERKL; CERSI; CERS2; CERS3; CERS4; CERSB; CESh CES2; CES3; CETNI; CETN2; CETN3; CETP; CFAPI2B; CFAP3B; CFAP44; CFAP52; CFAP53; CFAP57; CFAP58; CFAPBI; CFAPBB; CFAP97; CFB; CFCIB; CFCI; CFD; CFDPI; CFH; CFHRI; CFHR2; CFHR3; CFHR4; CFH 5; CFI; CFLI; CFL2; CFLAR; CFP; CFTR; CGA; CGBI; CGB2; CGB5; CGB7; CBN; CGNLI; CGRRFI: CH25H; CHACI; CHAD; CHAFIA; CHAFIB; CHAMPI: CHAT; CHCHDIO; CHCHDI; CHCHD3; CHCHD5; CHCHDB; CHCHD7; CHDI; CHD2; CD3; CD4; CHDB; CD7; CHD8: CDH; CHEKI; CHEK2; CHERP; CHFR; CHGA; CHGB; CHI3LI; CHICI; CHIC2; CHITI; CHKA; CHKB; CHLI; CHM; CHML; CHAMPIA; CHMPIB; CHMP2B; CHMP3; CHMP4A; CHMP4B; CHMP4C; CHMP5; CHMI: CHN2; CHDDL; CHORDI; CHPI: CHP2; CHPF; CHPTI: CHRACI; CHRD; CHRDLI: CHRFAM7A; CHRMI; CHRM2; CHRM3; CHRM4; CHRM5; CHRNAIO; CHRNAI; CHRNA2; CHRNA3; CHRNA4; CHRNA5; CHRNAB; CH NA7; CHRNBI; CHRNB2; CHRNB3; CHRNB4; CHRND; CHRNE; CHRNG; CHSTIO; CHSTII; CHSTI2; CHSTI3; CHSTI4; CHSTI5; CHSTI; CHST2; CHST3; CHST4; CHST5; CHSTB; CHST8; CHST9; CHSYI; CHSY3; CHTFI8; CHTOP; CURCI; WHAT? CHIAPINI; CIBI; CIB2; CIC; CIDEB; CIDEC; CIITA; CILP2; CILP; CINP; CIPC; CHIRP GIRL; CIRHIA; CISDI; CISD2; CISH; CITED1; CITED2; CIT; CIZI: CKAP2; CKAP2L; CKAP4; CKAP5; CKB; CKLF; CKM; CKMTIA; CKMTIB; CKMT2; CKSIB; CKS2; CLAPS; CLASP2; CLCA2; CLCA4; CLCFI; CLC; CLCNI; CLCN2; CLCN3; CLGN4; CLCN5; CLCNB; CLCN7; CLCNKB; CLDNID; THE CLDNIES; CLDNI4; CLDNI5; CLDNIB; CLDNI8; CLDNl; CLDN23; CLDN2; CLDN5; CLDNB; CLDN7; CLDN8; CLDNB; CLECIDA; CLECIA; CLECI2A; CLECI4A; CLECIBA; CLECIB; CLEC2A; CLEC2B; CLEC2D; CLEC2L; CLEC3B; CLEC4A; CLEC4C; CLEC4D; CLEC4E; CLEC4G; CLEC4M; CLEC5A; CLECBA; CLEC7A; CLEC9A; CLECLI; CLGN; CLICI; CLIC3; CLIC5; CLICB; CLINTI; CLIP1; CLIP2; CLK1; CLK2; CLLUI; CLMN; CLMP; CLN3; CLN5; CLNB; CLNB: CLNK; CLNSIA; CLOCK; CLP; CLPP; CLPS; CLPTMI; CLPTMIL; CLRNI; CLSPN; CLSTNI; CLSTN2; CLTA; CLTC; CLTCLI: CLUAPI; CLU; CLUES; CLVSI: CLYBL; CMAI; DMAS; CMCI; CMC2; CMC4; CMIP; CMKLRI; CMPK2; CMSSI; CMTM3; CMTM5; CMTM7; CMTM8; CMTRI; CMTR2; CMYA5; CNBDI; CNBP; CNDPI; CNDP2; CNGAI; CNGA3; CNGBI; CNGB3; CNIH3; CNKSRI; CNKSR2; CNKSR3; CNNI; CNN2; CNNMI: CNNM2; CNNM4; CNQTI; CNBT2; CNDT3; CN0T4; CNDTB; CNOTGL; CN0T7; CN0T8; CNP; CNPY2; CNPY3; CNRI: CNR2; CNRIPI: CNST; CNTF; CNTFR; CNTLN; CNTNI; CNTN2; CNTN3; CNTN4; CNTN5; CNTNB; CNTNAPI; CNTNAP2; CNTNAP3; CNTNAP4; CNTNAP5; CNTRL; CNTROB; COAI; C0A5; CDASY; COBL; COBLLI; COCH; COGI; COG2; COG3; COG4; COG5; COGB; COG7; COG8; COIL; COLIDAI; COLIIAI; COLIIA2; COLI2AI; COLI3AI; COLI4AI; COLI5AI; COLIBAI; COLI7AI; COLI8AI; COLLIES; COLIA2; COL2OAI; COL2IAI; COL22AI; COL23AI: COL24AI; COL25AI; COL2BAI; COL27AI; COL28AI; COL2AI; COL3AI; COL4AI; COL4A2; COL4A3BP; COL4A3; COL4A4; COL4A5; COL4AB; COL5AI; COL5A2; COL5A3; COLGAI; COLBA2; COLBA3; COLBA5; COL7AI; COL8AI; COL8A2; COLGAI; COL9A2; COL9A3; COLCAI; COLCA2; COLLECTION; COLLECII: COLLEC2; COLGALT2; COLQ; COMMISSION; COMMAND; COMMD3-BMII; COMMD5; COMMD7; COMP; COMT; cup COPBI; COPB2; BEGIN; COPG2; COPRS; COPS2; COPS3; COPS4; COPS5; COPSE; COPS7A; COPS8; COPZ2; COD2; COO3; COO4; COO5; COO6; COO7; COO9; CORIN; CORDIA; CORDIB; COROIC; CORO2A; CORO2B; COROB; CHORUS7; CORO7-PAMIG; COTLI; cooking twelve; COXI4; COXI5; COOKED; COOKIE7; COOKIE8; COX19; COX4II; COX4I2; COX5A; COX5B; COXBAI; COXBA2; COXBBI; COXGC; COX7AI; COX7A2; COX7A2L; COX7B2; COX7B; COX7C; COX8A; CPA1; CPA2; CPA3; CPA4; CPAB; CPAMD8; CPBI; CPB2; CPD; CPEBI; CPEB3; CPEB4; CPEOI; CPE; CP; CPLXI; CPLX2; CPLX3; CPLX4; CPM CPNI; CPN2; CPNEI; CPNE2; CPNE3: CPNE4; CPNE7; CPNE8: CPD; CPDX: CPPEOI; CPD; CPSI; CPSFI; CPSF2; CPSF3; CPSF3L; CPSF4; CPSFB; CPSF7; CPTIA; CPTIB; CPTIC; CPVL; CPXCRI; CPZ; CRI; CR2; CRABS; CRABP2; CRACR2A; CRADD; CRAMPIL; CRAT; 100 BI; CRB2; CRB3; CRBN; CRCP; CRCTI; CREBI; CREB3; CREB3LI; CREB3L2; CREB3L3; CREB3L4; CREB5; CREBBP; CREBRF; CREBZF; CREGI; CRELDI; CRELD2; CREM; CRHBP; CRH; CRHRI: CRHR2; CRIMI; CRIP2; CRIP3; CRIPAK; CRIPT; CRISPI; CRISP2; CRISP3; CRISPLDI; CRISPLD2; CRK; CRKL; CRLFI; CRLF2: CRLF3; CRLSI; CRMPI; CRNKLI: CRNN; CRDCC; CROT; CRP; CRTACI: CRTAM; CRTAP; CRTCI; CRTC2; CRTC3; CRX; CRYI; CRY2; CRYAB; CRYBAI; CRYBA2; CRYBA4; CRYBBI; CRYBB2; CRYBB3; CRYGB; CRYGC; CRYGD; CRYGS; CRYLI: CRYM; CRYZLI; CSAD; CSAG3; CSEIL; CSFIR; CSF2; CSF2RA; CSF2RB; CSF3; CSGALNACTI; CSGALNACT2; CSHI; CSH2; CSHLI; CS; CSK; CSMDI; CSMD2; CSMD3; CSNISI; CSN2; CSN3; CSNKIAI: CSNKID; CSNKIG3; CSNK2AI: CSNK2A2; CSNK2B; CSPG4; CSPG5; CSPPI; CSRNPI; CSRNP3; CSRPI: CSRP2BP; CSRP2; CSRP3; CSTI; CST2; CST3; CST4; CST5; CSTB; CST7; CST8; CST9; CSTBL; CSTA; CSTB; CSTFI; CSTF2; CSTF2T: CSTLI: CT45AI; CT55; CT83: CTAGIA; CTAG2; CTAGEI; CTAGE5; CTBPI; CTBP2; CTCI; CTCF; CTCFL; CTDP1: CTDSPI; CTDSP2; CTDSPL; CTFI; CTGF; CTHRCI; CTIF; CTLA4; CTNNAI; CTNNA2; CTNNA3; CTNNALI; CTNNBt; CTNNBLI: CTNNDI; CTNND2; CTNS; CTPSI; CTR9; CTRBI; CTRB2; CTRC; CTRL; CTSA; CTSB; CTSC; CTSD; CTSE; CTSF; CTSG; CTSH; CTSL; CTSD; CTSV; CTSW; CTSZ; CTTNBP2; CTTN; CTUI; CTXN3; CUBN; CUEDCI; CUEDC2; CULI: CUL2; CUL3; CUL4A; CUL4B; CUL5; CUL7; CUL9; CUTA; CUXI; CUX2; CUZDI; CWC22; CWC27; CWFIBLI; CWFIBL2; CWH43; CX3CLI; CX3CRI; CXADR; CXCLIO; CXCLII: CXC LIZ; CXCLI3; CXCLI4; CXCLIB; CXCLI7; CXCLI; CXCL2; CXCL3; CXCL5; CXCLB; CXCL8; CXCL9; CXCRI; CXCR2; CXCR3; CXCR4; CXCR5; CXCRB; CXXCI; CXXC4; CYB5BID2; CYB5BI; CYB5A; CYB5B; CYB5R3; CYB5R4; CYBA; CYBB; CYBRDI: CYCI; CYCS; CYFIPI; CYFIP2; CYGB; CYLCI; CYLC2; CYLD; CYP11A1; CYPIIBI: CYPIIB2; CYPI7AI; CYPI9AI; CYP1A1: CYPIA2; CYPIBI; CYP2IA2; CYP24AI; CYP2BAI; CYP2BBI; CYP2GCI; CYP27AI; CYP27BI; CYP27CI: CYP2AI3; CYP2AB; CYP2A7; CYP2BB; CYP2CI8; CYP2CI9; CYP2C8; CYP2C9; CYP2DG; CYP2EI; CYP2FI; CYP2RI; CYP2SI; CYP2UI; CYP2WI; CYP39AI; CYP3A43; CYP3A4: CYP3A5; CYP3A7-CYP3A5IP; CYP3A7; CYP4BAI; CYP4AII; CYP4BI; CYP4FII; CYP4FI2; CYP4F22; CYP4F2; CYP4F3; CYP4F8; CYP4V2; CYP5IAI; CYP7AI; CYP7BI; CYP8BI; CYSI; CYSLTRI; CYTHI; CYTH3; CYTIP; CYTLI; BODY; D2HGDH; DAAM: DAAM2; DAB2; DAB2IP; ROOF; DACH2; DACTI; DACT2; DACT3; BODY: MEAT; DAND5; OAOA: DAD; DAPS; DAP; DAPC: DAPC2; DAPK3; DARS2; DARS; KEY: DAXX; DAZI; DAZ2; DAZ3; DAZ4; DAZAPl; DAZAP2; DAZL; DBF4; DBH; DBI; DBNI; DBNL; DBP; DBRI; DBXI; DCAFI2; DCAFI3; DCAFI7; DCAF4; DCAF5; DCAFB; DCAF7; DCAF8; DCANPI; DCBLDI: DCBLD2; DCC; DCDC2C; DCDC2; DCD; DCHSI; DCHS2; DCK; DCLKI; DCLK2; DCLK3; DCLREIA; DCLREIC; DCN; DCPIA; DCPIB; DCPS; DCSTI; DCST2; DCSTAMP; DCTD; DCT; DCTNI; DCTN2; DCTN3; DCTN4; DCTN5; DCTNB; DCUNIID: OCX; DCXR; DDAHI; DDAH2; DDBI: DDB2; DDC; DDHDI; DDHD2; DON: DDIAS; DDIT3; DDIT4; DDIT4L; DON; ODD: DDRI; DDR2; DDRGKI; DDT; DDTL; DDXIO; DDXII; DDXI7; DDXI8; DDXIBA; DDXI; DDX2I; DDX25; DDX27; DDX28; DDX31; DDX39A; DDX39B; DDX3X; DDX3Y; DDX4I; DDX42; DDX43; DDX4G; DDX4; DDX5D; DDX5I; DDX52; DDX53; DDX54; DDX5B; 00X58; DDX59; D0X5; DDXBD; D0X6; DEAR; DECI: DECRI; DEDD; DEFG; DEFAIB; DEFA3; DEFA4; DEFA5; DEFAG; DEFB103B; DEFBI04B; DEFBI05A; DEFBIOBA; DEFBI08B; DEFBII2; DEFBI25; DEFBI2G; DEFBI; DEFB4A; DEBSI; DEGS2; DEK: DENNDIA; DENNDIB; DENND2A; DENND4A; DENR; DEPDCIB; DEPDC5; DEPTDR; DERA; OERLI; DERL2; DERL3; DES; DESI2; DEXI; DFFB; DFNA5; DFNB3I: 0FNB59; DGATI; DGAT2; DGCR2; DGCRBL; DGCR8; DGKA; DGKB; DGKD; DGKE; DGKG; DGKH; DGKI; DGKK; DGKfl; DGKZ; DGUOK; DHCR7; DHDH; DHFR; DHFRLI; DHH; DHDDH; DHPS; DHRSII; DHRS2; DHRS4; DHRS7C; DHRS9; DHTKDI; DHXI5; DHXIB; DHX32; DHX34; DHX3B; DHX38; DHX4D; DHX58; DHX8; DHX9; DEVIL; DIAPHI; DIAPH2; DIAPH3; SAID; DIDOI; DIEXF; DIP2A; DIP2B; DIP2C; DURATION; DIRAS2; SAY; DIRC2; DIS3; DIS3L2; DIS3L; DISC; DISPLAY: OIXOCI; DKCI: DKKI: DKK2; DKK3; DKK4; DKKLI; DLAT; DLCI; WATER; DLEC1; DLEU7; DLGI; DLB2; DLG3; DLG4; DLG5; DLGAPI; DLGAP2; DLGAP3; DLGAP5; DLKI; DLL1; DLLS; DLL4; DLST; DLXI: DLX2; DLX3; DLX4; DLX5; OLXG; DMBTI; DMCI; DMD; DMGDH; DMKN; DMPI: DMPK; DM TI: DMRT2; DMRT3; DMRTAI; DMTFf; DMTN; DMWD; DMXLI: DMXL2; DNA2; YOUR AGE; DNAAF2; DNAAF3; DNAAF5; DNAHII; DNAHI2; DNAHI7; DNAHI; DNAH2; DNAH3; DNAH5; ONAHB; DNAH7; DNAH8; DNAH9; DNAII; DNAI2; DNAJAI: DNAJA2; DNAJA3; DNAJBM: DNAJBI3; DNAJBI; DNAJB2; DNAJB5; DNAJBB; DNAJB7; DNAJB8; DNAJB9; DNAJCIO; DNAJC12; DNAJGI3; DNAJCI4; DNAJCI5; DNAJC18; DNAJCI9; NOW; DNAJC27; DNAJC28; DNAJC2; DNAJC3; DNAJC5; DNAJC7; DNALI; DNASEI; DNASEIL2; DNASEIL3; DNASE2B; DNASE2; DNDI; DNER; DNHDI; DNLZ; DNMI: DNMIL; DNM2; DNM3; DNMBP; DNMTI; DNMT3A; DNMT3B; DNMT3L; DNPEP; DNTT; DDC2A; DDC2B; DOCKIO; DDCKII:DDCKII; DDCK2; DOCKS; D0CK4; DDCK5; DOCKS; DDCK7; DDCK8; DDCKFJ; DDHH; DDKI; DOK2; DDK3; D0K4; DDKS; DDKB; DDK7; DDLK; DDNSDN; DDPEY2; DDTIL; DPABTI: DPCD; DPCRI:DPEPI; DPEP2; DPEP3; DPF1; DPF3; DPHI; DPH3; DPHB; DPH7; DPMI; DPM2; DPM3; DPID; DPP3; DPP4; DPPG; DPP7; DPP8; DPPB; DPPA2; DPPA3; DPPA4; DPT; DPYI9L2; DPYI9L3; DPY30; DPYS; DPYSL2; DPYSL3; DPYSL4; DPYSL5; DRAMI; DRAPI; ORCI; DRDI; DRD2; DRD3; DRD4; DR05; DRGI; DRGX; DRDSHA:DRP2; OSCI; DSC2; DSC3; DSCAM; DSCAMLI; DSCCI: DSCR4; DSE; DSEL; DSGI; DSG2; DSG3; DSG4; DSP; DSPP; DST; DSTN; DSTYK; DTDI; DTHDI:DTL; DTNA; DTNB; DTNBPI; DTXI: DTX2; DTX3; DTX4; DTYMK; DUOXI; DU0X2; OUDXAI; D00XA2; DUPDI; DUS2; DUSPIO; DUSPII; DUSPI2; DUSPI3; DUSPI4; DUSPI5; DOSPIB; DUSPI8; DUSPI; DUSP2I; DUSP22; DUSP23; DUSP27; DUSP28; DUSP2; DUSP3; DUSP4; DUSP5; DOSPB; DUSP7; D0SP8; DUSP9; OUT; DUX4; DVL2; DVL3; DXO; DYM; DYNAP; DYNCIHI; DYNC1I1: DYNCII2; DYNCILII; DYNCZHI: DYNLLI; DYNLL2; DYNLRBI; DYNLTI; DYNLT3; DYRKIA; DYRKIB; DYRK2; DYRK3; DYSF; DYXIC1:DZIPI; EZFI; E2F3; E2F4; E2F5; E2FB; E2F7; E2F8; E4FI; EAR; EAF2; EARS2; EBAG9; EBFI:EBF2; EBF3; EBF4; EBI3; EBP; EBPL; ECD; ECE2; ECELI; ECHDC1: ECHDC3; ECHSI; ECU; ECI2; ECSCR; ECSIT; ECT2; EDA2R; EDA; EDARADD; EDAR; EDC4; EDEMI; EDIL3; EDNI; EDN3; EDNRA; EDNRB; EEAI; EED; EEFIAI; EEFIA2; EEFIB2; EEFID; EEFIEI; EEFIG; EEF2; EEFSEC; EFCABII; EFCABI; EFEMPI; EFEMP2; EFHB; EFHCI; EFHC2; EFHOI; EFNAI; EFNA2; EFNA3; EFNA4; EFNA5; EFNBI; EFNB2; EFNB3; EFR3A; EFR3B; EFS; EFTUDI; EFTUD2; EGF; EGFLB; EGFL7; EGFL8; EGFLAM; EGFR; EGLNI; EGLN2; EGLN3; CURVE; EGR2; EGR3; EGR4; EHBPI: EHDI; EHD2; EHD3; EHD4; EHF; EHHADH; EHMTI; EHMT2; EI24; EIDI: EIFIAD; EIFIAX; EIFIAY; EIFI; EIF2A; EIF2AKI: EIF2AK2; EIF2AK3; EIF2AK4; EIFZBI: EIF2B2; EIF2B3; EIF2B4; EIF2B5; EIFZSI; EIF2S2; EIF2S3; EIF3A; EIF3B; EIF3C; EIF3E; EIF3F; EIF3H; EIF3J; EIF3K; EIF3M; EIF4AI; EIF4A2; EIF4A3; EIF4B; EIF4E2; EIF4E3; EIF4EBPI; EIF4EBP2; EIF4EBP3; EIF4E; EIF4ENIFI: EIF4GI; EIF4G2; EIF4H; EIF5A2; EIF5A; EIF5; EIFB; ELACI; ELAC2; ELANE; GROW; ELAVL2; ELAVL3; ELAVL4; ELFI; ELF2; ELF3; ELF4; ELF5; ELKI; ELK3; ELK4; ELL2; ELL; HE SAYS; ELMO2; ELMODI; ELMOD2; ELMOD3; ELSANI; ELN; ELOFI; ELOVL2; ELOVL4; ELOVL5; ELOVLB; ELOVL7; ELP2; ELP3; ELP4; ELPB; ELSPBPI; EMB; EMCIO; EMC2; EMC3; EMC7; EMC8; EMCN; EMD; MOTHER; MOTHER; EMILY; EMILIN2; EMILIN3; EMU; EML2; EML4; EML5; EMLB; EMPI: EMP2; EMXI; EMX2; ENI; EN2; ENAH: SIX; ENCI; ENDDG; ENDDU; ENDDV; ENGASE; ENG; ENHO; ENO2; ENO3; ENO4; ENBPHI: ENOSFI: ENDXI: EN0X2; ENPEP; ENPPI; ENPP2; ENPP3; ENPP5; ENPP7; ENTHD2; ENTPDI; ENTPD2; ENTPD4; ENTPD5; ENTPDB; ENTPD7; EOGT; EOMES; EP300; EP400; SPACE; EPB4ILI: EPB4IL2; EPB4IL3; EPB4IL4A; EPB4IL4B; EPB42; EPCI: EPC2; EPCAM; EPDRI; EPG5; EPGN; EPHAI: EPHA3; EPHA4; EPHA5; EPHAB; EPHA7; EPHBI; EPHB3; EPHB4; EPHBB; EPHXI; EPHX2; EPHX3; EPM2A; EPM2AIPI; EPNI; EPO; EPOR; EPPIN; EPPIN-WFDCB; EPP I: EPRS; EPSI5LI; EPS8; EPS8L2; EPSTil: EPX; EPYC; ERALI; THERAPY; ERAP2; ERAS; ERBB2; ERBB2IP; ERBB3; ERBB4; ERCI; ERC2; ERCCI; ERCC2; ERCC3; ERCC4; ERCC5; ERCCB; ERCCBL2; ERCCB-PGBD3; ERCC8; EREG; ERF; ERG; ERGICI; ERGIC2; ERGIC3; ERI3; ERICH5; ERICHBB; I picked it up; Erlin; ERLIN2; ERMAP; ERMARD; I took off; ERNI; ERN2; EROILB; ERDIL; ERP29; ERP44; ERV3-1: ERVW-1; I ate; I followed; ESC02; ESD ESFI; I am EXPLORE; ESPN; I was ESR2; ESRPI; ESRP2; ESRRA; ESRRB; ESRRG; EXXI; ESYT: ESYT2; ESYT3; ETAAI; ETFI; ETFA; ETFB; ETFDH; ETHEUS; ETN1: ETNK2; ETNPPL; ETSI: ETS2; ETVI: ETV3; ETV4; ETV5; ETVB; ETV7; Evaia; Evacuated; EVC2; EVC; EVI2A; EVI2B; EVI5; EVL; EVPL; EVX1; EVX2; EWSRI: EXO2; EXO3; I went out; I cast out; EXOC2; EXOC3LI; EXOC3L2; EXOC4; EXOC5; EXOC7; EXOG; EXBSCI; EXDSC2; EXBSC3; EXBSC4; EXDSC5; EXDSCB: EXBSC7; EXDSC8; EXPH5; EXTI; EXT2; EXTL2; EXTL3; EYAI; EYA2; EYA4; EYES; EZHI; EZH2; EZR; FID; Fll; A thief; FI2; FI3AI; FI3B; F2; F2R; F2RLI; F2RL2; F2RL3; F5; F7; F8; FB; FA2H; FAAH2; FABP: FABP2; FABP4; 5 FABP5; FABPB; FABP7; FABPB; FADD; FADS: FADS2; FADS3; FAF2; FAHD2A; FAH FAIM2; FAIM3; FAMID2A; FAMILY03AI; FAMID5A; FAMID7A; FAMI07B; FAMI09A; FAMIIBA; FAMIIBB; FAMIIBC; FAMIItB; FAMII4AI: FAMI20B; FAMI2DC; FAMI24B; FAMI2BA; FAMI29A; FAMI29B; FAMI34B; FAMI35A; FAMI35B; FAM13BA; FAMI3A; FAMI3C; FAMI49A; FAMI50B; FAMI55A; FAMIBOBI; FAMI6IA; FAMIB3A; FAMIB3B; FAMIB7A; FAMIB8A; FAMIB8B; FAMIB9B; FAMI7DA; FAMI72A; FAMI73B; FAMI74A; FAMI75A; FAMI75B; FAMI77AI: FAMI77B; FAMI78A; FAMI78B; FAMI79B; FAMI8DA; FAMI84A; FAMI84B; FAMI87B; FAMI88A; FAMI88B; FAMI89B; FAMI93B; FAMIBBA; FAMI9BB; ID FAMI98B; FAMI9AI:FAMI9A2; FAMI9A4; FAMI9A5; FAM2D4A; FAM2D5A; FAM2DA; FAM2DB; FAM20C; FAM2IDB: FAM2I3A; FAM2I4A; FAM2IBA; FAM220A; FAM227B; FAM32A; FA 3A; FAM3B; FAM3C; FAM3D; FAM4BA; FAM4BD; FAM49A; FAM49B; FAM5BB; FAM53B; FAM57A; FAM58A; FAMBDA; FAMB3B; FAMB4A; FAM65B; FAMBBC; FAM7IFI; FAM7IF2; FAM72B; FAM78B; FAM8IB; FAM83A; FAM83B; FAM83D; FAM83H; FAM84A; FAM84B; FAM89A; FAM92AI; FAM92B; FAM9B; FAN1; FANCA; FANCB; FANCC; FANGD2; FANCE; FANCF; FANCG; FANCI; FANCL; FANCM; FANKI; FAP; FARI; FARPl; FARP2; FARS2; FARSA; FAS; FASLG; FASN; FASTKD2; FASTK; FAT; FAT2; FATS; I5 FAT4; FATEI; FALL FBFI; FBL; FBLIMI; FBLNI; FBLN2; FBLN5; FBNI; FBN2; FBN3; FBPI; FBP2; FBRS; FBXLI5: FBXLI7; FBXLI9; FBXL2D; FBXL2; FBXL3; FBXL4; FBXL5; FBXL7; FBXOID; FBXDII; FBX0I5; FBXDI7; FBXDI8; FBXD28; FBXD3D; FBXD3I; FBXD32; FBXD33; FBXD38; FBXD3; FBXD4D; FBX047; FBXD4; FBX05; FBXD7; FBXD8; FBXD9; FBXWIL FBXW4; FBXW7; FBXW8; FCAR; FCERIA; FCERIG; FCER2; FCGBP; FCGR2A; FCGR2B; FCGR3A; FCGR3B; FCGRT; FCHOI; FCHD2; FCHSD2; FCN FCN2; FCRLI; FCRL2; FCRL3; FCRL4; FCRL5; FCRLB; FCRLA; FCRLB; FDFTI; FDPS; FDXI; FDXIL; FDXR; TRY; FEMIA; FEMIB; FEMIC; FENI; FERD3L; FER; FERMTI; FERMT2; FERMT3;0 FES; FEV; FEZI; FEZ2; FEZFI; FEZF2; FFARI; FFAR2; FFAR3; FFAR4; FGA; FGB; FGDI; FGD2; FGD3; FGD4; FGD5; FGDB; FGFID; FBFII; FGFI2; FGFI3; FGFI4; FGFIB; FGFI7; FGFI8; FGFI9; FBFI; FGF2D; FGF2I:FGF23; FGF2; FGF3; FGF4; FGF5; FGFB; FGF7; FGF8; FGF9; FGFBPI; FGFBP2; FGFBP3; FGFRI; FGFRIDP2; FGFRIDP; FGFR2; FGFR3; FGFR4; FGFRLI; FGG; FGGY; FGLI; FGL2; FGR; FHDCI:FH; FHIT; FHLL FHL2; FHL5; FHDDI; FHDD3; FIBP; FIG4; FIGF; FIGLA; FIGN; FILIPI; FILIPIL; FIP1L1; FISL FIT I; FITM2; FJXI; FKBPID; FKBPII; FKBPI4; FKBPI5; FKBPIA; FKBPIB; FK8P2; FKBP3; FKBP4; FKBP5; FKBPB; FKBP7; FKBP8; FKBP9; FKBPL; FKRP; FKTN; FLADI:FLCN; FLG2; FLG; FLU; FLU;5 FLNA; FLNB; FLNC; FLOTI; FLDT2; FLRT2; FLRT3; FLTI: FLT3; FLT3LG; FLT4; FLVCRI; FLVCR2; FMNL FMN2; FMNLI; FNL2; FMNL3; FHOI: FMD2; FMD3; FMD4; FMOD; FMRI; FNI; FN3K; FN3KRP; FNBPI; FNDCI; FNDC3A; FNDC3B; FNDC4; FNTA; FNTB; FDCAD; FOLHI: FDLRl; FDLR2; FDLR3; FOPNL; FOSB; FDS; FDSLI: FDSL2; FOXA1; FOXA2; FOXA3; FOXBI; FOXCI: FOXC2; FOXDI; FOXEI; FOXFI; FOXF2; FOXGI; FOX; FOXII; FDXJI; FDXJ2; FOXKI; FOXK2; FOXLI; FOXL2; FOXMI; FOX; FOXN2; FOXN3; FOXO1; FOXO3; FOXO4; FOXOB; FOXPI: FOXP2; FOXP3; FOXP4; FOXQI; FOXRI; FOXR2; FOXREDY; FPGS; FPRI; FPR2; FPR3; SENTENCES; BROTHERS; FRAT2; FREMf: FREM2; FREM3; FRGI; FRG2;0 FRK; FRMD3; FRMD4A; FRMD4B; FRMD5; FRMDB; FRMD7; FRMPDI; FRMPD2; FRMPD4; FRRSIL; FRS2; FRS3; FRY; FRYL; FRZB; FSBP; FSCB; FSCNI; FSCN2; FSDI; FSDIL; FSD2; FSHB; FSHR; FSIPI; FST; FSTLI; FSTL3; FSTL4; FSTL5; FD; FTHI: FTL; FTMT; FTO; FTSJI; FTSJ2; FTSJ3; FUBPI: FUBP3; FUCAt: FOCA2; FUND: FUND2; FDRIN; FUS; PHOTO; MUST; FOOT; FDT2; FUT3; FUT4; FUT5; FUTG; FUT7; FUT8; FOT9; FUZ; FXN; FXRI; FXR2; FXYDI; FXYD2; FXYD3; FXYD5; FXYDB; KNOWLEDGE; FYCDI; FYN; FZDIO; FZDI; FZD2; FZD3; FZD4; FZD5; FZDB; FZD7; FZDB; FZD9; FZRI; GDS2; G2E3; G3BPI; GGPC2; GGPC3; GBPC; GBPD; GAA; GABI; GAB2; GAB3; GABARAP; GABARAPLI; 5GABARAPL2; GABBRI:GABBR2; GABPA; GABPBI; GABRAI; GABRA2; GABRA3; GABRA4; GABRA5; GABRAB; GABRBI; GABRB2; GABRB3; GABRE; GABRGI; GABRG2; GABRG3; GABRP; GABRQ; GABRRI; GABRR2; GADI; GAO2; GADD45B; GAOD45G; GADD 5GIPI; GADLI; GAGEID; GAGEI; GAK; GALC; GAL; GALKI; GALK2; GALN; GALNS; GALNTI2; GALNTI3; GALNTI4; GALNTI5; GALNTI8; GALNTI; GALNT2; GALNT3; GALNT4; GALNT5; GALNTB; GALNT7; GALNT8; GALNT9; GALNTLB; GALP; GALRI; GALR2; GALR3; GALT; GAMT; BANAB:GANG; GAN; GAP43; GAPDH; GAPDHS; GARI; GAREM; GARNL3; GARS; GART; GASI; GAS2; GAS2LI; GASB; GAS7; GAS8; GAST; GATAI: GATA2; GATA3; GATA4; GATA5; GATAB; GATADI: GATAO2A; GATAD2B; GATB; GATM; GBA2; GBA; GBAS; GBEI; GBFI; GBGTI; BBXf; GBX2; GCA; GCCI; GCDH; GCFC2; GCG; GCGR; GCHI; GCHFR; GC; GCK; GCKR; GCLC; GCMI; GCM2; GCNILI; GCNTI; GCNT2; GCNT3; GCNT7; GCOHI; GCSAM; GCSAML; GCSH; GDA; GDAPI; GOEI; GDFIQ; GDFII; GDFI5; GDFI: GDF2; GDF3; GDF5; GDFB; GDF7; GDF9; GDII; GDI2; GDNF; GDPD3; GDPO5; GEM; GEMIN2; GEMIN4; GE IN6; GENI: GET4; GFAP; GFER; GFIIB; GFII; GFMI; GFPTI; GFPT2; GFRAI; GFRA2; GFRA3; GFRA4; GGAI; GGA3; GGACT; GGCT: GGCX; GGH; GGNBP2: GGN; GGPSI; GGTI; GGT2; GGT5; GGTLCI; GHI; GH2; BHITM; GHRH; GHR; GHRHR; GHRL; GHSR; GID8; GIF; GIGYFI; GIGYF2; GIMAP5; GIMAP7; GIMAP8; GINI; GINSI; GINS2; GIPCI; GIPC3; GIP; GIPR; GITI; GIT2; GJAI; GJA3; GJA8; GJBI; GJB2; GJBB; GJCI; GJC2; GJC3; GJD2; GJB3; GK; GKNI: GKN2; GLA; GLBI; GLCCII; GLCE; GLDC; GLDN; GLEI; GLGI; GUI:GLI2; GLI3; GLIPRI; GLIPR2; GLIS2; BLISS; GLMN; GLDI: GLDD4; GLPIR; GLP2R; GLRAI; GLRA2; GLRA3; GLRB; GLRX2; GLRX3; GLRX5; GLRX; GLS2; GLS; GLTIDI; GLTBDI; GLT8DI; GLTSCRI; GLTSCR2; GLUDI:GLUD2; GLUL; GLYAT; GLYATL3; GLYCTK; GM2A; GMCLI; GMDS; GMFB; GMFG; GMIP; GML; GMNN: GMPPA; GMPPB; GMPR2; GMPR; GMPS; GNAII; GNAI2; GNAI3; GNAI4; GNAI5; GNAII; GNAI2; GNAL; GNADI; GNAQ: GNAS; GMATI: GNATS; GNAZ; GNBIL; GNB2LI; GNB3; GNB4; GNB5; GNE; GNGIB; GNGII; GNG2; GNG4; GNG7; GNG8; GNGTI; GNGT2; GNU; GNL3; GNL3L; GNLY; GNMT; GNPAT; GNPDAI; GNPDA2; GNPTAB; GNPTG; GNRHI; GNRH2; GNRHR; GNS; GOLGAI; GDLGA2; G0LGA3; GDLGA4; GDLGA5; GDLGA8B; GDLGBI; GDLMI; GBLPH3; GBLTIA; GBLTIB; GBN4L; GDPC; GDRAB; GDRASPI; GDRASP2; GDSRI; G0SR2; GDTI: GDT2; GPIBA; GPIBB; GP2; GP5; BPS; GP9; GPA33; GPAAI; GPALPPI; GPAM; GPANKI; GPAT2; GPATCHI; GPATCH2; GPATCH2L; GPATCH8; GPBARI; GPCI; GPC2; GPC3; GPC4; GPC5; GPCB; GPCPDI; GPDI; GPDIL; GPD2; GPERI; GPHA2; GPHN; GPIHBPI; GPI; GPKOW; GPLDI; GPMBA; GPMBB; GPNI; GPNMB; GPRIDI: GPRIIB; GPRI2; GPRI32; GPRI35; GPRI37C; GPRI39; GPR143; GPRI48; GPRI49; GPRI50; GPRI5I; GPRI52; GPR153; GPRI55; GPRI5B; GPRI58; GPRI5; GPRIBO; GPRIGI; GPRIB2; GPRI7I; GPRI74; GPRI7B; GPRI7B; GPRI7; GPRI80; GPRI82; GPRI83; GPRI9; GPRI: GPR2D; GPR22; GPR2B; GPR34; GPR35; GPR37; GPR37LI; GPR39; GPR4; GPR5D; GPR52; GPR55; GPRB5; GPRB8; GPRB; GPR75; GPR78; GPR83; GPR87; GPRASPI; GPRC5A; GPRC5B; GPRC5C; GPRC5D; GPRCBA; GPRINs: GPRIN2; GPRIN3; GPS2; GPSHI: GPSM2; GPSM3; GPT2; GPT; GPX5; GRAMOIB; GRAMB3; GRAMD4; GRAP2; GRAP; GRASP; UGLY; HUMPS4; GRB2; GRB7; GREBl; GO; GO2; THROATS; GRHL2; GRHPR; GRIAI; GRIA2; GRIA3; GRIA4; GRIDS; GRID2; GREEKS; GRIK2; GRIK4; GREEK5; Mites: GRIN2A; GRIN2B; GRIN2C; GRIN2D; GRIN3A; GRIN3B; GRINA; FLU; THE GREEKS; GRK4; GRK5; GRKB; GRK7; GRMI; GRM2; GRM3; GRM4; GRM5; GRMB; GRM7; GRMB; GRN; GRPELI; GRP; GRPR; GRSFI; GRXCRI; GRXCR2; GSC2; GSC; GSDMA; GSDMB; GSDMC; GSDMD; GSEI; GSGIL; GSK3A; GSK3B; GSN; GSPTI; GSPT2; GSR: GSS; GSTAI; GSTA2; GSTA4; GSTA5; GSTCD; GSTI: GSTM3; GSTDI: GSTD2; GSTPI; GSTTI:GSTT2B; GSTT2; GSTZI; GSXI: GSX2; GTDCI:GTF2AI; GTF2AIL; GTF2A2; GTF2EI; GTF2E2; GTF2FI; GTF2F2; GTFZHI:GTF2H2C2; GTF2H2C; GTF2H2; GTF2H3; GTF2H4; GTF2H5; GTF2I; GTF2IRDI; GTF2IRD2; GTF3A; GTF3CI; GTBPPI:GTPBP3; GTP8P4; GTSFI:GDCA1A; GUCAIB; GUCDI; GUCYIA2; GDCYIA3; GDCYIB3; GUCY2C; GUGY2D; GUCY2F; GDKI; GULPI; GDSB; GYGI; GYG2; GYLTLIB; GYPA; GYPB; GYPC; GYPE; GYSI; GYS2; GZFI: GZMA; GZMB; GZMH; GZMK; GZMM; HIFD; HIFX; H2AFJ; H2AFX; H2AFY2; H2AFY; H2AFZ; H2BFWT; H3F3B; HAAO; HABP2; HABP4; HACDI: HAC02; HACD4; HACEI; HACLI; HADHA; HADHB; HADH; HAGH; HAL; HAMP; HANOI; HAND2; HADI: HA02; HAPI; HAPLNI: HAPLN4; HARS2; HARS; HASf: HAS2; HAS3; HATI; HAVCRI; HAVCR2; HAXI; HBA2; HBB; HBO; HBEI: HBEGF; HBGI: HBG2; HBM; HBPI; HBQI: HBSIL; HBZ; HCARI; HCAR2; HCAR3; HCCS; HCFCI; HCFCZ; HCK; HCLSI; HCNI; HCN2; HCN3; HCN4; HCRT; HCRTRZ; HCST; HDACIO; HDACIt HDACI; HDACZ; HDAC3; HDAC4; HDAC5; HDACB; HDAC7; HDAC8; HDAC9; HDC; HDDCZ; HDGF; HDBFLI; HDGF P3; HDHDI; HDLBP; HEAT I; HEATR3; HEATR5B; HEATRB; HEBPI; HEBPZ; HECA; HECTDZ; HECTD4; HECWI: HECWZ; HEGI; HELLS; HELP; HEALTH; HELZZ; HELZ; HEMGN; HEPACAM; HEPH; LUCKY; HERCI; HERC2; HERC3; HERC5; HERCB; HERPUOI; HESI; HES2; HESB; HES7; HESXI; HEXA; HEXB; HEXDC; EXAMINATION; HEY; HEYZ; HFE; 5 HFMI; HGD; HGFAC; HGF; HGHI; HGS; HGSNAT; HHAT; HHATL; HHEX; HHIP; HHIPLI; SELECT; HHLAZ; HIATI; HIBAOH: HIBGH; HICl; HICZ; HIDI; HIFIA; HIFIAN; HIF3A; HIGDIA; HIGDIC; HIGDZA; HILPDA; HINFP; STOP; H1NT2; HIPI; HIPIR; HIPKIE; HIPKZ; HIPK3; THEY; HIRP3; HISTHIA; HISTIHIB; HISTHIC; HISTHIDE; HISTICS; HISTIHIT; HISTIHZAE; HISTIH2AH; HISTIHZBG; HISTIH2BH; HISTIH2BM; HISTIH3G; HISTIH4D; HIST3H3; HIVEPI; HIVEP2; HJURP; IPR; HK2; HK3; HKDCI; HLA-A; HLA-B; HLA-C; H LA-DMA; HLA-DMB; HLA-DOA; H LA-DOB; HLA-DPAI; HLA-DPBI; HLA-DQAI; HLA-DQA2; HLA-arrow: HLA-DOB2; HLA-DRA; HLA-DRBI; HLA-DRB3; HLA-DRB4; HLA-DRB5; HLA-E; HLA-F ID; HLA-G; HLCS; HLF; HLTF; HLX; HMI3; HMBOXI; HMBS; HMCNI; HMG2DA; HMG2OB; HMGAI: HMGA2; HMGBI; HMGBZ; HMGB3; HMGCR; HMGCSI; HMGNI; HMGN4; HMGN5; HMGXB3; HMGXB4; HMHAI; HMMR; HMOXI; HMDXZ; HMPIB; HMSD; HMXI; SKIRT; HNIL; HNFIA; HNFIB; HNF4A; HNF4G; HNT: HNRNPAO; HNRNPAI: HNRNPAZBI; HNRNPA3; HNRNPAB; HNRNPC; HNRNPD; HNRNPDL; HNRNPF; HNRNPHI; HNRNPHZ; HNRNPK; HNRNPL; HNRNPM; HNRNPR; HNRNPU; HNRNPULI: HDGAI; HOMER): HOMERZ; HOMERS: MAN; HODKZ; HODK3; HOPX; HORMAD2: HOXAIO; HOXAII; HOXAI3; HOXAI; HOXA2; HOXA3; HOXA4; HOXA5; HOXAB; HOXA7; HOXA9; HOXBI3; HOXBI; HOXB2; HOXB3; HOXB4; HOXB5; HOXB6; HOXB7; HOXB8; HOXB9; HOXC10; HOXCII; HOXCI2; HOXCI3; HOXC4; HOXC5; HOXCB; HOXC8; HOXCB; HOXDIO; HOXDII; HOXDI2; HOXDI3; HOXDI: HOXD3; HOXO4; HOXO8; HOXO9; HPIBP3; HPCALI; HPD; HPGD; HPGDS; HP; HPN; HPR; HPRTI; HPSI; HPS3; HPS4; HPS5; HPSB; HPSE2; HPSE; HPX; HRAS; HRASLS; HRC; HRG; HRHI; HRH2; HRH3; HRH4; HR; HRK; HRNR; HRSPIZ; HSIBP3; HS3STI; HS3STZ; HS3ST3AI; HS3ST3BI; HS3ST4; HS3ST5; HS3STB; HSBSTI; HSBSTZ; HSBST3; HSBPI; HSDIIBI; HSOIIBIL; HSDIIB2; HSDI7BI0; HSDI7BII; HSDI7BI2; HSDI7BI3; HSDI7BI4; HSDI7BI; HSDI7B2; HSDI7B3; HSDI7B4; HSDI7B6; HSDI7B7; HSDI7BB; HSD3BI; HSD3B7; HSDLI; HSDL2; HSFI; HSFZ; HSF4; HSF5; HSFY2; HSH2D; HSP90AAI: HSP90ABI; HSP90BI; HSPAI2A; HSPAI2B; HSPAI3; HSPAI4; HSPAIA; HSPAIL; HSPA2; HSPA4; HSPA4L; HSPA5; HSPAB; HSPA8; HSPA9; HSPBI: HSPB2; HSPB3; HSPBB; HSPB7; HSPB8; HSPB9; HSPBAPI; HSPBPI: HSPDI; HSPEI: HSPG2; HSPHI; HTATIPZ; HTNI; HTN3; HTRIA; HTRIB; HTRIE; HTRIF; HTRZA; HTRZB; HTRZC; HTR3A; HTR3B; HTR3C; HTR3D; HTR3E; HTR4; HTR5A; HTR7; HTRAI; HTRAZ; HTRA3; HTRA4; HTT; HUNK; HUSIB; HUSI; HUWEI; HVCNI; HYALI; HYALZ; HYAL3; HYAL4; HYDIN; HYKK; HYLSI; HYOUI: HYPM; IAPP; IARS2; IARS; IBA57;5 IBSP; IBTK; ICAI; ICAMI; ICAMZ; ICAM3; ICAM4; ICAM5; ICEI: ICE2; ICK; ICMT; ICOS; ICOSLG; IDI: ID2; 104; IDE; IDHI; IDH2; IDH3B; IDNK; IDOI; IDO2; IDS; IDUA; IER2; IER3; IER3IPI; IER5; IFFOI:IFFOZ; IFIIB; IFIZ7; IFI30: IFI35: IFI44; IFIHI; IFITI; IFITZ; IFIT3; IFIT5: IFITMI; IFITMZ; IFITM3; IFITM5; IFNAIO; IFNAI3; IFNAI4; IFNAIB; IFNAI7; IFNAI; IFNAZI; IFNA2; IFNA4; IFNA5; IFNAG; IFNA7; IFNA8; IFNARI: IFNAR2; IFNBI; IFNE; IFNG; IFNGRI; IFNGR2; IFNK; IFNLI:IFNL2; IFNL3; IFNWI; IFRDI; IFTI22; IFTI40; IFTI72; IFT27; IFT43; IFT57; IFT74; IFT80; IFT88; IGBPI; IGDCC3; IGFI; IGFIR; IGF2BPI; IGF2BP2; IGF2BP3; IGF2; IGF2R; IGFALS; IGFBPI; IGFBP2; IGFBP3; IGFBP4; IGFBP5; IGFBPB; IGFBP7; IGFBPLI; IGFLI; IGFLRI; IGHMBP2; IGJ; IGLLI; IGSFIO; IGSFII; IGSFI; IGSF5; IGSFB; IGSF8; IHH; IKB AP; IKBKB; IKBKE; IKBKG; IK; IKZFI; IKZF2; IKZF3; IKZF4; ILIO; ILIORA; ILIORB; ILII; ILIIRA; ILIZA: ILI2B; ILI2RBI; ILI3; ILI3RAI; ILI3RA2; ILI5: ILI5RA; ILIB; ILI7A; ILI7B; ILI7C; ILI7D: ILI7F; ILI7RA; ILI7RB; ILI7RC; ILI7RD; ILI7RE; ILI7REL; ILI8BP; ILI8: ILI8RI; ILI8RAP; ILI9; ILIA; ILIB; ILIFIO; ILIRI; ILIRZ: ILIRAP; ILIRAPLI: ILIRAPLZ; HANGING; IRIRLZ; ILIRN; ILZO; ILZDRA; ILZORB; ILLIZI; ILZIR; ILZZ; IL22RA2; ILZ3A; IL23R; IL24; IL25; IL2B; IL27; ILZ7RA; IL2: IL2RA; IL2RB; IL2RG; IL3I; IL3IRA; IL32; IL33; IL34; IL3BA; IL3BB; IL3GG; IL3GRN; IL37; IL3: IL3RA; IL4;5 IL4II; IL4R; IL5; IL5RA; ILB; ILBR; ILBST; IL7; IL7R; IL9: IL9R; ILDRI; ILDRZ; ILFZ; ILF3; ILK; IMMPIL; IMMPZL; IMMT; IMPS; IMPAI; IMPACT; IMPACT; IHPAD!; IMPDHI; IMPDH2; IMPBI; IMPG2; 1NADL: MOTHER; INCENP; INF2; INGI; ING2; ING3; ING4; ING5; 1NHA; INHBA; INHBB; INHBC; INHBE; INB8BB; INOSDD; IND8D; INPPI: INP4A; INPP4B; INPP5A; INPP5B; INPP5D; INPP5E; INPP5F; INPP5K; IMPLI; INSC: INS; INSIG; INSIG2; INS-IGF2; INSL3; INSL4; INSLB; INSMI: INSMI2; INSR; INSRR; INTSI2; INTSI; INTS2; INTS3; INTS4; INTS5; !NTSB; 1NTS7; INTS8; INTU; INVS; !PBKI; IP6K2; IPGK3; IPCEFI; IPM ; IPBtl; IPDI3; IPB7; IPB8; IPB9; IDCBI; IDCG; IQCH; IQCJ; IDCJ-SHIP: IflC; IDGAPI; IBGAP2; IQGAP3: IDSECI: IQSEC2; IQSEC3; IRAKIBPI; IRAQ; IRAK2; IRAK3; IRAQ4; IREB2; IRFI; IRF2BP2; IRF2BPL; IRF2; IRF3; IRF4; IRF5; IRFB; IRF7; IRF8; IRF9; IRGI: IRGM; IRSI; IRS2; IRS4; IRXI; IRX2; IRX3;IRX4; IRX5; ISCU; ISG2B; GROOM; NAME: ISM2; ISPD; ISTI; ISX; ISYNAI; ITCH; ITFGI; ITFG3; ITGAIO; ITGAII; ITGAI; ITGA2B; ITGA2; ITGA3; ITGA4; ITGA5; ITGAB; ITGA7; ITGA8; ITGA9; ITGAD; ITGAE; ITGAL; ITGAM; GIVE; ITGAX; ITGBIPPI; ITGBI; ITGB2; ITGB3; ITGB4; ITGB5; ITGBB; ITGB7; ITGB8; SOLD; BLACK; ITIH2: ITIH3; ITIH4; ITIH5: ITK; ITLNI: ITLN2; ITM2A; ITM2B; ITM2C; ITPA; ITPKt; ITPKA; ITPKC; ITPRI; ITPR2; ITPR3; ITSNI; ITSN2; IVD: IVL; IVNSIABP; IYD: ZUMBERS; JAOEI; JADE2; ANSWER: JAG2; JAGNI; JAK2; JAK3; JAK IPI: JAKMIP2; JAKMIP3; JAM2; JAM3; JARID2; JAZFI: JDP2; JMJOIC; JMJDB; JMY; JPH2; JPH3; JPH4; JR ; JS PI; JTB; JUNB; JUNO; JUP; KALI; KALRN; WHEN; CANCER2; CANCER4; CANCEL: CANCEL3; CARS; CAT2A; KAT2B; FOURTH5; ADDITIONAL; WRITING; FOUR7; FOUR8; CATNAI; CATNAL2; CATNBI; CAZALDI; TREASURY; KBTBDII: KBTBDI3; KBTBD8; KCMFI; KCHAI: KCNA4; KCNA5; KGNAB; KCNA7; KCNABI: KCNAB2; KCNAB3; CNBI; KCNB2; KCNCI; KCNC2; KCNC3; KCND2; KCNEi: KCNE2; KCNE3; KCNE4; KCNE5; KCNG3; KCNG4; CNHI; KCNH2; KCNH3; KCNH4; KCNH5;KCNHB; KCNH7; KCNH8; KCNIPI; KCNIP2; KCNIP3; KCNIP4; KCNJID; KCNJ1I; KCNJ12; KCNJI3; KCNJ14; KCNJI5; KCNJIB; KCNJI8; KCNJi; KCNJ2; KCNJ3; KCNJ4; KCNJ5; KCNJ6; KCNJB; KCNJ9; KCNKIB; KCNKI2; KCNKIB; KCNKI7; KCNKI8; CNKI; KCNK2; KCNK3; KCN 5; KGNKB; KCNK9; KCNMAI; KCNBI; KCNMB2; KCNMB3; KCNMB4; KCNNI; KCNN2; KCNN3; KCNN4; KCNOI; KCN02; KCN03; KCNQ5; KCNRG; KCNSI; KCNS3; KCNTI; KCNT2; CNUI; KCNVI; KCNV2; KCTDID; CTDII; KCTDI2; KCT0I3; KCTDI5; KCTDIB; KCTDI; KCTD2I; KCTD2; KCTD3; KCTDB; KCTD7; KCTD9; KDELCI: KDELRI; KDM2A; KDM2B; KDM3A; KDM3B; KDM4B; KDM4C; KDM5A; KDM5B; KDM5C; KDM5D; KDMBA; KDMBB; KDR; KOSR; KEAPI; KEL; KERA; KHDC3L; KHDRBS2; KHBRBS3; KHK; KHSRP; KIAADB2B; KIAAQD4D; KIAADIBD; KIAADIDI: KIAADIBB; KIAAD22G; KIAAD22BL; KIAAD232; KIAAD3I9; KIAAD3I9L; KIAAD355; KIAAD3BI; KIAAB58G; KIAAD825; KIAAD9D7; KIAAD922; KIAAID24; KIAAI033; KIAAII09; KIAAII47; KIAAIIBI; KIAAI2II; KIAAI2IIL; KIAAI2I7; KIAAI279; KIAAI324; KIAAI324L; KIAAI377; KIAAI45B; KIAAI4B2; KIAAI4B8; KIAAI524;KIAAI549; KIAAI55I; KIAAI598; KIAAI7I5; KIAAI8D4; KIAAI84I; KIAAI9I9; KIAA2D22; KIDINS220; KIFII; KIFI3A; KIFI4; KIFI5: KIFIBB; KIFI7; KIFI8A; KIFIA; KIFIC; KIF20A; KIF2BB; KIF2IA; KIF2IB; KIF22; KIF23; KIF24; KIF25; KIF2BA; KIF2BB; KIF2A; KIF2B; KIF2C; KIF3A; KIF3B; KIF3C; KIF4A; KIF4B; KIF5A; KIF5B; KIF5C; KIFB; KIF7; KIF9; KIFAP3; KIFCI; KIFC3; KIN; KIR2DLI; KIR2DL2; KIR2DL3; KIR2DL4; KIR2DL5A; KIR2DL5B; KIR2DSI; KIR2DS2; KIR2DS3; KIR2DS4; KIR3DLI; KIR3DL2; KIR3DL3; KIRREL2; KIRREL3; KIRREL; KISSI; ISSi; KIT; KITLG; KLB; KLCI; KLFID; KLFII: KLFI2; KLFI3; KLFI4; KLFI5; KLFIB; KLFI: KLF2; KLF3; KLF4; KLF5; KLFB; KLF7; KLF8; KLF9; KLHDCI; KLHDC2; KLHDC8A; KLHDC8B; KLHLIO; KLHLI2; KLHLI; KLHL2D; KLHL25; KLHL2B; KLHL29; KLHL2; KLHL3I; KLHL35; KLHL3; KLHL40; KLHL4I; KLHL42; KLHL5; KLHLB; KLHL7; KLHLB; KL; KLKIO; KLKII; KLKI2; KLKI3; KLKI4; KLKI5; KLKI; KLK2; KLK3; KLK4; KLK5; KLKB; KLK7; KLK8; KLK9; KLKBI; KLLN; KLRBI; KLRCI; KLRC2; KLRC4; KLRC4-KLRKI: KLRDI; KLRGI; KLRG2; KMD; KMT2A;KMT2B; KMT2C; KMT2D; KMT2E; KNGI; KNSTRN; KNTCl; KPNAI; KPNA2; KPNA3; KPNA4; KPNAB; KPNA7; KPNBI; KPRP; KPTN; CRASS; KRB0X4; CREAM1; KRITI; CREDIT; KRTI2; KRTI3; KRTI4; KRTI5; CRTIB; KRTI7; KRTI8; KRTI9; CRTI; KRT2D; KRT23; KRT2; KRT3I: KRT32; KRT34; KRT35; KRT3; KRT4; KRT5; KRTBA; KRTBB; KRTGC; KRT7I; KRT72; K T74; KRT75; KRT7B; KRT78; KRT7; KRT8D; KRT8I; KRT82; KRT83; KRT85; KRT8G; KRT8; KRT9; CHAPTER-I; KRTAP5-I; KRTAP5-9; KSRI: KSR2; TNI; KYNU; BODY; L2HGDH; L3MBTLI; L3MBTL2; L3MBTL3; L3MBTL4; LACCI; LACEI; LACRT; LACTB; LADY; LAG3; LAYERS: LAYERS2; LABBA; LAMAI; LAMA2; LAMA3; LAMA4; LAMA5; LAMB!: LAMB2; LAMB3; LAMB4; NO; LAMC2; LAMC3; LAMP1: LAMP2; LAMP3; LAMTORI; LAMTQR2; LAMT0R3; IANCLI: LANCL2; LAP3; LAPTM4B; LOOSE; LARP1; LARP4; LARPG; LARP7; LARS2; MONEY; GLASS; LASPI; LAT2; LAT; MILK; LATS2; LAXI; LAYH; LBH; LBP; LBR; LBXI: LBX2; LCA5; LCAT; LCEIC; LCE3A; LCE3B: LCE3C; LCE3D; LCE3E; LCE5A; LCK; LCLATI; LCMTI; LCNI:LCN2; LCOR; LCPt:LCP2; LCT; LDBI; LDB2; LDB3; LDHA; LDHALBB; LDHB; LDHC; LDHD; LDLRAD3; LDLRAD4; LDLR; LDDCI; LDDCIL; LEAP2; LECT1; LECT2; LEFI; LEFTYI; LEFTY2; LEKRI; LEMD2; LEMD3; LEDI; LEP; LEPRDTLI; LETMI; LETMDI; LEUTX; LFNG; LGALSI2; LGALSI3; LGALSI4; LGALSIB; LGALSI; LGALS2; LGALS3BP; LGALS3; LGALS4; LGALS7B; LGALS8; LGALSB; LGALSL; LGII; LGI2; LGI4; LGMN; LGR4; LGR5; LGRB; LGSN; LHB; LHCGR; LHFP; LHFPLI: LHFPL2; LHFPL3; LHFPL4; LHFPL5; LHPP; LHXI; LHX2; LHX3; LHX4; LHX5; LHXB-. LHX9; LIAS; LIE; LIFR; LIGI; LIG3; LIG4; LILRAI; LILRA2; LILRA3; LILRA4; LILRA5; LILRBI; LILRB2; LILRB3; LILRB4; LILRB5; LIM2; LIMAI: LIMCHI; LIMDI; LIND2; LIMKI; LI K2; LIMSI; LIMS2; LIN28B; LIN52; LIN7A; LIN7B; LIN7C; UNO; LINGDI; LING02: LINGB4; LINS; LIPA; LIPC; LIPE; LIPF; LIPG; LIPH; LIPI; LIPN; LIPTI:LIPT2; LITAF; LIXI; LLLGLI; LLGL2; LMANI; LMANIL: LMAN2L; LMBRI; LMBRDI; LMBRD2; L CDI; LMFi: LMLN; LMNA; LMNBI: LNB2; LMNTDI; LMOI; LMO2; LMO3; LMO7; LMODI; LDD3; LMTK2; LT3; LMXIA; LMXIB; LNPEP; LNXI; LNX2; LDCID02889BB; LOCIOIOBD32I; LDCID2723475; L0CI0272399B; L0CI02724I27; LDC1027245BD; LDCI02724770; LQCI027250IB; L0CID2725035; LDC400499; LOC400927-CSNKIE; LOCB45I77; LONPI; LONRFI: LOR; LOXHDI:LOX; LOXLI; LOXL2; LOXL3; LOXL4; LPA; LPARI; LPAR2; LPAR3; LPARB; LPCATI; LPCAT2; LPCAT3; LPCAT4; LPGATI; LPINI; LPIN2; LPL; LPD; LPP; LPPR2; LPPR4; LPXN; LRAT; LRBA; LRCHI; LRCH4; LRFN2; LRFN5; LRGI; LRGUK; LRIFI; LRIGI; LRIG3; LRITI; LRIT3; LRMP; LRPID; LRPI2; LRPIB; LRPI; LRP2BP; LRP2; LRP4; LRP5; LRPB; LRPAPI; LRPPRC; LRRI; LRRCI5; LRRCIBA; LRRCIBB; LRRCI7; LRRCI8; LRRCI; LRRC2D; LRRC2B; LRRC3D; LRRC32; LRRC37A; LRRC37B; LRRC39; LRRC49; LRRC4B; LRRC4C; LRRC4; LRRC52; LRRC59; LRRCBI; LRRCB3; LRRCB9; LRRCB; LRRC74A; LRRC7; LRRC8A; LRRC8C; LRRCCI; LRRFIPI; LRRFIP2; LRR I; LRRK2; LRRNI; LRRN2; LRRN3; LRRN4; LRRTMI; LRRTM2; LRRTM3; LRRTM4; LRSAMI; LRTMI; LRTDMT; LSAMP; LSMII:LSMI:LSM2; LSM3; LSM4; LS 5; LSMB; LSM7; LSPI; LSR; LSS: LSTI; LTA4H; LTA; LTB4R2; LTB4R: LTB; LTBPI; LTBP2; LTBP3; LTBP4; LTBR; LTC4S; LTF; LTK; L0C7L3; L0C7L; LUM; LURAPIL; LUZP4; LOZPB; LVRN; LXN; LYBD; LYBE; LYBG5B; LYBG5C; LYBGBC; LYBGBF; LYB; LY75-CD302; LY75; LY8B; LY9B; LY9; LYL1; LYN; LYNX; LYPDI; LYPD2; LYPD3; LYPD4; LYPD5; LYPOB; LYPD8; LYPLAI; LYPLALI; LYRM1: LYR 4; LYRM7; LYRM9; LYST; LYVEI; LYZ; LYZLI; LYZL2; LYZLB; LZTFLI: LZTRI: LZTSI; MBPR; WATER; WORDS2; MAB2IL2; MAB2IL3; NOT; MARCRDY; MACR0D2; MAOIL; MAD2LIBP; MAO2LI; MAD2L2; JUDGMENTS; LOUD; MAEA: MAEL; MAP; HEAVY; MAFB; MAFF; MAFG; MAF; MAFK; Mageius; MAGEAIII; MAGEAI2; MAGEAI; MAGEA2B; MAGEA3; MAGEA4; MAGEAB; MAGEA9; EVIL7; MAGEBI; MAGEB2; MAGEBB; MAGIC; MAGEC2; MAGEC3; GATE; MAGED2; MAGED4B; MAGED4; MAGEE; GENERATION; MAGEL2; MAG; MAGIC; MAGI2; MAGI3; MIGHTY; MAKIB; MAK; MAL; MALL; MALRDI; MALTI; MAMLI; MAML2; MAML3; MAMLOY: MANIAH; MANIBI; MAN2A: MAN2A2; MAN2BI; MAN2CI: FATHER; MANEA; MANF; WEIGHT; MAOA; MAOB; MAPIO; MAP; MAP; MAPILC3A; MAPILC3B2; MAPILC3B; MAP; MAP2; MAP2KI; MAP2K2; MAP2K3; MAP2K4; MAP2K5; MAP2 B; MAP2K7; MAP3KI0; MAP3KEY; MAP3K2; MAP3K3; MAP3K4; MAP3K9; MAP3KEY; MAP3K2; MAP3K3; MAP3K4; MAP3K5; MAP3KB; MAP3K7CL; MAP3K7; MAP3K8; MAP3K9; MAP4; MAP4KEY; MAP4K2; MAP4K3; MAP4K4; MAP4K5; MAPG; MAP7; MAP: MAPKIO; MAPKII; MAPKI2; MAPKI3; MAPKI4; MAPKI5; MAPKI; MAPK3; MAPKB; MAPK7; MAPKB; MAPK8IPI; MAPK8IP2; MAPK8IP3; MAPK9; MAPKAPI: MAPKAPK2; MAPKAPK3; MAPKBPI: MAPREI; MAPRE2; MAPRE3; MAPT: MARCI; MARC2: MARCHI; MARCH2-、MARCH5; MARCHB; MARCH7; MARCH8; MARCKS; MARCO; MARKI; MARK2; MARK3; MARK4; MARS2; MARS; MARVELDI; MARVELD2; MARVELD3; MASI; MASIL; MASPI; MAST2; MAST4; MASTL; MATIA; MAT2A; MAT2B; MATK; MATN2; MATN3; MATR3; MAU2; MAVS; MAX; MAZ; MB2IDI; MB2ID2; MBDI; MBD2; MBD3; MBD3L2; MBD4; MBD5; MBDB; MB; MBIP; MBL2; MBNLI; MBNL2: MBDATI; MB0AT2; MBDAT4; MBP; MBTDI; MBTPSI; MBTPS2; MCIR; MC2R; C3R; MC4R; MC5R; MCAM; MCAT; MCCCI; MCCCZ; MCCDI: MCC; MCEE; MCP2; NCF2L2; CF2L; MCFD2; MCHRI; MCHR2; MCIDAS; MCMIO; CM2: MCM3AP; MCM3; MCM4; MCM5; MCMG; CM7; CM8: MCM9; CMBP; MCDLNI; MC0LN3; MCPHI; MCRSI; MCTPI: MCTP2; MCTSI: MCG; MCURI; MDCI; DFIC; DFI; MDGAI; MDGA2; MDHI: MDH2; MD; MDMI: MDM2; MDM4; MEI: ME2; ME3; MEAI: MECDM; MECP2; MEDI2; MEDI2L; MEDI3; MEDI3L; MEDI4; MEDI5; MEOIG; MEDI7; MEDI9; MEDI; MED22; MED23; MED24; MED25: MED28; MED29; MED3D; MED4; MEDG; MED9; MEF2A; MEF2B; MEF2BNB-MEF2B; MEF2C; MEF2D; MEFV; MEGFIO; MEGFII; MEGF8; MEGF9; MEIl; MEISI; MEIS2; MELK; MEMDI; MENI; MEDXI; ME0X2; MEPIA; MEPE; MERTK; MESDCI; MESDC2; MESP2; MEST; METAPID; METAPI; METAP2; MET; METRN; METTLI3; METTLIG; METTLI7; METTLI8; METTLI; METTL2IA; METTL2IB; METTL2IC; METTL24; METTLE; METTL7A; METTL9; MEX3B; MEX3C; MEX3D; MFAP3; MFAP4; MFAP5; MFGE8; MFHASI: MFI2; MFNI; MFRP; MFSDII: MFSDI2; MFSDI: MFSOG; MFSD7; MFS08; MGA; MGAM; MGARP; MGATI; MGAT2; MGAT3; MGAT4A; MGAT4B; MGAT4C; MGAT5B; MGAT5; MGEA5; MGLL; MGMEI; MGMT; MGP; MGRNf: MGSTI; MGST2; MGST3; MIA2; MIA3; MIA; MIBI; MIB2; MICA; MICAL2; MICALCL; MICB; MICUI; MICU3; MIDI; MID2; MAINT: MER2; WED3; MIF; MILRI; MINA; MINKI; MINPPI; MIDX: MEPEP; MIP; MIPDLI; MIRI-IHG; MISI8BPI; MITF; MIXTURE; MKIG7; MCCS; MKLI; MKL2; MKLN1; MKNKI; MKNK2; MCRNI; MKRN3; MKSI; MLANA; MLCI; MLEC; MLFI; MLF2; MLHI: MLH3; MLKL; MLLTIO; MLLTI; MLLT3; MLLT4; MLLTG; MLN; MLNR; MLPH; MLST8; MLX; MLXIP; MLXIPL; MLYCD; MMAA; MMAB; MMADHC; MMD2; MMD; MME; MMELI; MMPID; MMPII; MMPI2; MMPI3; MMPI4; MMPI5; MMPIG; MMPI7; MMPI9; MMPI; MMP20; MMP2I; MMP24; MMP25; MMP2B: MMP28; MMP2; MMP3; MMP7; MMP8; MMP9; MMRNI; MMRN2; MMSI9: MMS22L; MNI; MNATI; MNDA; MNSI: MNT; MNXI; MDAPI; MDBIA; MDBIB; MDB2; M0B3B; M0B4; MOBP; MOCDS; MORE; M0CS2; MOGATI; M0GAT2; M0GAT3; MOG; MOGS; MDC; MONIA; MONIB; MDN2; MDRC3; MDRF4LI; PURE; M0RN2; MDRN5; MOS; MOVIOLI: MPCI; MPC2; MPDUt; MPDZ; RATE: MPG; MPHDSPHIO; MPHDSPHB; MPHDSPH8; MPHDSPH9; MPI; MPLKIP; MPD; MPPI; MPP2; MPP3: MPP5; MPP7; MPPEI; MPPED2; MPRIP; MPST; MPVI7; MPVI7L2; MPZ; MPZLI; MPZL2; MPZL3; MRI; MRAP2; MRAP; MRAS; MRCI: MRC2; MREIIA; MREG; MRFAPI: MRGBP; MRGPRF; MRGPRXI; MRGPRX3; MRGPRX4; MRU; MRI; MR0H2B: MRO; MRPLIO; MRPL1I; MRPLI3; MRPLI5; MRPLI7; MRPLI9; MRPLI; MRPL23; MRPL28; MRPL33; MRPL3B; MRPL3; MRPL4D; MRPL4I; MRPL44; MRPL4B; MRPL52; MRPL9; MRPSII; MRPSI2; MRPSIG; MRPSI8B; MRPS22; MRPS23; MRPS28; MRPS30; MRPS3I; MRPS33; MRPSB; MRPS7; MRPS9; MRRF; MRS2; MRVII; MS4AI2; MS4AI; MS4A2; MS4A3; MS4A4A; MS4AGA; MS4A8; MSANTD3-TMEFFI; MSC; MSGNI; MSH2; MSH3; MSH5; MSHB: MSII; MSI2; MSLN; MSMB; MSMOI; MSMP; MSN; MSRI; MSRA; MSRB2; MSRB3; MSTI; MSTIR; MSTN; MSTDI; MSXI; MSX2; MTIA; MTIB; MTIE: MTIF; MTIG; MTIH; MTIM; MTIX; MT2A; MT3; MT4; MTAI: MTA2; MTA3; MTAP; MTBP; MTCHI: MTC2; MTCLI; MTCPI; MTDH; MTERFI; MTFI: MTFMT; MTFPI; MTGI; MTHFDI; MTHFDIL; MTHFD2; MTHFR; MTHFS; MTIF2; MTIF3; MTL5; MTMI: MTMRII; MTMRI2; MTMRI4; MTMRI; MTMR2; MTMR3; MTMR4; MTMRG; MTMR7; MTMR8; MTMR9; MTNRIA; MTNRIB; MTDI; MTPAP; MTPN; MTRFI; MTR; MTRNR2L7; MTRR; MTSSI; MTTP; MTDRN; MTUSI; MTUS2; MTX; MTX2; MUCI2; MDCI3; MUCI5; MUCI7; MUCI9; MUCI; MUC2D; MUC2I; MUC22; MUC2; MUC3A; MUC4; M0C5AC; MDC5B; MUCB; MDC7; MUCLI: MUMI; MDRC; MUS8I; MUSK; MOT; MUTYH; MVBI2B; MVD; MVK; MVP; MXI; MX2; MXDI; MXD3; MXD4; MXII; MXRA5; MYADM; MYBBPIA; MYB; My furniture; MYBL2; MYBPCI; MYBPC2; MYBPC3; MYBPH; MYCBP2; MYCBPAP; MYC; MYCN; MYCTI; MYD88; MYDGF; MYEF2; MYEOV; MYF5; MYFG; MYHIO; MYHII; MYHI3; MYHI4; MYHI5; MYHI: MYH2; MYH3; MYH4; MYHG; MYH7B; MYH7; MYH8; MYH9; MYLI2A; MYLI2B; WASHING; MYL2; MYL3; MYL4; MYLG; MYL7; MYL9; MYLIP; MYLK2; MYLK3; MYLK; MYLPF; MYNN; MYDID; MYDI5A; MYOIG; MY0I8B; MYDIA; MYOIB; MYDIC; MYDID; MYDIE; MYDIF; MYD3A; MYD3B; MY05A; MY05B; MYD5C; MYDG; MYD7A; MYD7B; MYD9A; MYD9B; MYDCD; MYOC; MYODI; MYDF; MYDG; MYDMI; MY0M2; MYOT; MYOZI; MYDZ2; MYDZ3; MYPN; MYRF; MYRFL; MYRIP; MYTI; MYTIL; MYZAP; MZBI: MZFI; N4BPI; N4BP2LI; N4BP2L2; NAAID; NAAI5; NAAIB; NAA20; NAA25; NAA30; NAA35; NAA4D; NAA50; NAAGD; NAAA; Fenced2; NAALAOLI; NAALADL2; NASI: NAB2; NABPf; NABP2; NACA; NACCi; NACC2; NAOSYNI; NAEI; NAFI; NAGA; NAGK; NAGLU; NAGPA; NAGS; NAIP; NALCN; AND PT; NANOG; NANDSI; NANDS2; NAN0S3; NANS; PLEASE: PLEASE3; NAPIL4; NAPIL5; NAPA; NAPEPLD; NAPG; NAPRT; NAPSA; NARFL; NARR; AND S; NATID; NATI4; NATI; NAT2; NATB; NAT8B; NATS; NAT8L; NAVI: NAV2; NAV3; NBAS; MBEA; NBEALi; NBEAL2; NBN; NBPF3; NBRI; NCALD; NCAMI; NCAM2; NCAN; NCAPD2; NCAPD3; NCAPG2; NCAPG; NCBP2; NCEHI; NCFI; NCF2; NCF4; 5 NCKI: NCK2; NCKAPI; NCKAPIL; NCKAP5; NCKIPSD; NCL; NCOAI; NCDA2; NC0A3; NC0A4; NCDA5; NCDAB; NCDA7; NCDRI; NCDR2; NCRI; NCR2; NCR3; NCR3LGI; NCSI; NCSTN; NDC8D; NDEI; NDELI; NDFIPI; NDFIP2; NDNF; NDN; NDP; NDRGI; NDRG2; NDRG3; NDRG4; NDSTI; NDST2; NDST3; NDST4; NDUFAID; NDUFAII; NDUFAI2; NDUFAI3; NDUFAI; NDUFA2; NDUFA5; NDUFAB; NDUFAB; NDUFABI; NDUFAFI; NDUFAF2; NDUFAF3; NDUFAF4; NDUFAF5; NDUFAFB; NDUFBID; NDUFBII: NDUFB2; NDUFB3: NDUFB4; NDUFB5; NDUFBB; NDUFB8; NDUFBB; NDUFC2; NDUFSI; NDUFS2; NDUFS3; NDUFS4; NDUFSB; NDUFS7; NDUFSB; NDUFV1; NDUFV2; NDUFV3; NEB; NEBL; ID NECABI; NECAB3; NECAPI; NEDDI; NEDD4; NEDD4L; NEDD8; NEDD9; NEFH; NEFM; NEILI; NEIL2; NEIL3; NE IO; NEKII; NEK1: NEK2; NEK3; NEK4; NEKB; NE 7; NE 8; NEK9; NELFA; NELFB; NELFCD; NELFE; NELLI; NELL2; NEMF; NEDI; NES; NETI; NETOI; NETD2; NEW; NEU3; NEURLI; NEURL2; NEURODI; NELIR0D2; NEURDD4; NEURDDB; NEURDGI; NEURDG2; NEURDG3; NFI; NF2; NFAMI; NFASC; NFAT5; NFATCI: NFATC2; NFATC3; NFATC4; NFE2; NFE2LI:NFE2L2; NFE2L3; NFIA; NFIB; NFIC; NFIL3; NFIX; NFKBI; NFKB2; NFKBIA; NFKBIB; NFKBIE; NFKBILI; NFKBIZ; NFRKB; NFSI: NFUI; NFYA; NFYB; NFYC; NGB; NGDN; NGEF; NGF; NGFRAPI; NGFR; NGLYI; NHEJI; NHLHI; NHLRCI: 15 NHLRC3; NHP2; NHP2LI; NHS; NHSLI; NICNI; NIDI; NID2; NIF3LI; NIMIK; NIN; N1NJI: NINJ2; NINL; NIPAI; NIPA2; NIPAL3; NIPAL4; NIPBL; NIPSNAPI; NIPSNAP3B; NISCH; NITI; NIT2; NKAIN2; NKAIN3; NKAP; NKDI; NKD2; NKG7; NKIRASI; NKIRAS2; NKRF; NKTR; NKXI-I; NKXI-2; NKX2-I; NKX2-2; NKX2-3; NKX2-5; NKX2-B; NKX2-8; NKX3-I; NKXB-I; NKXB-2; NLEI; NLGNI; NLGN2; NLGN3; NLGN4X; NLGN4Y; NLK; NLN; NLRC3; NLRC4; NLRC5; NLRPIO; NLRPII; NLRPI2; NLRPI3; NLRPI4; NLRPI; NLRP2; NLRP3; NLRP4; NLRP5; NLRPB; NLRP7; NLRP8; NLRP9; NMB; NMBR; NMEI; NMEI-NME2; NME2; NME3; NME4; NME5; NMEB; NME7; NME8; NME9; NMI; N NATI; N NAT2; NMNAT3; NMS; NMTI; NMT2; NU; NMURI; NMUR2; NNAT; NNMT; NNT; NOAf; NOBI; NDBDX; NDC3L; NODI: NDD2; NODAL; NOG; NOLII: NDL3; NDL4; NOLB; NDL8; NOLCI; NDMI: ND OI; NOND; NOPID; NDPI4; NDPIB; N0P2; NDP5G; NDPB; NOSIAP; NOSI; NDS2; N0S3; NOSIP; NDSTRIN; NOTCHI; NOTCH2; NOTCH3; NOTCH4; NOTUM; NDVAI:NOVA2; NOV; NOX1; NOX3; NOX4; NOX5; NOXAI: NOXDI; NPAPI; NPAS2; NPAS3; NPAS4; NPAT; NPB; NPBWRI; NPCI; NPCILI:NPC2; NPDCI; NPEPLI; NPEPPS; NPFF; NPFFR2; NPHPI; NPHP3; NPHP4; NPHSI:NPHS2; NPL; NPL0C4; NPMI; NPM2; NPNT; NPPC; NPRI; NPR2; NPR3; NPRL2; NPRL3; NPS; NPSRI; NPTN; NPTXI; NPTX2; NPTXR; NPVF; NPW;5 NPYIR; NPY2R; NPY5R; NPY; NODI; NDD2; NROBI; NRIDI; NRID2; NRIH2; NRIH3; NRIH4; NRII2; NRII3; NR2CI: NR2C2; NRZEI; NR2E3; NR2FI; NR2F2; NR2FB; NR3CI; NR3C2; NR4AI; NR4A2; NR4A3; NR5AI: NR5A2; NRGAI; NRAP; NRARP; NRBPI; NRBP2; NRCAM; NRDI: NRDE2; NREP; NRFI; NRGI; NRG2; NRG3; NRG4; NRGN; NRIPI; NRIP2; NRK; NRL; NRM; NRNI: NRPI; NRP2; NRSNI; NRSN2; NRTN; NRXNI; NRXN2; NRXN3; NSA2; NSDI: NSDHL: NSF; NSFLIC; NSGI; NSMAF; NSMCE2; NSMF; NSRPI; NSUN2; NSUN3; NSUN5; NSUN7; NT5CIB; NT5CIB-RDHI4; NT5C2; NT5C3A; NT5C; NT5DCI; NT5DC3; NT5E; NT5M; TIME; NTF3; NTF4; RAIN; NTM; NTNI; NTN4; NTNGI: NTNG2;0 NTPCR; NTRKI; NTRK2; NTRK3; NTS; NTSRI; NTSR2; HUNGER; NUAK2; NUBI; SECOND; NUBP2; NUBPL; NUCBI; NUCB2; NUCKSI; NUDCD; NUDCD3; NUDC; NUDTIO; NUDTII; NUDTI5; NUDTI9; NUDTI: NUDT2I; NUDT2; NUDT3; NUDTB; NUDT7; NUF2; NUFIPI; NUFIP2; NUGGC; ONLY; NUMB; NUMBER53; WIFE55; NUP205; NUP2I0; NUP2I4; NUP35; NUP37; NUP43; NUP50; NUPB2; NUP85; NUP88; NUP93; NUPB8; NUPL2; NUPRI; NUSI; NUSAPI; NUTF2; NUTMI; NUTM2A; NUTM2B; NVL; NWDI; NXFI; NXF2B; NXF3; NXF5; NXN; NXNL1; NXNL2; NXPEI; NXPE2; NXPE4; NXPHI: NXPHI2; NXTI: NXT2; NYAP2; NYX; OARDI; OASI; OAS2; OAS3; OASL; OAT; OAZI; OAZ2; OBFCI; OBP2A;5 OBSCN; OBSLI; OC90; OCA2; OCIADI; OCIAD2; OCLM; OCLN; OCM2; OCM; OCRL; ODAM; ODCI; ODFI; ODF3B; ODF4; OFCCt OFDI; OGDH; OGDHL; OGFDDI; OGFR; OGGI; OGN; OGT; OIPS; OIT3; OLAI; OLFMI; OLFM2; OLFM4; OLFMLZB; OLI6I; OLIG2; OL1G3: OLRI; OMD; OMG; OMP; ONECUTI; ONECUT2; OPAI; OPA3; OPCML; OPHNI; OPNILW; OPNIMW2; OPNISW; OPN3; OPN4; OPN5; OPRKI; OPRU; OPRMI; OPTC; OPTN; ORIDA2; ORIOA4; ORIOCI; ORIOJI; ORIOJ3; ORIOJ5; ORIOKI; ORIOK2; ORIOR2; ORIOT2; ORIOXI; ORIOZI; ORIIAI; ORI2D2; ORI2D3; ORI3C3; ORI3C4; ORI3FI: ORI3GI; ORI3JI; ORI4JI; ORIAI; ORICI; ORID2; ORIEI; ORIE2; ORIJ2; ORIKI; ORIL8; ORIMI: ORINI; ORIN2; OR2A25; OR2AGI; OR2AK2; OR2AT4; OR2B2; OR2B3; OR2BB; OR2CI; OR2F2; OR2G2; OR2G3; OR2H2; OR2J2; OR2J3; OR2L2; OR2M3; OR2M4; OR2M7; OR2S2; OR2TID; OR2TI2; OR2TI; OR2T2; OR2T33; OR2T4; OR2T5; OR2W1; ORZYI; OR2ZI; OR3AI; OR4AI5; OR4CI2; OR4CI3; OR4CB; OR4DI0; OR4KI3; OR4P4; OR4S2; OR5IA2; OR5IA7; OR5IEI; OR5IE2; OR5IF2; OR5IVI; OR52B2: OR52B4; OR52DI; OR52EG; OR52II; OR52I2; OR52KI; OR52K2; OR5ZMI: OR5DI8; OR5H2; OR5HB; OR5KI; OR5K2; OR5VI; ORGBI; OR6B2; ORBCI: ORBFI; ORGK2; ORGK3; ORBK6; ORBNI; OR6N2; ORBXI: ORGYI; OR7CI; OR7D2; OR7EZ4; OR8SI: ORBK2; OR9Q2; ORAM; ORAI3; ORAOVI; ORC3; ORC4; ORC5; ORCB; ORMI: ORM2; ORMDL3: OS3; OSBP2; OSBP; OSBPLID; OSBPLII; OSBPLIA; OSBPL2; OSBPL3; OSBPL5; OSBPLB; OSBPL8; OSBPLB; OSCAR; OSERI: OSGEP; OSGINI; OSM; OSMR; OSRI; OSR2; OSTFI; OSTMI; OTC; OTDA; OTOF; OTDG; OTDGL; OTOLI; OTOPI; OTOR; OTP; OTUBI; OTUDI; OTUD4; OTUD7A; OTUD7B; OTULIN; OTXI; OTX2; OVCA2; OVDLI; OVDL2; OXAIL; OXCTI; OXERY; OXGRI; OXRI; OXSRI; OXT; OXTR; P2RXI; P2RX2; P2RX3; P2RX4; P2RX5: P2RXG; P2RX7; P2RYIII; P2RYI2; P2RYI3; P2RYI4; P2RYI; P2RY2; P2RY4; P2RYB; P2RY8; P3H2; P3H3; P3H4; P4HAI; P4HA2; P4HB; P4HTM; PA2G4; PABPCI; PA8PC3; 15 PABPC4L; PABPNI; PACRG; PACSI; PACS2; PACSINI; PACSIN2; PADI4; PAEP; PAFI; PAFAHIBI; PAFAHIB2; PAFAH2; MORNING: MORNING; PAGE4; PAGE5; PAGE; PAH; PAICS; PIPES; PAIP2; PLEASE; PACKAGING; PAK2; PAK3; PAK4; PAKB; PAK7; PALB2; FALSE; PALLD; PALM2-AKAP2; PAMIB; PAM; PAMRI; PAN2; PANTS; BANKS; PANK2; PANXI; PANX2; PAOX; PAP07; PAPL; PAPOLA; PAPOLG; PAPPA2; DAD; PAPSSI; PAPSS2; PA0R3; PAQR5; PADR7; PARD3B; PARD3; CHANGE; PARDGB; PARG; PARK2; PARL; AMONG; PARN; PARPI2; PARPI4; PARPI5; PARPI; PARP2; PARP3; PARP4; PARPB; PARPB; PARPBP; PARS2; PARVA; PARVB; PARVG; PASDI; PASK; PATEI; PATZI; PAWR; PAXI:D PAX2: PAX3; PAX4; PAX5; PAXB; PAX8; PAXB; PAXIPI; PBK; PBLD; PBOVI: PBRMI; PBXI; PBX2; PBX3; PBX4; PCBDI: PCBD2; PCBPI; PCBP2; PCBP3; PCBP4; PCCA; PCCB; PCDHID; PCDHIIX; PCDHIIY; PC0HI5; PCDHI7; PCDHI8; PCDHI9; PCDHI: PCDH2D; PCDH7; PCDH8; PCDHB; PCDHAI; PCDHA4; PCDHAB; PCDHBI: PCDHB2; PCDHB3; PCDHB8; PCDHGAII; PCDHGA3; PCDHGB4; PCDHGBB; PCDHGC3; PCEDIB; PCFII; PCGFI: PCGF2; PCGF3; PCGFB; PC; PCID2; PCKI; PCK2; PCLO; PCMI: PCMTI: PCMTDI; PCNA; PCNT; PCNXL2; PCNXL4; PC0LCE2; PCDLCE; PCP2; PCP4; PCSKI; PCSKIN; PCSK2; PCSK4; PCSK5; PCSKB; PCSK7; PCTP; PCYTIA; PCYTIB; PDAPI;5 POCDIO; PDCDI; PDCDILG2; PDCD2; PDCD4; PDCD5; PDCD6; PDCOGIP; PDCD7; PDC; PDCL2; PDCL3; PDEIDA; PDEIIA; PDEI2; PDEIA; PDEIB; PDEIC; PDE2A; PDE3A; PDE3B; PDE4A; PDE4D; PDE5A; PDEBA; PDEBB; PDEGC; PDEBD; PDEGG; PDEGH; PDE7A; PDE7B: PDE8A; PDE8B; PDE9A; PDF; PDGFA; POGFB; POGFC; PDGFD; PDGFRA; PDGFRB; PDGFRL; PDHAI; PDHB; PDHX; PDIA2; PDIA3; PDIA4; PDIA5; PDIAB; PDKI; PDK2; PDK3; PDK4; PDLIMI; PDLIM2; PDLIM3; PDLIM4; PDLIM5; PDLIM7; PDPI: PDP2; PDPKI; PDPR; PDRGI; PDS5A; PDS5B; PDSSI; PDSS2; PDXI; PDXDCI; PDXK; PDXP; PDYN; PDZD2; PDZD4; PDZD7; PDZD8: PDZKI; PDZRN3; PDZRN4; PEAI5; PEAKI; PEARI; PEBPI; PEBP4; PECAMI; PECR; PEGID; PEG3; PELII: PELI2; PELPI; PEMT; PENK; PEPD; PERI; PER2; PER3; PERM!: PERP; PESI; PETIOD; PETII7; PEXIIA; PEXI2; PEXI3; PEXI4; PEXIG; PEXI9; PEXI; PEX2B; PEX2; PEX3; PEX5; PEX5L; PEXB; PEX7; PF4; PF4VI; PFDN4; PFDN5; PFDNB; PFKFBI; PFKFB2; PFKFB3; PFKFB4; PFKL; PFKM; PFKP; PFNI; PFN2; PGA3; PGA4; PGA5; PGA I; PGAM2; PGAM4; PGAPI; PGAP2; PGAP3; PGBDI; PGBD5; PGC; PGD; PGF; PGGTIB; PGKI; PGK2; PGLS; PGLYRPI; PGLYRP2; PGLYRP3; PGLYRP4; PGM3; PGPEPI; PGP; PGR; PGRMCI; PGRMC2; PHACTRI; PHACTR2; PHACTR3; PHB2; PHB; PHCI; PHC2; PHC3; PHEX; PHFIO; PHFII; PHFI2; PHFI9; PHFI;5 PHF20; PHF2IA; PHF23; PHF2; PHF3; PHF5A; PHFB; PHF8; PHGDH; PHIP; PHKAI; PHKA2; PCB; PHCGI; PHCG2; PHLDAI; PHLDA2; PHLDA3; PHLDBI: PHLPPI; PHLPP2; PH0X2A; PH0X2B; PHPTI; PHRFI; PHTFf; PHTF2; PHYH; PHYHIP; PHYKPL; PII5; PUB; PI3; PI4 2A; PI4 2B; PI4KA; PI4 B; PIASt; PIAS2; PIAS4; PIBFI; PICALM; SMALL; ASK; PIDDI; FOOTSTEPS; PIECE2; PIFI; FIFO; PIGA: PIGF; PIGG; PIGL; PIGM; PIGN; PIGD; PIGP; PIGB; PIGR; PIGT; PIGU; PIGW: PIGY; PIHIDI; PIK3API; PIK3C2A; PI 3C2B; PIK3C2G; PI 3C3; PIK3CA; PIK3CB; PIK3CD; PIK3CG; PIK3IPI; PIK3R1: PI 3R2; PIK3R3; PIK3R4; PI 3R5; PIKFYVE; PILLAR; MEASUREMENT; PIM2; PIM3; PIN: PIN4; PINX: PIP4K2A; PIP4K2B; PIP4K2C; PIP5KIA; PIP5 IB; PIP5 IC; PIP5CLI; PIP; PIPOX; PIR; PISD; PITPNA; CHILDREN; PITPNM3: PITRMI; PITXl; PITX2; PITX3; PIWILI; PIWIL2; CONSTITUTION3; CONSTITUTION4; PJAI; PJA2; P DI; PKDILI; PKDIL2; PKDIL3; PKD2; PKD2LI; PKDCC; PKDREJ; PKHDI; PKIA; GDP; PKLR; PKM; PKMYTI; PKNI; PKN2; PKN3; PKNOX; PKN0X2; PKPI; PKP2; PKP3; PKP4; PLA1A; PLA2GIO; PLA2GI2A; PLA2GI2B; PLA2GI5; PLA2GIB; PLA2GIB; PLA2G3; PLA2G4A; PLA2G4B; PLA2G4C; PLA2G4D: PLA2G5; PLA2GB; PLA2G7; PLA2RI; PLAA; PLACE; PLAC8; PLAGIARISM; PLAGLI; PLAGL2; PLOT; PLAU; CRYING; PLBh PLBDI; PLCBI; PLCB2; PLCB3; PLCB4; PLCDI: PLCD3; PLCD4; PLCEI; PLCGI; PLCG2; PLCHI; PLCLI; PLCL2; PLCXD2; PLCXD3; PLCZI; PLDI; PLD2; PLD3; PLD4; PLD5; PLEC; PLEK2; PLEKHAI; PLEKHA2; PLEKHA5; PLEKHAB; PLEKHA7; PLEKHBI; WRONG; PLEKHFI; PLEKHF2; PLEKHGI; PLEKHG2; PLEKHG3; PLEKHG4; PLEKHGB; PLEKHH2; REPLACEMENT; WRONG; PLEKH02; PLACES; PLG; PLGLB2; PLINI; PLIN2; PLIN3; PLIN4; PLIN5; PLKi: PLK2; PLC4; PLC5; PLLP; NLP; PL0D2; PLPI; PLP2; PLRGI; PLSI; PLS3; PLSCRI; PLSCR3; PLSCR4; PLSCR5; PLTP; PLVAP; PLXDCI; PLXDC2; PLXNAI; PLXNA2; PLXNA3; PLXNA4; PLXNB1; PLXNB3; PLXNCI; PLXNDI; PM2DDI; PMAIPI: PMCH; PMEL; PMEPAI; PMFI-BGLAP; PMFI; PML; PMMI; PMM2; PMP22; PMPCA; PMPCB; PMSI; PMS2; PMVK; PNCK; PNKD; PNKP; PNLDCI; PNLIP; PNLIPRP2; PNMAI; PNMA2; PNMT; PNN; PNDI; PNOC; PNP; PNPLA1; PNPLA2; PNPLA3; PNPLA4; PNPLA5; PNPLAG; PNPLA8; PNPO; PNPTI; PNRCf; POCIA; POCIB; POC5; PDDXL; POFIB; POFUTI; POFUT2; POGK; POGLUTI; POLAI; POLA2; POLB; PDLOI; POLD2; POLD3; PDLD4; POLDIP3; POLE2; POLE3; POLE4; POLE; POLG2; POLG; POLH; POLL POLK; POLL; POLM; POLN; POLO; POLRIA; POLRIB; POLRIC; POLRID; POLR2A; POLR2B; POLR2C; POLR2D; POLR2E; POLR2F; POLR2G; POLR2H; POLR2J; POLR2K; POLR2M; POLR3A; POLR3B; POLR3E; POLR3K; POLRMT; POMI2I; POMC; POMGNTI; POMGNT2; POMK; POMP; POMTI; POMT2; POMZP3; PONI: PON2; PONS; POP1; POP4; POPDC3; PORCN; POR; POSTN; POTI; POTED; POTEF; POTEG; POTEH; POTEM; POUIFI; POO2AFI; POU2FI; POU2F2; POU2F3; POU3F2; POU3F3; POU3F4; POU4FI; POU4F2; POO4F3; POU5FIB; POU5FI: POUBFI: POOBF2; PPAI; PPA2; PPAP2A; PPAP2C; PPAPDCIB; PPAPDC2; PPAPDC3; PPARA; PPARD; PPARGCIA; PPARGCIB; PPARG; PPAT; PPBP; PPCDC; PPEFI; PPEF2; PPFIAI: PPFIA2; PPFIA4; PPFIBPI: PPFIBP2; PPIA; PPIB; PPIC; PPID; PPIF; PPIG; PPILI; PPIL2; PPIL3; PPIP5I; PPL; PPMIA; PPMIB; PPMID; PPMIE; PPMIF; PPMIG; PPMIH; PPMIK; PPMIL; PPMIM; PPMEI; PPOX; PPPICA; PPPICC; PPPIRIO; PPPIRII; PPPIRI2A; PPPIRI2B; PPPIRI2C; PPPIRI3B; PPPIRI3L; PPPIRI4A; PPPIRI4B; PPPIRI4C; PPPIRI5A; PPPIRI5B; PPPIRI7; PPPIRI8; PPPIRIA; PPPIRIB; PPPIR2; PPPIR3A; PPPIR3B; PPPIR3C; PPPIR42; PPPIR7; PPPIR9A; PPP2CA; PPP2CB; PPP2RIA: PPP2RIB; PPP2R2A; PPP2R2B; PPP2R2C; PPP2R3A; PPP2R3B; PPP2R4; PPP2R5A; PPP2R5B; PPP2R5C; PPP2R5D; PPP2R5E; PPP3CA; PPP3CB; PPP3CC; PPP3RI; PPP3R2; PPP4C; PPP4RI; PPP5C; PPPBC; PPPBR2; PPPBR3; PPRCI; PPT2; PPY; PQBPI: P0LC3; WORK; WORK2; SNAPPERS; PRAF2; PRAMI; STRAIGHT; PRAPI; PRBI; PRB2; PRB3; PRB4; PRCI; PRCC; PRCD; FRCP; FARDMIO; PRDMII; PRDMI3; PRDMI4; FART; PRDM4; PRDM5; PRDMB; PRDM7; PRDM8; PRDM9; PROX2; PRDX3; PRDX4; PRDX5; PRDXG; PREB; PRELP; PREP; SWITCH; PREXI; PREX2; PRFI; PRG2; PRG4; PRHI; PRH2; PRICKLEY; PRICKLE2; PRICKLE4; PRIM1; PRIMAL PRIMPOL; PR AAI; PRAKABI; SNAPPER; PRKACB; PRKACG; PRKABI: PRKAG2; PRKAG3; PRAKARIA; PRKARIB; PRKAR2A; PRKAR2B; PRKCA; PRKCB; PRKCDBP; PRKCD; PRKCE; PRKCG; PRKCH; PRKCI; PRKCQ; PRKCSH; PRKCZ; PRKDI; PRKD3; SPRING; PRKGI; PRKG2; PRKRA; PRKRIR; PRKX; PRLH; PRL; PRLHR; PRLR; PRMI: PRM2; PRM3; PRMTI; PRMT2; PRMT3; PRMT5; PRMT8; PRND; PRNP; PROC; PROCR; PRODH; PR0K2; PRBKRI: PR0KR2; PROLI; PROMI; PR0M2; PROSI PROPL; PROSERIES; PRBXI: PROZ; PRPFI9; PRPF3I: PRPF3BB; PRPF3; PRPF40A; PRPF4B; PRPF4; PRPFFJ; PRPF8; PRPH2; PRPH; PRPSI; PRPSILI; PRPS2; PRPSAPI; PRPSAP2; PRRII; PRRI3; PRRI5; PRRIB; PRR34; PRR3; PRR5; PRR9; PRRCI: PRRC2A; PRRC2C; PRRG4; PRRTI; PRRT2; PRRXI; PRRX2; PRSSI2; PRSSI6; PRSSI: PRSS2I; PRSS22; PRSS23; PRSS27; PRSS2; PRSS33; PRSS35; PRSS3; PRSS5D; PRSS53; PRSS55; PRSS57; PRSS58; PRSS8; PRTFDCI; PRTG; P TN3; PRUNE2; PRUNE; PRX; PRY; PSAP; PSATI; PSCA; PSD3; PSD4; PSD; PSENI: PSEN2; PSENEN; PSBI; PSB2; PSG5; PSGB; PSG8; PSG9; PSIPI; 5 PSKHI; PSMAI; PSMA2; PSMA3; PSMA4; PSMAB; PSMA7; PSMBID; PSMBI; PSMB4; PSMB5; PSMBB; PSMB7; PSMBB; PSMB9; PSMCI; PSMC2; PSMC3; PSMC3IP; PSMC4; PSMC5; PSMCB; PSMDIO; PSMDI2; PSMDI3; PSMDI4; PSMDI: PSMD2: PSMD3; PSMD4; PSMDB; PSMD7; PSMD8; PSMDB; PSMEI; PSME2; PSME3; PSME4; PSMFI; PSMBI; PSMG2; PSMG3; PSORSIGI; PS0RSIC2; PSPCI; PSPH; PSPN; PSTPIPI; PSTPIP2; PTBPI; PTBP2; PTCDI; PTCHI: PTCHDI; PTCHD4; PTCRA; PTDSSI; PTEN; PTER; PTFIA; PTGDR2; PTGDR; PTGDS; PTGERI; PTGER2; PTGER3; PTGER4; PTGES2; PTGES3; PTGES; PTGIR; PTGIS; PTG i; PTGSI; PTGS2; PTHIR; PTH2; PTH2R; PTH; PTHLH; ID PTK2B; PTK2; PTKB; PTK7; PTMA; PTMS; PTN; PTDVI; PTP4AI; PTP4A3; PTPMTI; PTPNII; PTPNI2; PTPNI3; PTPNI4; PTPNI8; PTPNI; PTPN2I; PTPN22; PTPN23; PTPN2; PTPN3; PTPN4; PTPN5; PTPNB; PTPN7; PTPN9; PTPRA; PTPRB; PTPRCAP; PTPRD; PTPRE; PTPRG; PTPRH; PTPRJ; PTPRK; PTPRM; PTPRN2; PTPRN; PTPRD; PTPRfl; PTPRR; PTPRS; PTPRT; PTPRZI; PTRF; PTRHI; PTRH2; PTRHDI; PTS; PTTGI: PTTGIIP; PHG2; PTX3; PUFBD; PDM2; PURA; PURB; PUSID; PUS1; PVALB; PVR; PVRLI; PVRL2; PVRL3; PVRL4; PWP2; PWWP2B; PXDN; PXDNL; PXK; PXMP2; PXN; PXTI; PYCARD; PYCRI; PYDCI; PYDC2; PYGB; PYGL; PYGM; PYGDI; PYGD2; PYHINI; PYROXDI; PYY; PZP; OARS; DDPR; OKI; QPCT; QPCTL; OPRT; QRFP; ORFPR; ORSLI; OSDXI; QSOX2; QTRTI; R3HCCI; R3HCCIL; R3HDMI; R3HDML; RABIIA; RABI1B; RABIIFIPI; RABIIFIP2; RABIIFIP3; RABIIFIP4; RABIIFIP5; RABI2; RABI4; RABI5; RABI8; RABIA; RABIB; RAB20; RAB2I; RAB22A; RAB23; RAB24; RAB25; RAB27A; RAB27B; RAB28; RAB2B; RAB2A; RAB3I; RAB32; RAB33B; RAB34; RAB35; RAB3B; RAB37; RAB38; RAB39A; RAB39B; RAB3A; RA83D; RAB3GAPI; RAB3GAP2; RAB3ILI; RAB3IP; RAB40AL; RAB4DB; RAB4DC; RAB4A; RAB4B; RAB5A; RAB5B; RAB5C; RABGA; RABBB; RABBC; RAB7A; RAB8A; RAB8B; RAB9A; RABACI; RABEPI; RABEP2; RABEPK; RABGAPIL; RABGEFI; RABIF; RABLB; RACI; RAC2; RAC3; RACGAPI; RADI7; RADI8; RADI; RAD2I; RAD2ILI; RAD23A; RAD23B; RAD50; RAD5IAPI: RAD5IB; RAD5IC; RAD5ID; RA05I: RAD52; RAD54B; RAD9A; RAD9B; RAEI; RAETIE; RAETIL; RAFI; RAGI; RAG2; RAII4; RAIL RAI2; RALA; RALB; RALBPI; RALGAPAI: RALGAPA2; RALGAPB; RALGDS; RALGPSL RALY; RALYL; RAMP RAMP2; RAMP3; RANBPIO; RANBPI7; RANBPI; RANBP2; RANBP3; RANBP3L; RANBPB; RANBP9; RANGAP RANGRF; RAN; RAPIB; RAPIGAP2; RAPIGDSI; RAP2A; RAP2B; RAPGEFI; RAPGEF2; RAPGEF3; RAPGEF4; RAPGEF5; RAPH RAPSN; RARA; RARB; RARG; RARRESL RARRES2; RARRES3; RARS2; RARS;5 RASAI; RASA2; RASALL RASAL2; RASDL RASD2; RASEF; RASGEFIA; RASGEFIC; RASBRFI; RASGRF2; RASGRPI; RASGRP2; RASGRP3; RASGRP4; RASIPI; RASLIOA; RASLIDB; RASLIIA; RASLIIB; RASLI2; RASSF RASSF2; RASSF3; RASSF4; RASSF5; RASSFB; RASSF7; RASSF8; RAX2; RAX; RBICCI; RBI; RBAK; RBBP5; RBBPB; RBBP7; RBBP8; RBBP9; RBCKL RBFBXI; RBFDX2; RBFDX3; RBLI; RBL2; RBMID; RBMI2; RBMI4; RBMI4-RBM4; RBMI5; RBMI7; RBM2D; RBM25; RBM2B; RBM27; RBM28; RBM38; RBM39; RBM3; RBM45; RBM4B; RBM47; RBM4; RBM5; RBMB; RBM7; RBMS RBMS2; RBMS3; RBMX2; RBMX; RBMXL2; RBMYIAL RBPI; RBP2; RBP3; RBP4; RBPJ; RBPMS2; RBSN; RBXI; RC3HI; RCANI; RCAN2; RCBTBI: RCBTB2; RCHYI; RCLL RCN RCN2; RCBRI; RCSDL RCVRN; RD3; RDHIO; RDHII; RDHI2; RDHI4; RDHIB; RDH5; RDH8; RD I; RDX; REC8; RECK; REC0L5; RECOL; REEPI; REEP2; REEP3; REEP5; REEPB; DIRECTORY; REGIB; REG3A; RELA; RELB; REL; RELN; REM RENBP; REN; REPSL REPS2; RERG; RERGL; REST; RET; RETN; RETNLB; RETSAT: REVI; REV3L; REXDI; REXD2; REX04; RFCI; RFC2; RFC3; RFC4; RFC5; RFFL; RFK; RFPL RFTI; RFTNL RFTN2; RFWD2; RFWD3; RFX RFX2; RFX3; RFX4; RFX5; RFXG; RFX8; RFXANK; RFXAP; RGCC; RBLI: RGL2; RGL4; RGMA; RGMB; RGN; GDPR2; RGR; RGSID; RGSII; RGSI2;5 RGSI3; RGSI4; RGSIB; RGSI7; RGSI8; RGSI9; RGSI; RGS20; RGS2I; RGS22; RGS2; RGS3; RGS4; RGS5; RGSB; RGS7BP; RGS7; RGS8; RBS9BP; RBS9; RGSLI; RHAB; RHBD02; RHBDD3; RHBDFI: RHBDF2; RHBDLI: RHBDL2; RHCE; RHCG; RHEB; RHEBLI: RHNDI: RHOB; RHBBTBI; RHDBTB2; RH08TB3; RHOD; RHDF; RHOG; RHDH; RHD; RHDJ; RHDll: RHDTI; RHDU; RHOV; RHOXFI: RHDXF2: HPNI: RHPN2; RIBC2; RICI; RIC3: RICTOR; RIFI; RILP:RILPLI:RIMBP2; RIMBP3C:RIMSI:RIMS2; RIMS4:RINI; RIN2; RIN3; INB1; RINTI; RIDKI; RI0K2; RI0K3; RIP I; RIP 2; RIP 3; RIP4: RIPPLY2; RITI; RIT2: RITAI: RLBPI: RLF; RUM; RLNI: RLN2; RLN3; RMDNI; RDN2; RMDN3; RMII; RMI2; RHNDI; RNASEII; RNASEI2; RNASEI3:RNASEI:RNASE2; RNASE3; RNASE4; RNASEB; RNASE7; RNASE8; RNASEB; RNASEHI; RNASEH2A; RNASEH2B; RNASEH2C; RNASEK; RNASEL; RNASET2; RNDI; RND3; RNFI03-CHMP3; RNFI03; RNFIII; NF112: RNFII4; RNFI23; RNFI25; RNFI28; RNFI30; RNFI35: RNFI38; RNFI39; RNFI44A; RNFI44B; RNFI4B; RNFI49; RNFI4; RNFI50; RNFI52; RNFI57; RNFIG7; RNFIB8; RNFI7D; RNFI80; RNFI82: RNFI9A; RNF2D7; RNF20; RNF2I3; RNF2I4; RNF2IB; RNF24; RNF2; RNF3I: RNF34; RNF39; RNF40; RNF4I; RNF43; RNF44; RNF4; RNF5; RNFB; RNF7; RNFS; RNGTT; RNHI; RNLS; RNMT; RNPEP; RNPOPLE; RNPSI; RDBOI; R0BD2; R0B03; R0B04; ROCKI: R0C 2; ROGDI; ROMI; RDPNIB; RDPNI; ROPNIL: RORIE; R0R2; RORA; RORB; RDRC; ISDN; RPI: RPILI; RP2; RP9; RPAI; RPA2; RPA3; RPA4; RPAIN; RPAPI; RPE; RPGR; RPGRIPI; RPGRIPIL; RPH3A; RPH3AL: RPIA; RPLIOA; RPLIO; RPLIDL; RPLI2; RPLI3; RPLI4; RPLI5; RPLI7; RPLI8; RPLI9; RPL2I; RPL23A: RPL23: RPL24; RPL27A; RPL29; RPL3D; RPL3I; RPL34; RPL35; RPL3BA; RPL3BAL; RPL37A; RPL38; RPL39; RPL39L; RPL3; RPL4I; RPL4; RPLB; RPL7A; RPL7; RPLPD; RPLPI: RPNI; RPN2; RPPI4; RPP2I; RPP25; RPP38; RPP4D; RPRDIA; RPRDIB; RPRD2; RPRM; RPSIO; RPSI4; RPSI5A; RPSIB; RPSI8; RPSI9BPI; RPS20; RPS24; RPS27A; RPS27; RPS27L; RPS29; RPS2; RPS3A; RPS3; RPS4X; RPS4YI: RPSBKA2; RPSBKA3; RPSBKA4; RPSBKA5; RPSG AG; RPSBCBI; RPSBKB2; RPS9; RPSA; RPTOR; RDCDI; RRAD; RRAGA: RRAS2: RRAS; RRBPl; RREBI; HR; RRMI; RRM2B; RRN2; RRN3; RRNADI; RRPIB; RRP1; RRP9; RSI: RSI: RSAD2; RSFI: RSLIDI; RSL24DI; RSPHI: RSPH4A; RSPH9; RSPO2; RSPQ3: RSP04; RSRCI; RSRC2; RSRPI; RSUI; RTCB; RTELI; RTKN2; RTKN; RTLI: RTNI: RTN2; RTN3; RTN4: RTN4IPI: RTN4R: RTP3; RTP4; RTTN; RUFFY; RUFY3; RUNDC3B; RUN; RUNX2; RUNX3: ROUBLE; RUVBL2; RXFPI: RXFP2; RXFP3; RXRA; RXRB; RXRG; RYBP; RYK: RYRI; RYR2; RYR3; SIDDAIO; SIODAII; SIDOAI2: SIDOAI3; THEY4; SIOOAIB; SIODAI; SIOOA2; SIDOA3; SIODA4: SIOOA5; SIODAB; SIOOA7A; SIOOA7; THEY8; SIODAB; SIOOB; SIDOPS: SIDOSE; SIPR2; SIPR3; SIPR4; SIPR5; SAAI: SAA2: SAA4; SAALI; SAC3DI; SACMIL; SACS; SAEI; SAFB2; SAFB; SAGEI; SAG; SALLI; SALL2; SALL3; SALL4; SATURDAY4; SATURDAY; SAMD4A; SAMD5; SAMD9; SAMD9L; SAMHDI; SAMM5D; SAMSNI; SAP30BP; SAP3DL; SAPCDf; SAPCD2; SARIA; BODY; SARDH; CONTENT; SARNP; SARS2; CHARTER; SART3; SASHI; SASH3; SATI; SAT2; SATBI; SATB2; SATLI; KNOWLEDGE: SBDS; SBFI: SBF2; SBNOI; SBND2; SBSN; SC50; SCAFII; SCAFI; SCAF4; SCAF8; SCAI; SCAMP2; SCAMP5; SCAPER; SCAP; SCARA3; SCARAB; SCARBI; SCARB2; SCARF2; SCCPDH; SCD5; SCO; SCFDI; SCFD2; SCG2; SCG3; SCG5; SCGBIAI; SCGBIDI; SCGBID2; SCGB2AI: SCGB2A2; SCGB2B2; SCGB3AI; SCGB3A2; SCGN; SHIPS; SGIN; SCLTI; SCLY; SCML2; SCML4; SCNIBA; SCNIIA; SGNIA; SCNIB; SCN2A; SCN2B; SCN3A; SCN3B; SCN4A; SCN4B; SCN5A; SCN7A; SCN8A; SCN9A; SCNMI; SCNN1A; SCNNIB; SCNNID; SCNNIG; SCDI; SC02; SCPZDI: SCPEPI: SCRIB; SCRNI; SCT; SCTR; SCUBEI: SCUBE2; SCUBE3; SCYLI; SCYL3; SDCI; SDC2; SDC3; SDC4; SDCBP2; SDCBP; SDCCAG3; SDCCAG8; SDF2; SDF2LI; SDF4; SDHAFI; SDHAF2; SDHAF4; SDHA; SDHC; SDHD; SDKI; SDK2; SDPR; SDR42EI; SDR9C7; SOS; SECIIA; SECIIC; SECI3; SECI4LI; SECI4L2; SECI4L3; SECIBB; SEC23A; SEC23B; SEC23IP; SEC24A; SEC24B; SEC24C; SEC3IA; SECBIAI; SECBIB; SECB2; SECB3; SECISBP2; SECISBP2L; SECTMI; CELL; WHAT IS; SELENBP1; SELL; SELP; SELPLG; SEMA3A; SEMA3B; SEMA3C; SEMA3D; SEMA3E; SEMA3F; SEMA3G; SEMA4A; SEMA4B; SEMA4D; SEMA4F; SEMA4G; SEMA5A; SEMA5B; SEMABA; SEMABB; SEM ABD; SEMA7A; SEMGI; SEMG2; SENPI; SENP2; SENP3; SENP5; SENPB; SENP8: SEPHSI; SEPSECS; SERACI; SERFIA; SERGEF; SERINCI: SERINC3; SERINC5; SERPI; SERP2; SERPINAIO; SERPINAII; SERPINAI2; SERPINAI: SERPINA3; SERPINA4; SERPINA5; SERPINAB; SERPINA7; SERPINA9; SERPINBIO; SERPINBI3; SERPINBI; SERPINB2; SERPINB3; SERPINB4; SERPINB5; SERPINBG; SERPINB7; SERPINB8; SERPINB9; SE PINCI; SERPINDI; SERPINEI; SERPINE2; SERPINE3; SERPINFI: SERPINF2; SERPINGI; SERPINHI; SERPINII; SERPINI2; SERTADI: SERTA02; SESNI; SESN3; SETBPI; SETDIA; SETDIB; SETD2; SETD3; SETD5; SET07; SETD8; SETDB2; SET; SETMAR; SETX; SEZB; SEZBL2; SEZGL; SFI: SF3AI; SF3BI; SF3B2; SF3BB; SFII; SFMBTI; SFMBT2; SFRI; SFRPI; SFRP2; SFRP4; SFRP5; SFSWAP; SFT2D2; SFT203; SFTA2; SFTA3; SFTPAI; SFTPA2; SFTPB; SRPC; SFTPD; SFXNI; SFXN2; SFXN4; SGCA; SGCB; SGCD; SGCE; SGCG; SGCZ; SGIPI; SGKi; SGK223; SGK2; SGK3; SGMSI: SGMS2; SGDLI; SGPLI; SGPPI; SGPP2; SGSH; SGSM2; SGSM3; SGTA; SH2BI; SH2B2; ​​SH2B3; SH2DIA; SH202A; SH2D3A; SH2D3C; SH2D4A; SH2D4B; SH3BGR; SH3BGRL2; SH3BGRL; SH3BPI; SH3BP2; SH3BP4; SH3BP5; SH3DI9; SH3GLI; SH3GL2; SH3GL3; SH3 BPI; SH3PXD2A; SH3PXD2B; SH3RFI; SH3RF3; SH3TC2; SH3YLI; SHANKI; SHANK2; SHANK3; SHARPIN; SHBG; SHB; SHCI; SHC2; SHC3; SHC4; SHCBPI; SHE; SHFMI; SHH; SHISA2; SHISA3; SHISAB; SHISA9; SHMTI; SHMT2; SH0C2; SHDX2; SHDX; SHPK; SHPRH; SHQI; SHRDDM2; SHRDDM3; SHR0DM4; SIAE; SIAHI; SIAH2; SIDTI; SIGIRR; SIGLECII; SIGLECI4; SIGLECI; SIGLEC5; SIGLEC7; SIGLECB; SIGLEC9; SIGMARI; SI; SIKI:SIK2; SI3; Sill; SIMI; SIM2; SIN3A; SIN3B; SIPAI; SIPAIL2; SIPAIL3; SIRPA; SIRPBI; SIRPG; SIRTI; SIRT2; SIRT3; SIRT4; SIRT5; SIRTG; SIRT7; SITI; SIVAI; SIX1; SIX2; SIX3; SIX4; SIX5; SIXG; SKAI; SKA2; SKAPI:SKAP2; SIL; SIV2L2; SIV2L; SKORI; SOR2; SKPI; SKP2; SLA2; SLA; SLAIN2; SLAMFI; SLAMFB; SLAMF7; SLAMF8; SLBP; SLCIDAI; SLCIQA2; SLCIDAG; SLCIDA7; SLCIIAI; SLCIIA2; SLCI2AI; SLCI2A2; SLCI2A3; SLCI2A4; SLCI2A5; SLCI2AB; SLCI2A7; SLCI2A8; SLCI2A9; SLCI3AI; SLCI3A2; SLCI3A3; SLCI3A5; SLCI4AI; SLCI4A2; SLCI5A1; SLCI5A2; SLCI5A4; SLCIBAIO; SLCIBAII; SLCIBAI2; SLCIBAI3; SLCIBAI; SLCIBA2; SLCIBA3; SLCIBAB; SLCIBA7; SLCIBA8; SLCIBA9; SLCI7AI; SLCI7A2; SLCI7A3; SLCI7A4; SLCI7A5; SLCI7AB; SLCI7A7; SLCI7A8; SLCIBAI; SLCI8A2; SLCI8A3; SLCI9AI: SLCI9A2; SLCI9A3; SLCIAI; SLCIA2; SLCIA3; SLCIA4; SLCIA5; SLCIAB; SLC2DAI: SLC20A2; SLC22AII; SLC2ZAI2; SLC22AI3; SLC22AI4; SLC22AIB; SLC22AI7; SLC22AI8AS; SLC22AI8; SLC22AI; SLC22A23; SLC22A24; SLC22A2; SLC22A3; SLC22A4; SLC22A5; SLC22AB; SLC22A7; SLC22A8; SLCZ3AI; SLC23A2; SLC24AI; SLC24A2; SLC24A3; SLC24A4; SLC24A5; SLC25AIQ; SLC25AI2; SLC25AI3; SLC25AI4; SLC25AI5; SLC25AIB; SLC25AI8; SLC25AI9; SLC25AI; SLC25A20; SLCZ5A2I; SLC25A22; SLC25A23; SLC25A25; SLC25A27; SLC25A2; SLC25A3B; SLC25A37; SLC25A38; SLC25A3; SLC25A40; SLC25A4I; SLC25A42; SLC25A43; SLC25A45; SLC25A4B; SLC25A47; SLC25A4; SLC25A52; SLC25A5; SLC25AB; SLC2BAI; SLC2BA2; SLC2BA3; SLC2BA4; SLC2BA5; SLC2BAB; SLC2BA7; SLC2BA8; SLC2BA9; SLC27AI; SLC27A2; SLC27A3; SLC27A4; SLC27A5; SLC28AI; SLC28A2; SLC28A3; SLC29AI; SLC29A2; SLC29A3; SLC29A4; SLC2AI0; SLC2AII; SLC2AI2; SLC2AI3; SLC2AI4; SLC2A2; SLC2A3; SLC2A4RG; SLC2A5; SLC2AB; SLC2A8; SLC2A9; SLC30AI0; SLC30AI: SLC30A3; SLC30A4; SLC30A5; SLC30AB; SLC30A7; SLC30A8; SLC30A9; SLC3IAI: SLC3IA2; SLC32AI; SLC33AI; SLC34AI; SLC34A2; SLC34A3; SLC35AI; SLC35A2; SLG35A3; SLC35A4; SLC35B2; SLC35B4; SLC35CI; SLC35D3; SLC35FI; SLC35F2; SLC35F3; SLC35F4; SLC35FB; SLC35GI; SLC35G2; SLC35G5; SLC35GB; SLC3BAI; SLC3BA2; SLC37AI; SLC37A2; SLC37A4; SLC38AI; SLC38A2; SLC38A4; SLC38A5; SLC38AB; SLC38A7; SLC38A8; SLC38A9; SLC39AID; SLC39AII; SLC39AI2; SLC39AI3; SLC39AI4; SLC39AI; SLC39A2; SLC39A3; SLC39A4; SLC39AB; SLC39A7; SLC39A8; SLC39A9; SLG3AI; SLC3A2; SLC4DAI; SLC4IAI; SLC43AI; SLC43A2; SLC43A3; SLC44AI; SLC44A2; SLC44A4; SLC44A5; SLC45A2; SLC45A3; SLC45A4; SLC4BAI: SLC4BA2; SLC47AI; SLC48AI; SLC4AIO; SLC4AII:SLC4AIAP; SLC4AI; SLC4A2; SLG4A3; SLC4A4; SLC4A5; SLC4A7; SLC4A9; SLC5OAI; SLC5IA; SLC5IB; SLC5ZAI; SLC52A2; SLC52A3; SLC5AII; SLC5AI2; SLC5AI: SLC5A2; SLC5A3; SLC5A4; SLC5A5; SLC5AB; SLC5A7; SLC5A8; SLCBAII; SLCBAI2; SLCBAI3; SLGBAI4; SLCBAI5; SLCBAI8; SLCBAI9: SLCBAI: SLCBA20; SLCBA2; SLCBA4; SLCBA5; SLCBAB; SLCBA7; SLCBAB; SLCBA9; SLC7AI0; SLC7AII; SLC7AI3; SLC7AI4; SLC7AI; SLC7A2; SLC7A3; SLC7A4; SLC7A5; SLC7AB; SLC7A7; SLC7A8; SLC7A9; SLCBAI: SLC8A2; SLC8A3; SLCBAI: SLC9A2; SLC9A3; SLC9A3RI: SLC9A3R2; SLC9A4; SLC9A5; SLCBAB; SLC9A7; SLCBAB; SLC9A9; SLC9BI: SLC9B2; SLC9CI; SLC9C2; SLGQIA2; SLCGIBi; SLC0IB3; SLCDIB7; SLCDICI: SLCD2AI: SLCD2BI; SLCB3AI; SLCD4AI; SLCB4CI; SLCD5AI; SLCOBAI; SLFNI2; SLFNI2L; SLFNI4; SLFN5:SLITI:SLIT2; SLIT3; SLIT KI: SLITRK2; SLITRK3; SLITR 5; SLITR B; SLK; SL AP; SLM02; SLN; SLPI; SLTM; SLU7; SLURP1:SLX4; SLX4IP; SMADI; SMAD2; SMAD3; S AD4; SMAD5; SMADB; SMAD7; SMAD9; SMAGP; SMAPI; SMARCAI; SMARCA2; SMARCA4; SMARCA5; SMARCADI; SMARCALI; SMARCBI; SMARCCI; SMARCC2; SMARCDI; SMARCD3; SMARCEI; SMCIA; SMCIB; SMC2; SMC3; SMC4; SMC5; SMCB; SHCHDI; SMCD4; SMCP; SMEKI; SME 2; SMGI; SMGB; SMG8; SMIMI5; SMIMI9; SMIM2D; SMIM2I; SMIM23; SMIM5; SMN2; SMDCI; SMBC2; SMO; SMQX; SMPDI; SMPD2; SMPD3; SMPOL3A; SMPDL3B; SMPX; SMR3B; SMS; SMTN; SMTNLI; SMUI; SMUGI; SMURFI; SMURF2; SMYDI; SMYD2; SMYD3; SMYD4; SMYD5; SNAII; SNAI2; SNAI3; SNAP23; SNAP25; SNAP29; SNAP47; SNAP9I; SNAPCI: SNAPC4; SNAPC5; SNCA; SNCAIP; SNCB; SNCG; SNDI; SNEDI; SNF8; SNIPI:SNRK; SNRNP2BD; SNRNP27; SNNP7D; SNRPA; SNRPB; SNRPC; SN PDI: SNRPD3; SNRPE: SNRPF; SNRPN; SNTAI; SNTBI; SNTGI; SNTB2; SNUPN; SNURF; SNWI; SNXIO; SNXI2; SNXI4; SNXIB; SNXI8; SNXI9; SNXI: SNX2D; SNX24: SNX25; SNX29; SNX2; SNX3D; SNX3; SNX5; SNX9; SB ATI; SDAT2; SDBP; SOCSI:SDCS2; SDCS3; SDCS4; S0CS5; SDCSB; SDCS7; SDDI; SDD2; SDD3; SDHLHI; SDHLH2; SDN; SDRBSI; SDRBS2; SDRBS3; SDRCSI; SDRCS2; SDRCS3; SORD; SDRLI; SCSI:S0S2; SDSTDCI; SDST; SDXIO; SDXII: SDXI2; SDXI3; SDXI4; S0XI5; SDXI7; SDXI8; SOXI; S0X2I; SDX2; SDX3; S0X4; S0X5; SOXB; SDX7; SDX8; SDX9; SPIOD; SPUD; SPI4D; SPI; SP2; SP3; SP4; SP5; SPB; SP7; SP8; SPAI7; SPACAI; SPACA3; SPAGIIA; SPAGIIB; SPAGIB; SPAGI; SPAG4; SPAG5; SPAGB; SPAG7; SPAG8; SPAG9; SPAM1; SPANXA2; SPANXBI: SPANXD; SPANXN4; SPARC; SPARCLI: SPAST; SPATAI3; SPATAIB; SPATAI7; SPATAIB; SPATAIB; SPATA2D; SPATA2I; SPATA22; SPATA25; SPATA2; SPATA5; SPATA7; SPATA8; SPATA9; SPATCI; SPC24; SPC25; SPCS3; SPDEF; SPDLI; SPDYA; SPECCI: SPECCIL; SPEF2; SPEG; SPESPI; SPGII; SPG2D; SPG2I; SPG7; SPHKI; SPHK2; SPHKAP; SPII; SPIB; SPIC; SPIDR; SPIN1; SPIN2A; SPINKI; SPINK2; SPIN4; SPIN5; SPIN6; SPINK7; SPINTI; SPINT2: SPNSI: SPNS2; SPOII: SPDCKI; SPDC 2; SP0C 3; SPDNt; SPDN2; SPDP; SPPI; SPP2; SPPL2A; SPPL2B; SPPL2C; SPPL3; SPREAD; SPREAD2; SPREAD3; SPR; SPRN; SPRIA; SPRRIB; SPRR2A; SPRR2B; SPRR3; SPRTN; SPRYI; SPRY2; SPRY3; SPRY4; SPRYD7; SPSB3; SPSB4; SPTAI; SPTANI; SPTB; SPTBNI; SPTBN2; SPTBN4; SPTBN5; SPTLCI; SPTLC2; SPTLC3; SPTSSB; SPTY2DI; SPZI:SOLE; SDRDL; SQSTMI: SRAI; SRBDI; SRCAP; SRC; SRCINI; SRD5AI; SRD5A2; SRD5A3; SREBFI; SREBF2; SREKI; SREKIIPI; SRFBPI; SRF; SRGAP1; SRGAP2; SRGAP3; SRGN; SRI; SRL; SRMS; SRPI4; SRPI9; SRPG8; SRP72; SRP9; SRPI; SRPK2; SRPRB; SRPR; SRPX2; SRPX; SRR; SRRMI; SRRM2; SRRM4; SRRT; SRSFID; SRSFII; SRSFI2; SRSFI; SRSF2; SRSF3; SRSF4; SRSF5; SRSFB; SRSF7; SRSF9; SRXNI; SRY; SSI8; SSI8LI; SSB; SSBPI; SSBP2; SSFA2; SSHI; SSH2; SSMEMI; SSNAI; SSPN; SSPD; SSRI; SSR2; SSRPI; SSSCAI; SST; SSTRI; SSTR2; SSTR3; SSTR4; SSTR5; SSUH2; SSXI: SSX2B; SSX2IP; SSX4B; SSX5; STI3; STI4; STI8; ST20; ST3GALI; ST3GAL2; ST3GAL4; ST3GAL5; ST3GALB; ST5; STBGALI; STBGAL2; STBGALNACI; STBGALNAC2; STGGALNAC4; STGGALNACB; ST7; ST7L; ST8SIAI; ST8SIA2; ST8SIA3; ST8SIA4; ST8SIAB; STABLE; STAB2; STAC3; STAC; INTERNSHIP; STAGE2; STAGS; STAM2; STAMBP; STAMPLI; STAM; STOP; STAP2; STARDIO; STARDI3; STARD3; STARD3NL; STARD5; STARD7; STARD8; STARD9; STAR; STATE; STAT2; STAT3; STAT4; STAT5A; STAT5B; STATE; STATH; STAU2; STBDI; STCI; STC2; STEAPI; STEAP2; STEAP3; STEAP4; STH; STYLE; ESTIMATES; STIM2; STIPI; ST IO; STKII: STKIIIP; ST I7A; ST I7B; ST I9; STK24; ST 25; STK2B; STK3I; ST 32A; STK32B; ST 32C; STK33: ST 35; ST 38L; STK39; ST 3; STK4; STMN2; STMN3; STMN4; STORM; STDMLI; STDML2; STOML3; ST0NI-GTF2AIL; STDNI: STOCK; STRAI3; STRAB; STRA8; ROAD; STRADB; STRAP; STRC; STRN3; STRN4; STRN; STS; SH3A: STT3B; STUBI; STXII; STXIG; STXI7; STXI8; STXIA; STXIB; STX2; STX3; STX4: STX5; STXB; STX8; STXBPI; STXBP2; STXBP4; STXBP5; STXBP5L; STXBPB; STYKI; STYX; SUBI; SUCLA2; SUCLGI; SUCLG2; SUCNRI: SUCO; SOOS3; SOFU; SUGCT; SOGPI; SUGTI; SULFI; SULF2; SULTIAI; SOLTIA2; SOLT1A4; SULTIBI; SULTIC2; SOLTIEI; SULT2A1:SOLT2BI; SULT4AI; SUMFI; SUMFZ; SUMDI; SUM02; SUM03; SUMD4; SUNI; SUN2; SUN3; SUOX; SUPT2DH; SUPT3H; SUPT4HI; SUPT7L; SUPV3LI; SURFI; SURF4; SUSDI; SUSD2; SUSD4; SUSDB; S0V39HI; SUV39H2; SUV420H2; SUZI2; SV2B; SV2C; SVEPI: SVIL; SVIP; SVOP; SWAP7D:SWTI; SYBU; SYCEI; SYCEIL; SYCP2; SYCP2L; SYCP3; SYK; SYMPK; SYHI; SYN2; SYN3; SYNCRIP; SYNDIBI; SYNEI: SYNE2; SYNE4; SYNGAPI; SYNGRI; SYNG 2; SYNJI: SYNJ2BP; SYNJ2; SYNM; SYNP02; SYNPD; SYNPR; SYP; SYPLI; SYPL2; SYTII; SYT12; SYTI3; SYTI4; SYTI; SYT4; SYTB; SYT9; SYTLI; SYTL2; SmS; SYVNI; TAARI; TAAR2; TAAR5; TAARB; TABI; TAB2; TAB3; TACt; TAGS; TAC4; TACCI: TACC2; TACC3; TACDI; TAC I; TACR2; TAGR3; TADAI; TADA2A; TADA3; TAFI5; TAFIB; TAFIC; TAFID; TAFI; TAF2; TAF3; TAF4B; TAF4; TAF5L; TAFB; TAF7; TAF7L; TAF8; TAFB; TAGAP; TAGLN2; TAGLN; TALI; TAL2; TALDOI; TAMM4I; TANCI; TANC2; TANG02; TANK; TADKI; TAD 2; TAD3; TAPI; TAP2; TAPBP; TAPBPL; TARBPI; TARBP2; TARP; TARS; TARSL2; TAS2RIB; TAS2RI3; TAS2RI4; TAS2RIB; TAS2RI; TAS2R38; TAS2R5B; TAS2RBB; TAS2R9; TASPI; TATDNI; TAT; TAXIBPI; TAXIBP3; TAZ; TBATA; TBCIDI5; TBCIDIB; TBCIDI; TBCID2D; TBCID22A; TBCID22B; TBCID24; TBCID25; TBCID2; TBCID32; TBCID3C; TBCID3F; TBCID4; TBCID5; TBCID7; TBCID8; TBCID9; TBCA; TBCC; TBCD; TBCE; TBCEL; Ml: TBKBPI; TBLIX; TBLIXRI; TBLIY; TBL2; TBL3; TBP; TBPLI; TBPL2; TBRI; TBRGI; TBXID; TBXI8; TBXI9; TBXI: TBX2D; TBX2I; TBX22; TBX2; TBX3; TBX4; TBX5; TBXB; TBXA2R; TBXASI; TCAIM; TCAP; TCEAI; TCEA2; TCEA3; TCEALI; TCEAL2; TCEAL4; TCEAL7; TCEBI: TCEB2; TCEB3C; TGERGI; TCERGIL; TCFI2; TCFI5; TCFI9; TCF2B; TCF2I; TCF25; TCF3; TCF4; TCF7; TCF7LI; TGF7L2; TCFL5; TCHH; TCHP; TGIRGI; TCLIA; TCLIB; TCNI; TCN2; TCDFI; TCPIB; TCPIDL2; TCPIILI; TCPI; TCTA; TCTEI; TCTNI; TCTN2; TCTN3; TDGFI; TDG; TDD2; TDPI; TDP2; TDRDI; TDRD3; TDRD5; TDRDB; TDRD7; TDRD9; TDR H; TDRP; TEADI; TEAD2; TEAD3; TEAD4; TEC; TECPR2; TECR; TECRL; TECTA; TEF; TEFM; ONLY; TEXT; TECT5; TEL02; FRIENDS; TENM2; TENM3; TENM4; EDGE; TEPP; TERPHY; TERF2; TERF2IP; TERT; TESC; TES; TESPAI: STRONG; TET2; TET3; TEXTURE; TEXII; TEXI4; TEXI5; TEX2B4; TEX29; TEX3D; TEX35; TEX40; TFAM; TFAP2A; TFAP2B; TFAP2C; TFAP4; TFBIM; TFB2M; TFCP2; TFDPI: TFDP2; TFDP3; TFE3; TFEB; TFEC; TFFI: TFF2; TFF3; TFG; TF; TFPII: TFPI2; TFPI; TFPT; TFR2; TFRC; TGFA; TGFBI; TGFBIII; TGFB2; TGFB3; TGFBI; TGFBRI; TGFBR2; TGFBRAPI; TG; TGIFI; TGIF2-CZ0orf24; TGIF2; TGIF2LX; TGMI; TGM2; TGM3; TGM4; TGM5; TGMB; TGM7; TG0LN2; TGSI: THADA; SUPPORT; THAP1J: HIGH; THAP2; THAPG; THBD; THBSI; THBS2; THBS3; THBS4; THEG; SELECT4; COUNTRY5; THE G; THEMIS2; THEMIS; THGIL; TH; THNSLI; THNSL2; THDCI; THDC2; THDC5; THDCB; THDPI; THPD; THRA; THRB; THRSP; THSDI; THSD4; THSD7A; THYNI; TIAI: TIAFI: TIALI; TIAM: TIAM2; TEACH; TICAM2; TICRR; TIFA; TIGD2; TIGHT; TIMD4; TIMELESS; TIMMID; TIMMI7A; TIMM2I; TIMM22; TIMM23; TIMM44; TIMM5D; TIMM8A; TIMM8B; TIMMOCI; TIME; TIMP2; TIMP3; TIMP4; WORD; TINF2; TIPARP; TIP; TIPRL; THERAPY; TJPfc TJP2; TJP3; TKI; T 2; TCT; TKTLI; T TL2; TLDCI; HIGH; TLE2; TLE3; TLE4; TLEG; Ml; TLK2; TLLI; TLL2; TLNI; TLN2; TLRIO; TLRI; TLR2; TLR3; TLR4; TLR5; TLRB; TLR7; TLR8; TLR9; TLXI; TLX2; TLX3; TM4SFI; TM4SF2D; TM4SF4; TM4SF5; TMBSF2; TM7SF2; TM9SF2; TM9SF4; TMBIM4; TMBIMB; TMCI; TMC2; TMC3; TMC5; TMCB; TMC8; TMCCI; TMCC2; TMCC3; TMCDI; TMCD4; TMCD5A; TMEDID; TMEDI; TMED2; TMED3; TMED4; TMED7; TMED7-TICAM2; TMEDB; TMEFFI; TMEFF2; TMEMIOO; TMEMIDI; TMEMID5; TMEMIDBB; TMEMI08; TMEMII4; TMEMII5; TMEMII7; TMEMII; TMEMI2BA; TMEMI27; TMEMI28; TMEMI32A; TMEMI32B; TMEMI32C; TMEMI32D; TMEMI32E; TMEMI34; TMEMI35; TMEMI38; TMEMI5DB; TMEMI5IA; TMEMI5IB; TMEMI54; TMEMI58; TMEMIGO; TMEMIBIB; TMEMIB3; TMEMIG5; TMEMIB9; TMEMI70A; TMEM17I; TMEMI73; TMEMI75; TMEMI7GB; TMEMI78A; TMEMI82; TMEMI83A; TMEMI84C; TMEMI85A; TMEMI87; TMEMI89; TMEMI89-UBE2VI; TMEMI8; TMEMI99; TMEM2D0A; TMEM205; TMEM207; TMEM209; TMEM2I3; TMEM2I5; TMEM2IB; TMEM2I7; TMEM2I9; TMEM220; TMEM229A; TMEM23I; TMEM233; TMEM237; TMEM24I; TMEM244; TMEM245; TMEM259; TMEM25; TMEM2BI; TMEM27; TMEM2; TMEM30A; TMEM30B; TMEM37; TMEM38A; TMEM38B; TMEM39A; TMEM40; TMEM43; TMEM45A; TMEM47; TMEM50B; TMEM55A; TMEM57; TMEM5; TMEMBO; TMEMB2; TMEMB3A; TMEMB7; TMEM70; TMEM74B; TMEM79; TMEM87A; TMEM88; TMEM89; TMEM8B; TMEM95; TMEMB7; TMEM98: TMFI; TMIE; TMIGD2; TMIG03; TMLHE; TMODI: TMDD2; TMDD3; TM0D4; TMPO; TMPRSSIIA; TMPRSSIIB; TMPRSSIID; TMPRSSItE; TMPRSSI3; TMPRSSI5; TMPRSS2; TMPRSS3; TMPRSS4; T PRSSB: TMPRSS7; T PRSS9; TMSBID; TMSBI5B; TMSB4X; T TCI; TMTC2; TMTC3; TMXI: TMX2; TMX3; TNC; TNFAIPI: TNFAIP2; TNFAIP3; TNFAIP6; TNFAIP8; TNFAIP8L2; TNFAIP8L3; TNF; TNFRSFIOA; TNFRSFfOB; TNFRSFIOC; TNFRSFIOD; TNFRSFIIA; TNFRSFIIB; TNFRSF12A; TNFRSFI3B; TNFRSFI3C; TNFRSFI4; TNFRSFI8; TNFRSFIA; TNFRSFIB; TNF SF2I; TNFRSFBB; TNFRSF8; TNFSFIO; TNFSFII; TNFSFI2; TNFSFI2-TNFSFI3; TNFSFI3B; TNFSFI3: TNFSFI4; TNFSFI5; TNFSFIB; TNFSF4; TNFSFB; TNFSF3; TNIK; TNIPI; TNIP2; TNIP3; TNKI; TNK2; TNKS2; TNKS; TNMD; TNNCI; TNN; TNNII; TNNI2; TNNI3; TNNTI; TNNT2; TNNT3; TNPI; TNP2; TNPBI; TNPB2; TNPD3; TNRCI8; TNRCBA; TNRCBB; TNR; TNSI; TNS2; TNS3; TNS4; TNXB; TOBL; TDB2; TOLLIP; TDM: TOMIl; TOMM20; TOMM34; TOMM40; TOMM70A; TONSL; TOPI; T0P2A; T0P2B; T0P3A; T0P3B; TOPBPI; TOPORS; TORIA; TORIAIPI; T0RIAIP2; TORIB; TOR2A; T0X2; T0X3; T0X4; TOX; TP53AIPI; TP53BPI: TP53BP2; TP53; TP53III; TP53II3; TP53I3; TP53INPI; TP53INP2; TP53RK; TP53TG3C; TPB3; TP73; TPBG; TPCNI; TPCN2; TPD52; TPD52LI; TPD52L2; TPGS2; TPHI; TPH2; TPIt; TPKI; TPMI; TPM2; TPM3; TPM4; TPMT; TPD; TPPI; TPP2; TPPP2; TPPP3; TPPP; TPRGI; TPR; TPRN; TPSABI; TPSB2; TPSDI; TPSGI; TPTI; TPTE2; TPTE; TPX2; TRA2A; TRA2B; TRABD2A; TRABD; TRADD; TRAFI; TRAF2; TRAF3; TRAF3IPI; TRAF3IP2; TRAF4; TRAF5; TRAFB; TRAF7; TRAFDI: TRAKI; TRAK2; TRAMI; TRAMILI; TRAM2; TRAPI; TRAPPCIO; TRAPPCII; TRAPPCI; TRAPPC2; TRAPPC4; TRAPPC9; TRATI; TRDMTI:TRDN; TREH; TREMI; TREM2; TREMLI; TREML2; TRERFI; TREXI; TREX2; TRHDE; TRH; TRHR; TRIAPI; TRIBI; TRIB2; TRIB3; TRIMIO; TRIMII: TRIMI3; TRIMI5; TRIMIB; TRIMI7; TRIMZI: TRIM22; TRIM23; TRIM24; TRIM25; TRIM2B; TRIM27; TRIM28; TRIM29; TRIM2; TRIM3I; TRIM32; TRIM34; TRIM35; TRIM3B; TRIM37; TRIM38; TRIM39; TRIMS? TRIM40; TRIM42; TRIM44; TRIM50; TRIM5B; TRIM58; TRIM59; TRIMS? TRIMB2; TRIMBB? TRIMB8; TRIMB9; TRIMB-TRIM34; TRIM7I; TRIM72; TRIM73; TRIM74; TRIMS? TRIMS? TRIDBP; TRIO: TRIPIO? TRIPII? TRIPI3; TRIP4; TRIPB? TIQK? TRMTIOA; TRMTI2; TRMT1; TRMT44; TRMT5; TRMU? TRO; TROVE2; TRPAI? TRPCI; TRPC3; TRPC4AP; TRPC4; TRPC5; TRPCG? TRPC7; TRPMI; TRPM2; TRPM3; TRPM4; TRPM5; TRPMB? TRPM7; TRPM8; TRPSI? TRPVfc TRPV2; TRPV3; TRPV4; TRPV5; TRPVB? TRRAP? TSACC; TSCI: TSC22DI; TSC22D3; TSC22D4; TSC2; TSEN2; TSEN34; TSEN54; TSFM? TSGIDI? TSGAIO? TSHR? TSHZI? TSHZ2; TSHZ3; TSLP; TSNAX; TSN; TSPANIO; TSPANII; TSPANI2; TSPANI3; TSPANI4; TSPANIB; TSPANI8; TSPAN3I; TSPAH32; TSPAN33; TSPAN4; TSPANB; TSPAN7; TSPAN8; TSPAN9; TSPEAR; TSP02; TSPO; TSPYIO; TSPYI; TSPY3; TSPY4; TSPYLI; TSPYL2; TSPYL4; TSPYL5; TSRI; TSSCI; TSSKIB; TSSK2; TSSK4; TSTA3; TSTDI; TST; TTB I; TTBK2; TTCI2; TTCI7; TTCI9; TTCI; TTC2IB; TTC28; TTC29; TTC37; TTC39A; TTC39B; TTC3; TTC5; TTC6; TTC7A; TTC7B; TTC8; TTC9B; TTC9C: TTC9; TTFI; TTF2; TTII:TTI2; TTK; TTL; TTLLID; TTLLII; TTLLI2; mU; TTLL3; TTLL4; TTLL5; TTLLB; TTLL7; TTLL8; TTLL9; TTPA; TTR; TTYHI; TTYH2; TUBAIA; TUBAIB; TUBAIC; TUBA3D; TUBA4A; TUBA8; TUBBI; TUBB2A; TUBB2B; TUBB3; TUBB4A; TUBB4B; TUBBB; TUBB; TUBDI; TUBEI:TUBEI; TUBG2; T0BGCP2; TUBGCP3; TUBGCP4; TUBGCP5; TUBGCPB; TUB; TUFM; TUFTI; TULPI; T0LP2; TULP3; T0LP4; TUSCI; TUSC2; TUSC3; TUSC5; l; TVP23B; TWFI; TWISTI; TWIST2; TWSGI; TXK; TXLNG; TXN2; TXNDCI5; TXNDCIB; TXN0CI7; TXNDC5; TXN; TXNLI; TXNRD2; TXNRD3NB; TYK2; TYMP; TYMS; TYR; TYRD3; TYROBP; TYRPI; TYSNDI: TYWIB; U2AFI: U2AF2; UACA; UAPI; UBAI; UBA2; UBA3; UBA7; UBACI; UBAC2; UBAPI; UBAP2; UBASH3A; UBASH3B; UBB; OBC; UBD; UBE2A; UBE2B; 0BE2C; UBE2D1; UBE2D2; UBE2D3; UBE2EI; UBE2E2; UBE2E3; UBE2GI; UBE2G2; UBE2H; UBE2I; UBE2JI; UBE2K; UBE2L3; UBE2LB; UBE2M; UBE2N; UBE202; UBE2DLI; UBE2R2; UBE2S; UBE2T; UBE2U; UBE2VI; UBE2V2; UBE2Z; UBE3A; UBE3B; DBE3C; UBE4A; UBE4B: UBIAOI; UBL3; UBL4A; UBL5; UBL7; UBLCPI: UBNI; UB0X5; UBPI: UBOLNI; UBQLN2; UBOLNL; UBRI; UBR3; 0BR4; 0BR5; UBR7; UBTD2; UBTF; UBXNI; UBXN2A; UBXN2B; UBXN4; UCHLI; UCHL3; UCHL5; UCKI; UCK2; UCKLI; UCMA; 0CN2; UCN3; UCN; UCPI; UCP2; UCP3; UEVLD; UFOIL; UFLI; OFMI; UGCG; OGDH; UGGTI; UGGT2; UGP2; UGTIAIO; UGTIAI; UGTIA3; 0GTIA4; UGTIA5; UGTIAB; UGTIA7; UGTIA8; UGTIA9; UGT2AI; UGT2A2; UGT2A3; DGT2BI0; UGT2BII; UGT2BI5; UGT2B28; UBT2B4; UGT2B7; UGT3A2; UGT8; UHMKI; UHRFIBPI; UHRFI; UHRF2; UIMCI; ULBPI; ULBP2; ULBP3; ULKI; ULK2; ULK3; ULK4; UMBO; UMDOLI; UMPS; UNCII9; UNCI3A; UNCI3B; UNCI3C; UNCI3D; UNC45A; UNC45B; UNC5A; UNC5B; UNC5C; UNC5D; UNC79; UNCB3A; UNC93BI; UNG; UPBI; UPFI; UPF2; UPF3A; UPF3B; UPKIA; UPKIB; UPK2; UPK3A; UPPI; UPP2; UPRT; UQCCI; UQCC2; UQCRB; UDCRCI; UBCRC2; UQCRFSI:UflCRO; URB2; URGCP; URI; URMI; URDCI; UOD; UROS; USBI; USEI:USFi:USF2; USHIC; USHIG; USH2A; 5USUI; USPIO; USPII; USPI2; USPI3; USPI4; USPI5; USPI7L2; USPI7L3D; USPI8; USP20; USP22; USP25; USP2B; USP28; USP2; USP32; USP33; USP3B; USP37; USPS; USP4B; USP42; USP43; USP44; USP4B; USP48; USP49; USP4; USP5; USPB; USPBNL; USP7; USPS; USP9X; USP9Y; USPLI; UST; UTFI; UTPI4A; UTPI4C; UTP2B; UTRN; UTS2B; UTS2; UTS2R; UTY; UVRAG; UVSSA; UXSI: UXT; VACI4; VAMPI; VAMP2; VAMP4; VAMP7; VAMP8; VANGL2; VAPA; VAPB; VARS2; VARS; FOR; VASH2; VASP; VATI; VALID; VAVI; VAV2; VAV3; VAXI; VAX2; VBPI; VCAN; VCL; VCP; VCX2; VCX3A; VCX3B; VCX; VCY; VDACI; VDAC2; VDR; VEGFA; VEGFB; VEGFC; VENTX; VEPHI; VEZT; VGF ID; VGLLI; VGLL2; VGLL3; VGLL4; VHL; VHLL; VILI; VIM; VIPAS39; VIP; VIPRI; VIPR2; VIT; VKDRCI; VLDLR; VMA2I; VMDI; VMPI; VNIR2; VNIR4; VNNI: VNN2; VNN3; VOPPI: VPRBP; VPRICE; VPREB3; VPSII; VPSI3A; VPSI3B; VPSI3C; VPS2BA; VPS28; VPS33A; VPS33B; VPS35; VPS3B; VPS37A; VPS37B; VPS37C; VPS39; VPS4I; VPS4A; VPS4B; VPS5I; VPS52; VPS53; VPS54; VPS72; VPS8; VRKI: VRK2; VSIGID; VSIGI; VSIG2; VSIG4; VSNLI: VSTMI; VSXI; VSX2; VTAI; VTCNI; VTIIA; VTIIB; VTN; VWA2; VWA3A; VWA3B; VWA5A; VWA5BI: VWA7; VWA8; VWCE: VWDE; VWF; WAPAL; WARS2; WARS; WASFI; WASF3; WASHI; WAS; WASL; WBPIL; WBP2; WBSCRI7; WBSCR22; 15 WDFY2; WDFY4; WDHDI; WDPCP; WDRII; WDRI2; WDRI7; WDRI9; WDRI; WDR2D; WDR2B; WDR3I; WDR34; WDR35; WDR3B; WDR37; WDR43; WDR45B; WDR45; WDR4B; WDR48; WDR49; WDR4; WDR55; WDR5; WDRBD; WDRB2; WDRB4; WDRBB; WDR7D; WDR72; WDR74; WDR7B; WDR78; WDR7; WDR8I; WDR83; WDR8B; WDR93; WEEI; WFDCI: WFDC2; WFSI; WHSCI; WHSCILI; WIFI: WIPFI: WIPF2; WIPF3; WIPII; WIPI2; WISPI; WISP2; WISP3; WLS; WNKI; WNK2; WNK3; WNK4; WNTIDA; WNTIDB; WNTII; WNTIB; WNTI; WNT2B; WNT2; WNT3A; WNT3; WNT4; WNT5A: WNT5B; WNTB; WNT7A; WNT7B: WNT8A; WNT8B; WNT9A; WNT9B; WRAP53; WRB; WRN; WRN1P1; WSBI; WSCDI; WSCD2; WTI; WTAP; WTIP; WWCI; WWC2; WWDX; WWPI; WWP2; WWTRI; XAB2; XAFI; XAGEIB; XAGEIE; XBPI; XCLI; XCL2; XCRI; XDH; XG; XIAP; XIRPI; XIRP2; XK; XKR4; XKRG; XKR9; XPA; XPC; XPNPEPI; XPNPEP2; XPNPEP3; XPDI; XP04; XPD5; XPOB; XP07; XPRI; XRCCI; XRCC2; XRCC3; XRCC4; XRCC5; XRCCBBPI; XRCCB; XRNI; XRN2; XRRAI; XXYLTI; XYLB; XYLTI; XYLT2; YAEIOI; YAPI; YARS2; YBX2; YBX3; YDJC; YEATS4; YESI; YIFIA: YIPFI; YIPF3; YIPF5; YKTB; YLPMI; YMEILI; YPELI: YPEL2; YPEL3; YPEL4; YPEL5; YTHDCI; YTHDC2; YWHAB; YWHAE; YWHAG; YWHAH; YWHAD; YWHAZ; YYIAPI; YYI; ZACN; ZAK; ZAP7D; ZARI; ZARIL; ZASP; ZBEDI; ZBED4; ZBED5;5 ZBPI; ZBTBID; ZBTBI2; ZBTBI4; ZBTBIB; ZBTBI7; ZBTBI8; ZBTB2D; ZBTB2I; ZBTB22; ZBTB24; ZBTB2; ZBTB32; ZBTB33; ZBTB34; ZBTB38; ZBTB4I; ZBTB4B; Z8TB48; ZBTB49; ZBTB4; ZBTB5; ZBTB7C; ZBTB9; ZC2HCIB; ZC3HI0; ZC3HIIA; ZC3HI2C; ZC3HI2D; ZC3HI4; ZC3HI5; ZC3H3; ZC3H4; ZC3H7A; ZC3H7B; ZC3HAVI; ZC3HCI; ZC4H2; ZCCHCII; ZCCHCI2; ZCCHCI4; ZCCHC2; ZCCHC3; ZCCHCB; ZCCHC8; ZCRBI; ZCWPWI; ZDBF2; ZDHHCII; ZDHHCI2; ZDHHCI3; ZDHHCI4; ZDHHCI5; ZDHHCI7; ZDHHCI; ZDHHC2; ZDHHC7; ZDHHC8; ZDHHC9; ZEBI; ZEB2; ZFAND3; ZFAND5; ZFANDB; ZFAT; ZFC3HI:ZFHX2; ZFHX3; ZFHX4; ZFPI; ZFP30; ZFP3B; ZFP3GLI:ZFP3BL2; ZFP37; ZFP42; ZFP57; ZFPB4; ZFP82; ZFPBI; ZFPMI; ZFPM2; ZFR2; ZFR; ZFX; ZFY; ZFYVEI9; ZFYVE2I; ZFYVE2B; ZFYVE27; ZFYVE28; ZFYVE9; ZGIBB; ZGLPI; ZGPAT; ZHXI; ZHX2; ZICI; ZIC2; ZIC3; ZIC4; ZIC5; ZIKI; ZIM2; ZKSCANI; ZKSCAN3; ZKSCAN7; ZMAT3; ZMAT4; ZMIZI; ZMYM2; ZMYM3; ZMYM4; ZMYM5; ZMYNDID; ZMYNDII; ZMYND8; ZNFIDB; ZNFID7; ZNFID; ZNFII2; ZNFI2I: ZNFI3I; ZNFI32; ZNFI33; ZNFI4I; ZNFI43; ZNFI4B; ZNFI48; ZNFI54; ZNFIBD; ZNFIB9; ZNFI75; ZNFI77; ZNFI82; ZNFI84; ZNFI85; ZNFI89; ZNFI97; ZNF2D2; ZNF2D5; ZNF2D; ZNF2I2; ZNF2I4; ZNF2I5; ZNF2I7; ZNF224; ZNF22; ZNF23D; ZNF23B; ZNF239; ZNF23; ZNF248; ZNF24; ZNF253; ZMF2B0; ZHF2B3;5 ZNF2G4; ZNF2BB; ZNF2B7; ZNF2B8; ZNF273; ZNF274; ZNF27B; ZNF277; ZNF280B; ZNF28DD; ZNF28I; ZNF282; ZNFZ8BB; ZNF29B: ZNF2; ZNF3DD; ZNF3II; ZNF3I8; ZNF32D; ZNF322; ZNF32; ZNF33D; ZNF33I; ZNF334; ZNF335: ZNF343; ZNF35D; ZNF354A; ZNF35; ZNF3B5; ZNF3FJFJ; ZNF3B7; ZNF3B2; ZNF3B3: ZNF3S4; ZNF385A; ZNF385B; ZNF385D; ZNF39I: ZNF395; ZNF338; ZNF407; ZNF4ID; ZNF415; ZNF4I3; ZNF4I; ZNF423; ZNF430; ZNF432; ZNF433; ZNF438; ZNF443; ZNF444; ZNF44; ZNF45I: ZNF45; ZNF4B2; ZNF4B9: ZNF483; ZNF49D; ZNF4B2; ZNF4BB; ZNF5DI; ZNF5D7; ZNF5I2B; ZNF5I2; ZNF5I3; ZNF5IB; ZNF5I9; ZNF52I; ZNF53B; ZNF555; ZNF55B; 5 ZNF5B8; ZNF5B9; ZNF577; ZNF5SD; ZNF58I; ZNF582; ZNF583; ZNF585B; ZNF5B2: ZNF53B; ZNFBOB; ZNFBD7; ZNFB08; ZNFBI5; ZNFBI8; ZNFB27; ZNFB23; ZNFB33; ZNFB44; ZNFB45; ZNFB4B; ZNFB52; ZNF654; ZNFSB4; ZNFBB7; ZNFBB8; ZNFG74; ZNFB7B; ZNFB78; ZNFB83; ZNFB87; ZNFB83; ZNF703; ZNF7D4; ZNF7DB; ZNF7II; ZNF7I6; ZNF7I7; ZNF74B; ZNF74; ZNF750; ZNF7B3; ZNF7B4; ZNF7B5; ZNF7B; ZNF774: ZNF77B; ZNF778; ZNF7B4; ZNF79; ZNF7; ZNF8DD: ZNF804A; ZNF804B; ZNF80; ZNF8I2; ZNF8I3; ZNFS1B; ZNF8I; ZNF823; ZNF827; ZNF823; ZNFB3I: ZNF9I; ZNF32; ZNF33; ZNF38; ZNFX1; ZNHIT2; ZNHIT3; ZNRDI; ZN F3; ZPI; ZP4; ZPBP2; ZPLDI; ZPRI ID; ZRANB3; ZRSR2; ZSCANI8; ZSCAN22; ZSCAN2B; ZSCAN3I: ZSCAN32; ZSCAN9; ZSWIM2; ZSWIMB; ZWIO: ZWILCH; ZWINT; ZYX; ZZEFI;およびZZZ3。

[0118] In some embodiments, the therapeutic protein is OTC, ASL, PAH, ABCB4, ABCB11, PAH, AGL, CFTR, MUT, PCCA, PCCB, ASS1, FAH, HMBS, ATP7B, PFIC2, LDLR, G6PC, AGXT, FXN, PAL, BCKDHA, BCKDHB, DBT, UGT1A1, SLC25A13, CD46, CFH, CFI, FIX, FVII, FVIII, C2, C3, C5, GCHD, CBS , MPI, LNL, SERPING1, UROC1, SMPD1, GLA, GAA, GRHPR, ATP8B1, SERPINC1, PROS1, GBA, ACADVL, HFE, BCKDA, CDG1B, SERPINA1 , BMPR2, ENG, ACVR1, SMAD4, BMPR9, HBB, FLCN, HSP1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, PLDN, AP3D1, BRAF, NF -1, SLC34A2, FBN1, COL1A1, COL1A2, COL1A3, COL5A1, COL5A2, ADAMTS2, PLOD1, TNXB, ABCA3, SP-B, SP-C, GBA, NPC1, NPC2, F OXF1, NKX2-1, SFTPB, SFTPC, ABCA3, CSF2RA, SFTPD, MUC5B, BMPR2, EIF2AK4, CSF2RB, DNAH5, DNAI1, DNAH11, AKR1D1, AMACR, ATP8B1, CYP7A1, FOXC2, GATA2, GHR, HSD3B7, IGFALS, IKBKG, JAG1, KIF11, NOTCH1, NOTCH2, NR1H4, SOX18, TJP2, P53, P73, P63, VIPAS39, VPS33B, EPO, ARG1, CPS1, NAGS, NOS, KRAS, OX40L, IL12, VEGF-A, MMA, TTR, PCSK9, AT, and ALAS1.

[0119] Lipid-based formulations Lipid-based formulations have increasingly been recognized as one of the most promising delivery systems (also referred to herein as delivery vehicles or carriers) for RNA due to their biocompatibility and ease of large-scale production. Cationic lipids have been widely investigated as synthetic materials for RNA delivery. After mixing together, nucleic acids are condensed by the cationic lipids to form lipid / nucleic acid complexes known as lipoplexes. These lipid complexes can protect genetic material from the action of nucleases and deliver genetic material to cells by interacting with negatively charged cell membranes. Lipoplexes can be prepared by directly mixing positively charged lipids with negatively charged nucleic acids at physiological pH.

[0120] Traditional liposomes consist of a lipid bilayer, which can be composed of cationic, anionic, or neutral (phospho)lipids and cholesterol, enclosing an aqueous core. Both the lipid bilayer and the aqueous space can incorporate hydrophobic or hydrophilic compounds, respectively. The properties and behavior of liposomes in vivo can be modified by adding a hydrophilic polymer coating, such as polyethylene glycol (PEG), to the liposome surface to confer steric stabilization. Furthermore, liposomes can be used for specific targeting by attaching ligands (e.g., antibodies, peptides, carbohydrates) to their surface or to the termini of attached PEG chains (Front Pharmacol. 2015 Dec 1;6:286).

[0121] Liposomes are colloidal lipid- and surfactant-based delivery systems composed of a phospholipid bilayer surrounding an aqueous compartment. They may exist as spherical vesicles and can range in size from 20 nm to several microns. Cationic lipid-based liposomes can complex with negatively charged nucleic acids through electrostatic interactions, resulting in complexes that offer biocompatibility, low toxicity, and the potential for large-scale production required for in vivo clinical applications. Liposomes can fuse with cell membranes for uptake; once inside the cell, the liposomes are processed through the endocytic pathway, and the genetic material is then released from the endosome / carrier into the cytoplasm. Considering that liposomes are essentially analogs of biological membranes and can be prepared from both natural and synthetic phospholipids, liposomes have long been recognized as drug delivery vehicles due to their excellent biocompatibility (Int J Nanomedicine. 2014;9:1833-1843).

[0122] Cationic liposomes have traditionally been the most commonly used nonviral delivery system for oligonucleotides, including plasmid DNA, antisense oligos, and siRNA / small hairpin R A-shRNA. Cationic lipids, such as DOTAP (1,2-dioleoyl-3-trimethylammonium-propanediol) and DOTMA (N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate), form complexes or lipoplexes with negatively charged nucleic acids, forming nanoparticles through electrostatic interactions and providing high in vitro transfection efficiency. Furthermore, neutral lipid-based nanoliposomes have been developed for RNA delivery, such as neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC)-based nanoliposomes (Adv Drug Deliv Rev. 2014 Feb;66:110-116).

[0123] Preferably, the expressible polynucleotide and heterologous mRNA constructs described herein are lipid-formulated. The lipid formulation is preferably selected from, but not limited to, liposomes, lipoplexes, copolymers such as PLGA, and lipid nanoparticles. In a preferred embodiment, the lipid nanoparticle (LNP) comprises: (a) Nucleic acid, (b) cationic lipids, (c) aggregation-reducing agents (e.g., polyethylene glycol (PEG) lipids or PEG-modified lipids); (d) optionally, a non-cationic lipid (e.g., a neutral lipid), and (e) sterols, as appropriate.

[0124] Preferably, the lipid nanoparticle formulation consists of (i) at least one cationic lipid; (ii) a neutral lipid; (iii) a sterol, e.g., cholesterol; and (iv) a PEG-lipid, in a molar ratio of approximately 20-60% cationic lipid: 5-25% neutral lipid: 25-55% sterol; 0.5-15% PEG-lipid.

[0125] Some examples of lipids and lipid compositions for delivery of the active molecules of the present disclosure are shown in WO / 2015 / 074085 and U.S. Patent Application No. 15 / 387,067, each of which is incorporated herein by reference in its entirety. In certain embodiments, the lipid is a compound of the following formula I:

[0126] [ka] Formula I

[0127] (In the formula, R1 and R2 both consist of a straight chain alkyl of 1 to 14 carbons, or an alkenyl or alkynyl of 2 to 14 carbons; L1 and L2 are both straight-chain alkylene or alkenylene of 5 to 18 carbons or forming a heterocyclic ring with N; X is S; L3 is a bond or a straight chain alkylene of 1 to 6 carbons or forming a heterocycle with N; R3 consists of a straight or branched alkylene of 1 to 6 carbons; R4 and R5 are the same or different and each is hydrogen or a straight or branched alkyl group consisting of 1 to 6 carbon atoms. or a pharmaceutically acceptable salt thereof is.

[0128] The lipid formulation may include one or more ionizable cationic lipids (also referred to herein as "ATX lipids") selected from among the following:

[0129] [ka] [ka] [ka] [ka]

[0130] The lipid nanoparticles preferably comprise a cationic lipid suitable for forming lipid nanoparticles. Preferably, the cationic lipid carries a net positive charge at approximately physiological pH. Examples of cationic lipids include N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), 1,2-dioleoyltrimethylammonium propane chloride (DOTAP) [also known as N-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride and 1,2-dioleyloxy-3-trimethylaminopropane chloride salt], N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride, and 1,2-dioleyloxy-3-trimethylaminopropane chloride salt]. (2,3-Dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), l,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), l,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), l,2-di-γ-linolenyloxy-N,N-dimethylaminopropane (γ-DLenDMA), 1,2-dilinoleylcarbamoyloxy-3-dimethyl l,2-Dilinoleylaminopropane (DLin-C-DAP), l,2-Dilinoleyloxy-3-(dimethylamino)acetoxypropane (DLin-DAC), l,2-Dilinoleyloxy-3-morpholinopropane (DLin-MA), l,2-Dilinoleoyl-3-dimethylaminopropane (DLin-DAP), l,2-Dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), l-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), l,2-Dilinoleyl Noleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.CI), l,2-dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.CI), l,2-dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), or 3-(N,N-dilinoleylamino)-l,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-l,2-propanediol (DOAP), l,2-dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[l,3]-dioxolane (DLin-K-DMA), or its analogs, (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-5-amine, (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3), l,l'-(2-(4 -(2-((2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperazin-l-yl)ethylazanediyl)didodecan-2-ol (C12-200), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[l,3]-dioxolane (DLin-K-C2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[l,3]-dioxolane (DLin-K-DMA), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28 31-tetraen-19-yl 4-(dimethylamino)butanoate (DLin-M-C3-DMA), 3-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)-N,N-dimethylpropan-l-amine (MC3 ether), 4-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)-N,N-dimethylbutan-l-amine (MC4 ether), or any combination of any of the foregoing. Other cationic lipids include, but are not limited to, N,N-distearyl-N,N-dimethylammonium bromide (DDAB), 3P-(N-(N',N'-dimethylaminoethane)-carbamoyl)cholesterol (DC-Choi), N-(l-(2,3-dioleyloxy)propyl)-N-2-(sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoroacetate (DOSPA), dioctadecylamidoglycylcarboxyspermine (DOGS), l,2-dileoyl-sn-3-phosphoethanolamine (DOPE), l,Examples of suitable cationic lipids include 2-dioleoyl-3-dimethylammonium propane (DODAP), N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE), and 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (XTC). Additionally, commercially available cationic lipid products, such as Lipofectin (including DOTMA and DOPE, available from GIBCO / BRL) and Lipofectamine (including DOSPA and DOPE, available from GIBCO / BRL), can be used.

[0131] Other suitable cationic lipids are disclosed in International Publication Nos. WO09 / 086558, WO09 / 127060, WO10 / 048536, WO10 / 054406, WO10 / 088537, WO10 / 129709, and WO2011 / 153493; U.S. Patent Publication Nos. 2011 / 0256175, 2012 / 0128760, and 2012 / 0027803; U.S. Patent No. 8,158,601; and Love et al., PNAS, 107(5), 1864-69, 2010.

[0132] Other suitable amino lipids include those with alternative fatty acid groups and other dialkylamino groups, including those with different alkyl substituents (e.g., N-ethyl-N-methylamino- and N-propyl-N-ethylamino-). Generally, amino lipids with less saturated acyl chains are more easily sized, especially when complexes need to be sized below approximately 0.3 microns for filter sterilization purposes. Amino lipids containing unsaturated fatty acids with carbon chain lengths ranging from C14 to C22 can be used. Other scaffolds can also be used to separate the amino group from the fatty acid or fatty alkyl portion of the amino lipid.

[0133] Preferably, the LNPs comprise a cationic lipid of formula (III) as described in patent application PCT / EP2017 / 064066, the disclosure of which is in this context also incorporated herein by reference.

[0134] Preferably, the amino or cationic lipids of the present disclosure have at least one protonatable or deprotonatable group, such that the lipid is positively charged at a pH below physiological pH (e.g., pH 7.4) and neutral at a second pH, preferably above physiological pH. It will be understood, of course, that the addition or removal of protons as a function of pH is an equilibrium process, and reference to charged or neutral lipids refers to the nature of the predominant species and does not require that all lipids exist in a charged or neutral form. Lipids with multiple protonatable or deprotonatable groups, or lipids that are zwitterionic, are not excluded from use in the present disclosure. In certain embodiments, the protonatable lipid has a pKa of the protonatable group in the range of about 4 to about 11, e.g., a pKa of about 5 to about 7.

[0135] The cationic lipid comprises about 20 mol% to about 70 or 75 mol%, or about 45 to about 65 mol%, or about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70 mol% of the total lipid present in the particle. In another embodiment, the lipid nanoparticle comprises about 25% to about 75% cationic lipid on a molar basis, e.g., about 20 to about 70%, about 35 to about 65%, about 45 to about 65%, about 60%, about 57.5%, about 57.1%, about 50%, or about 40% on a molar basis (based on 100% total lipid molar content in the lipid nanoparticle). In one embodiment, the ratio of cationic lipid to nucleic acid is about 3 to about 15, e.g., about 5 to about 13, or about 7 to about 11.

[0136] Pharmaceutical Composition Preferably, the present disclosure provides a pharmaceutical composition comprising a codon-optimized mRNA encoding a modified human therapeutic protein of interest, preferably formulated in a lipid delivery system or lipid carrier, and preferably comprising a pharmaceutically acceptable excipient. The pharmaceutical composition disclosed herein preferably promotes expression of the mRNA in vivo.

[0137] Suitable routes of administration include, for example, oral, rectal, vaginal, buccal, intratracheal or pulmonary administration, including inhalation, or intestinal administration; intradermal, transdermal (topical), intramuscular, subcutaneous, intramedullary injection, and parenteral delivery, including intrathecal, direct intraventricular, intravenous, intraperitoneal, and intranasal injection.

[0138] Preferably, the intramuscular administration is to a muscle selected from the group consisting of skeletal muscle, smooth muscle, and cardiac muscle. In some embodiments, the administration results in delivery of the mRNA to muscle cells. In some embodiments, the administration results in delivery of the mRNA to hepatocytes (i.e., liver cells). In certain embodiments, the intramuscular administration results in delivery of the mRNA to muscle cells.

[0139] Preferably, mRNA and its lipid formulations can be administered locally rather than systemically, for example, by injecting the pharmaceutical composition directly into the target tissue, preferably in a sustained-release formulation. Local delivery can be affected in various ways depending on the tissue being targeted. For example, aerosols containing the compositions of the present disclosure can be inhaled (for nasal, tracheal, or bronchial delivery); they can be provided in the form of liquids, tablets, or capsules for administration to the stomach or intestines, or in the form of suppositories for rectal or vaginal application; or they can be delivered to the eye using creams, eye drops, or even injections. Formulations containing the provided compositions complexed with therapeutic molecules or ligands can even be administered surgically, for example, in combination with polymers or other structures or substances that allow the composition to diffuse from the site of implantation to surrounding cells. Alternatively, they can be applied surgically without the use of polymers or supports.

[0140] The pharmaceutical composition can be administered to any desired tissue. In some embodiments, the mRNA encoding the modified therapeutic protein delivered by the provided liposomes or compositions is expressed in the tissue to which the liposomes and / or compositions are administered. In some embodiments, the delivered mRNA is expressed in a tissue different from the tissue to which the liposomes and / or compositions are administered. Exemplary tissues to which the delivered mRNA can be delivered and / or expressed include, but are not limited to, the liver, kidney, heart, spleen, serum, brain, skeletal muscle, lymph nodes, skin, and / or cerebrospinal fluid.

[0141] Preferably, the pharmaceutical composition may comprise a polynucleotide as described herein, for example a primary DNA construct or mRNA as described herein, within a viral or bacterial vector.

[0142] Preferably, the primary DNA constructs of mRNA described herein or the mRNA described herein can be formulated with one or more excipients to (1) enhance stability; (2) increase cell transfection; (3) allow for sustained or delayed release (e.g., from a depot formulation of the polynucleotide, primary construct, or mRNA); (4) alter biodistribution (e.g., targeting the polynucleotide, primary construct, or mRNA to a particular tissue or cell type); (5) increase in vivo translation of the encoded protein; and / or (6) alter the in vivo release profile of the encoded protein.

[0143] In addition to conventional excipients, such as any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, tonicity agents, thickening or emulsifying agents, preservatives, excipients of the present disclosure can include, but are not limited to, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with primary DNA constructs, or mRNA (e.g., for implantation into a subject), hyaluronidase, nanoparticle mimics, and combinations thereof.

[0144] Thus, the formulations described herein can include one or more excipients in amounts that together increase the stability of the primary DNA construct or mRNA, increase cell transfection by the primary construct or mRNA, increase expression of the polynucleotide, primary construct, or mRNA-encoded protein, and / or alter the release profile of the polynucleotide, primary construct, or mRNA-encoded protein. Additionally, the primary constructs and mRNA of the present disclosure can be formulated using self-assembling nucleic acid nanoparticles.

[0145] The formulations of the pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparative methods include bringing into association the active ingredient(s) with an excipient(s) and / or one or more other accessory ingredients.

[0146] Pharmaceutical compositions according to the present disclosure can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses.As used herein, a "unit dose" refers to a discrete amount of a pharmaceutical composition containing a predetermined amount of active ingredient.The amount of active ingredient can generally be equal to the dosage of the active ingredient administered to a subject and / or a convenient fraction of such a dosage, including, but not limited to, one-half or one-third of such a dosage.

[0147] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition according to the present disclosure may vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. For example, the composition may contain 0.1% to 99% (w / w) of the active ingredient.

[0148] Pharmaceutical formulations may further comprise pharmaceutically acceptable excipients, which as used herein includes, but is not limited to, any and all solvents, dispersion media, diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, and the like, appropriate for the particular dosage form desired.

[0149] Various excipients for formulating pharmaceutical compositions and techniques for preparing compositions are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, AR Gennaro, Lippincott, Williams & Wilkins, Baltimore, Md., 2006, the entire contents of which are incorporated herein by reference). The use of conventional excipient vehicles may be considered within the scope of embodiments of the present disclosure, except insofar as any conventional excipient vehicle may be incompatible with the substance or its derivatives by producing any undesirable biological effects or by interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.

[0150] Therapeutic Use The mRNA sequences, primary DNA constructs transcribing the mRNA sequences described herein, and pharmaceutical compositions thereof provide numerous in vivo and in vitro methods useful for treating protein deficiencies. Treatment may include treating human patients with protein deficiencies. Similarly, the compositions described herein can be used in vitro or ex vivo to study OTC deficiencies in cell- or animal-based models. For example, cells deficient in the expression of a protein of interest can be used to analyze the ability to restore expression and / or activity of the protein of interest and the duration of expression and / or activity. Such cell and animal models are also suitable for identifying other factors involved in the pathway, whether they are binding partners or factors in the same biochemical pathway. In other embodiments, the compositions described herein can be used to study or track mitochondrial delivery.

[0151] The polynucleotides described herein, e.g., the DNA constructs or templates or mRNA sequences described herein, can be delivered to a patient or cell suffering from a deficiency of a protein of interest. For example, the mRNA sequence can comprise SEQ ID NO: 119, which encodes the modified protein of SEQ ID NO: 4. In another embodiment, the DNA sequence comprises SEQ ID NO: 221, which encodes the modified protein of SEQ ID NO: 4.

[0152] After administration, the modified protein of interest is expressed in the cell or subject. The modified protein of interest may have a signal peptide that directs it to be secreted or to become a membrane-bound protein. Preferably, the compositions described herein are delivered to a target organelle. In some embodiments, the organelle may be selected from the group consisting of mitochondria, nuclei, lysosomes, peroxisomes, endoplasmic reticulum, Golgi apparatus, and plasma membrane. In some embodiments, the compositions described herein are delivered to hepatocytes.

[0153] Exemplary mRNA sequences for use with these methods include those listed in Table 5. Exemplary cDNA templates used to transcribe the mRNA sequences described herein are listed in Table 6. Exemplary mRNA sequences to be administered to patients to treat a protein deficiency are SEQ ID NO:1799 and SEQ ID NO:1921.

[0154] In some embodiments, the polynucleotides described herein encoding the modified therapeutic proteins described herein can be used in gene therapy. Gene therapy is the technique of using genes to treat or prevent disease and can be used to treat disorders by inserting genes into a subject's cells. In some embodiments, the polynucleotides encoding the modified therapeutic proteins described herein replace a mutated gene that causes disease. In other embodiments, the polynucleotides encoding the modified therapeutic proteins described herein are used to inactivate or "knock out" an improperly functioning mutant gene. In yet other embodiments, the polynucleotides encoding the modified therapeutic proteins described herein introduce a new gene into a subject to help combat disease.

[0155] Gene therapy can use genetically engineered carriers or vectors to deliver genes. In some embodiments, the vector is a viral vector. The vector can be directly injected into specific tissues in the body or administered intravenously (IV), where it is taken up by individual cells. Alternatively, a sample of the subject's cells can be removed and exposed to the vector ex vivo. The cells containing the vector are then returned to the subject.

[0156] Administration An effective dose of the disclosed mRNA, protein, or pharmaceutical formulation thereof may be an amount sufficient to treat ORF protein deficiency in a cell and / or patient. A therapeutically effective dose may be an amount of an agent or formulation sufficient to produce a therapeutic effect. A therapeutically effective dose may be administered in one or more separate administrations via different routes. Generally, a therapeutically effective dose is sufficient to achieve a significant benefit in a subject (e.g., treating, regulating, curing, preventing, and / or ameliorating phenylketonuria). For example, a therapeutically effective amount may be an amount sufficient to achieve a desired therapeutic and / or prophylactic effect. Generally, the amount of a therapeutic agent administered to a subject in need thereof will depend on the subject's characteristics. Such characteristics include the subject's condition, disease severity, overall health, age, sex, and weight. Those skilled in the art can easily determine appropriate doses depending on these and other relevant factors. Furthermore, both objective and subjective assays may be used to identify optimal dosage ranges.

[0157] The methods provided herein contemplate single and multiple administrations of therapeutically effective amounts of the mRNA sequences described herein. Pharmaceutical compositions comprising the mRNA sequences encoding the ORF proteins described herein can be administered at regular intervals depending on the nature, severity and extent of the subject's condition. Preferably, the therapeutically effective amount of the mRNA sequences of the present disclosure can be administered periodically at regular intervals (for example, once a year, once every six months, once every four months, once every three months, once every two months, once a month), every other week, every week, every day, twice a day, three times a day, four times a day, five times a day, six times a day, or continuously.

[0158] Preferably, pharmaceutical compositions of mRNA of the present disclosure are formulated for sustained release of the translatable compound encoding the modified proteins described herein contained therein. Such sustained-release compositions can be conveniently administered to a subject at extended dosing intervals. For example, in one embodiment, a pharmaceutical composition of the present disclosure is administered to a subject twice daily, daily, or every other day. In some embodiments, a pharmaceutical composition of the present disclosure is administered to a subject twice weekly, once weekly, every 10 days, every 2 weeks, every 28 days, monthly, every 6 weeks, every 8 weeks, every other month, every 3 months, every 4 months, every 6 months, every 9 months, or once yearly. Also contemplated herein are pharmaceutical compositions formulated for depot administration (e.g., subcutaneous, intramuscular) that deliver or release mRNA sequences encoding the modified proteins described herein over an extended period of time. Preferably, the sustained-release means used are combined with modifications made to the translatable compound encoding the modified proteins described herein to enhance stability.

[0159] A therapeutically effective dose, upon administration, may result in serum or plasma levels of the modified therapeutic protein of interest of 1-1000 pg / ml, or 1-1000 ng / ml, or 1-1000 μg / ml, or more. In some embodiments, administration of a therapeutically effective dose of a composition comprising an mRNA sequence described herein may result in an increase in the level of the modified protein in a target tissue (e.g., liver, eye, lung, skin, etc.) of a treated subject. Preferably, administration of a composition comprising an mRNA described herein results in an increase in the level of the modified protein in the target tissue of 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% relative to the baseline modified protein level in the subject prior to treatment. Preferably, administration of a therapeutically effective dose of a composition comprising an mRNA described herein results in an increase in the level of the modified protein in the target tissue relative to the baseline level of the protein of interest in the subject prior to treatment. In some embodiments, the increase in modified protein levels in the target tissue relative to the baseline level of the protein of interest is at least 5%, 10%, 20%, 30%, 40%, 50%, 100%, 200%, or more.

[0160] Preferably, when administered regularly, a therapeutically effective dose will cause the expression of the therapeutic protein of interest in the liver to increase compared with the baseline level before treatment.Preferably, administering a therapeutically effective dose of the composition comprising the mRNA sequence described herein will cause the expression of modified protein levels of about 10ng / mg, about 20ng / mg, about 50ng / mg, about 100ng / mg, about 150ng / mg, about 200ng / mg, about 250ng / mg, about 300ng / mg, about 350ng / mg, about 400ng / mg, about 450ng / mg, about 500ng / mg, about 600ng / mg, about 700ng / mg, about 800ng / mg, about 900ng / mg, about 1000ng / mg, about 1200ng / mg or about 1500ng / mg or more of the total protein in the liver of treated subject.

[0161] A therapeutically effective in vivo dose of the mRNA described herein can be about 0.001 to about 500 mg / kg body weight. For example, a therapeutically effective dose can be about 0.001 to 0.01 mg / kg body weight, or 0.01 to 0.1 mg / kg, or 0.1 to 1 mg / kg, or 1 to 10 mg / kg, or 10 to 100 mg / kg. Preferably, lipid-enabled and non-immobilized nucleomonomer-modified RNA (LUNAR)-mRNA (see WO / 2015 / 074085 and U.S. Patent Application No. 15 / 387,067) encoding the modified proteins described herein is provided at a dose ranging from about 0.1 to about 10 mg / kg body weight.

[0162] combination The cDNA primary constructs, mRNA, or encoded modified therapeutic proteins described herein can be used in combination with one or more other therapeutic, prophylactic, diagnostic, or imaging agents. "In combination with" is not intended to mean that the agents must be administered simultaneously and / or formulated together for delivery, although these delivery methods are within the scope of this disclosure. The compositions may be administered simultaneously with, prior to, or after one or more other desired therapeutic or medical procedures. Generally, each agent is administered at a dose and / or time schedule determined for that agent. Preferably, the methods of treatment of the present disclosure include delivery of pharmaceutical, prophylactic, diagnostic, or imaging compositions in combination with agents that can improve bioavailability, reduce and / or modify metabolism, inhibit excretion, and / or modify biodistribution. As a non-limiting example, the mRNA described herein encoding the modified protein of SEQ ID NO: 4 can be used in combination with an agent for treating OTC deficiency. Drugs include, but are not limited to, one or more of sodium phenylbutyrate, glycerol phenylbutyrate, sodium phenylacetate, sodium benzoate, arginine, citrulline, multivitamins, calcium supplements, or low-protein / high-calorie diets.Generally, it is expected that the level of drugs used in combination will not exceed the level used individually.In some embodiments, the level used in combination will be lower than the level used individually.In one embodiment, the combination can be administered individually or together by a divided dose regimen known in the art. [Example]

[0163] material and method In vitro transcription protocol mRNA was synthesized in vitro using T7 RNA polymerase-mediated DNA-dependent RNA transcription, and uridine triphosphate (UTP) was transfected with modified UTP, e.g., 5-methoxy UTP (5MeOU), N, using a linear template for each UTR combination. 1 -Methoxymethyl pseudo-UTP(N 1 The mRNA was purified using column chromatography, and enzymatic reactions were used to remove DNA and all double-stranded mRNA contamination, and the mRNA was concentrated and buffer exchanged.

[0164] Preparation of lipid-encapsulated mRNA Lipid-encapsulated mRNA particles were prepared by mixing lipids (ATX lipid:DSPC:cholesterol:PEG-DMG) in ethanol with mRNA encoding the desired therapeutic polypeptide dissolved in citrate buffer. This mixture was rapidly diluted with phosphate buffer. The ethanol was removed by dialysis against phosphate buffer using a regenerated cellulose membrane (100 kD MWCO) or by tangential flow filtration (TFF) using a modified polyethersulfone (mPES) hollow fiber membrane (100 kD MWCO). After complete removal of the ethanol, the buffer was exchanged with HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer, pH 7.3, containing 50 mM NaCl and 9% sucrose. The formulation was concentrated and subsequently filtered to a 0.2 μm diameter using a PES filter. The mRNA concentration in this formulation was then determined by Ribogreen fluorescence assay, and the concentration was adjusted to the desired final concentration by dilution with 50 mM NaCl, 9% sucrose, HEPES buffer, pH 7.3, containing glycerol. The final formulation was then filtered through a 0.2 μm filter, filled into stoppered and capped glass vials, and placed at −70±5°C. The frozen formulations were characterized for mRNA content and encapsulation rate by Ribogreen assay, mRNA integrity by fragment analyzer, lipid content by high-performance liquid chromatography (HPLC), particle size by dynamic light scattering on a Malvern Zetasizer Nano ZS, pH, and osmolality.

[0165] In-Cell Western (ICW) Cells were seeded at the appropriate density in Dulbecco's Modified Eagle Medium (DMEM) / Fetal Bovine Serum (FBS) medium in 96-well collagen plates. At optimal confluence, cells were transfected with target mRNA diluted in a transfection reagent mix (MessengerMax and Opti-MEM). Cells were then placed in a CO2 incubator and allowed to grow. At the desired time points, the medium was removed, and cells were fixed with 4% fresh paraformaldehyde (PFA) for 20 minutes. The fixative was then removed, and cells were permeabilized with Tris-buffered saline with TWEEN (TBST) for several 5-minute washes. After permeabilization washes were complete, cells were incubated with blocking buffer [ODYSSEY® Blocking Buffer (PBS) (Li-Cor, Lincoln, NE)] for 45 minutes. Primary antibody was then added and incubated at room temperature for 1 hour. Cells were then washed several times with TBST and incubated with secondary antibody diluted in blocking buffer and containing CellTag700 stain for 1 hour. Finally, cells were washed several times with TBST, followed by a final wash with Tris-buffered saline (TBS). Plates were imaged using the Licor detection system, and data were normalized to the total number of CellTag700-labeled cells. [Example]

[0166] UTR screening in Hepa1,6 and Hep3B - correlation at 24 and 48 hours. The UTR library was screened in vitro using mRNA construct #571, which contains the sequence of SEQ ID NO:34 for OTC as the CDS (coding sequence). Using the in-cell Western assay described in Example 1, different mRNAs were transfected into Hepa1,6 and Hep3B cells using commercially available transfection reagents. OTC protein expression levels were measured using a near-infrared fluorescence imaging system. A commercially available OTC antibody was used for detection. Untransfected and reference sequences were used as internal controls. Panel A of Figure 1 shows scatter plots of OTC protein expression levels in Hepa1,6 and Hep3B cells at 24 hours. Panel B of Figure 1 shows scatter plots of OTC protein expression levels in Hepa1,6 and Hep3B cells at 48 hours. The goal of the screening was to determine UTR-specific effects on OTC expression levels in human (Hep3B) and mouse (Hepa1,6) hepatocyte cell lines, and which UTRs may be most beneficial in both models, particularly in determining translatability from mouse to human. Highly expressed UTRs were used in further profiling studies. [Example]

[0167] Round 1-Correlation of protein stability compounds screened in Hepa1,6 and Hep3B at 24 hours. In vitro screening of specific mRNA constructs in Table 5, designed based on the protein stability approach, was performed. The mRNA constructs were incubated with two different chemicals, N 11-methylpseudouridine (N1MPU) and 5-methoxyuridine (5MeOU) were tested, meaning that 100% of the uridines in each mRNA were either N1MPU alone or 5MeOU alone (not a combination of 5MeOU or N1MPU). Using the in-cell Western (ICW) assay described in Example 1, different mRNAs were transfected into Hepa1,6 and Hep3B cells using commercially available transfection reagents. OTC protein expression levels were measured using a near-infrared fluorescence imaging system. A commercially available OTC antibody was used for detection. Untransfected and reference sequences were used as internal controls. Panel A of Figure 2 is a scatter plot showing the correlation of OTC protein expression levels in Hepa1,6 cells at 24 hours as a function of mRNA tested with N1MPU and 5MeOU chemicals. Figure 2, panel B, is a scatter plot showing the correlation of OTC protein expression levels in Hep3B cells at 24 hours as a function of mRNA tested with N1MPU and 5MeOU chemicals. These figures show the degree of variation in expression levels when mRNA from two different chemicals was tested in mouse and human hepatocyte cell lines. In this experiment, it can be seen that most compounds were better expressed when N1MPU chemicals were used with mRNA. [Example]

[0168] Round 2 correlation of protein stability compounds screened in human primary hepatocytes at 24 and 48 hours. In vitro screening was performed on certain mRNA constructs in Table 5 designed based on the protein stability approach. The mRNA was tested with two different chemistries: N1MPU, where 100% of the uridines are indicated by ".1" after the name of the mRNA construct, and 5MeOU, where 100% of the uridines are indicated by ".7" after the name of the mRNA construct. Using the in-cell Western (ICW) assay described in Example 1, different mRNAs were transfected into human primary hepatocytes using commercially available transfection reagents. OTC protein expression levels were measured using a near-infrared fluorescence imaging system. A commercially available OTC antibody was used for detection. The untransfected sequence and the reference sequence were used as internal controls (Figure 3, panels A and B). The results suggest that both chemicals are similarly expressed in human primary hepatocytes, in contrast to experiments performed in cancer cell lines (Hepa1,6; Hep3B; Example 3). [Example]

[0169] Round 3 of protein stability compound screening in human primary hepatocytes at 24 and 48 hours: correlation. In vitro screening of novel compounds designed based on the protein stability approach was performed. mRNA was tested with two different chemicals: N1MPU, indicated by ".1" after the name of the mRNA construct, and 5MeOU, indicated by ".7" after the name of the mRNA construct. Using the in-cell Western (ICW) assay described in Example 1, different mRNAs were transfected into human primary hepatocytes using commercially available transfection reagents. OTC protein expression levels were measured using a near-infrared fluorescence imaging system. A commercially available antibody for OTC protein was used for detection. Untransfected and reference sequences were used as internal controls (Figure 4, panels A and B). The results suggest that both chemicals are similarly expressed in human primary hepatocytes, in contrast to experiments performed in cancer cell lines (Hepa1,6; Hep3B; Example 3). [Example]

[0170] OTC protein expression levels in human primary cells transfected with OTC mRNA constructs 1799.7 (5MeOu chemistry) encoding the OTC protein of SEQ ID NO: 3 and 1921.7 (5MeOu chemistry) encoding the modified OTC protein of SEQ ID NO: 4. Using the in-cell Western (ICW) assay described in Example 1, OTC mRNA was transfected into human primary hepatocytes using a commercially available transfection reagent. OTC protein expression levels were measured using a near-infrared fluorescence imaging system over a time course of up to 96 hours. A commercially available OTC antibody was used for detection. The untransfected sequence was used as an internal control. The plot shows OTC protein levels normalized to the untransfected control (Figure 5). The purpose of this study was to evaluate the half-life of the unmodified and modified protein sequences (1799.7, 1921.7) in transfected human primary hepatocytes under in vitro conditions. The results suggest that 1921.7 showed more stable expression than 1799.7. [Example]

[0171] OTC expression levels measured by multiple reaction monitoring (MRM) mass spectrometry in spf / ash mice administered 10 mg / kg. Spf / ash mice were injected IV with either PBS or lipid-formulated OTC mRNA at a dose of 10 mg / kg. WT mice were used as an internal control to determine endogenous levels. A time course (6, 24, and 48 h) was performed, and expression levels were measured by MRM using human- and mouse-specific epitopes of OTC. Graphs were generated showing the amount of protein (ng / mg tissue) detected by MRM specific for human OTC (Figure 6, Panel A) or mouse (Figure 6, Panel B). Human- and mouse-specific heavy peptides were designed to measure total OTC levels in both species. This dataset suggests that quantitative levels of human-specific OTC derived from translation of the delivered mRNA were detected. This expression remained stable at a high level for up to 48 h. [Example]

[0172] OTC expression levels measured by Western blot in WT mice administered at 3 mg / kg. Spf / ash mice were intravenously injected with either phosphate-buffered saline (PBS) or lipid-formulated OTC mRNA at a dose of 3 mg / kg using two different chemicals (N1MPU and 5MeO). WT mice were used as an internal control to determine endogenous levels. Animals were euthanized 24 hours after administration. OTC expression levels were measured by Western blot (WB) using an OTC-specific antibody. In the results presented in Figure 7, bars indicate the percentage of expression relative to WT levels (100%). The data generated in this figure demonstrate that WT levels of total OTC in the mouse background were achieved in several codon-optimized sequences. [Example]

[0173] OTC expression levels measured by MRM in a dose-range-finding study. Balb / c mice were IV-injected with either PBS or lipid-formulated OTC mRNA at three different doses: 0.3 mg / kg, 1 mg / kg, and 3 mg / kg, using two different chemicals (N1MPU and 5MeOU). 24 hours after administration, the animals were euthanized, and expression levels were measured by MRM using human- and mouse-specific epitopes of OTC. The graph in Figure 8 shows the percentage of human OTC expression (ng) per mg of liver tissue in Balb / c mice. The horizontal dotted line indicates the relative mouse OTC level in Balb / c mice (Figure 8). The expression levels of hOTC protein for mRNA construct 713 5MeOU and mRNA construct 571 N1MPU are indicated by arrows in Figure 8. In this figure, MRM was used to quantitatively measure human- and mouse-selective OTC protein levels. The data generated in this figure demonstrate that WT levels of human OTC in a mouse background are achieved with the codon-optimized sequences disclosed herein in a dose-dependent manner. [Example]

[0174] Urinary orotate levels measured in PBS and treated spf / ash mice. Spf / ash mice were intravenously injected with either PBS or lipid-formulated OTC-mRNA construct 1799.7 (5 MeOuC) at three different doses: 0.3 mg / kg, 1 mg / kg, and 3 mg / kg. WT and spf / ash mice were used to determine baseline and elevated urinary orotate levels, respectively. A time course of spf / ash mice was determined, and urinary orotate levels were measured at each time point. The results can be seen in Figure 9. Urinary orotate was normalized to creatinine, which is shown on the Y-axis graph over the time course and serves as proof-of-concept for functional recovery of OTC activity after injection. At 3 mg / kg, a sustained decrease in urinary orotate levels was observed for up to 14 days. [Example]

[0175] Pharmacokinetic / pharmacodynamic (PK / PD) analysis comparing human OTC expression levels and urinary orotate at 96 hours. Spf / ash mice were intravenously injected with PBS or specific lipid-formulated OTC mRNAs listed in Table 5 at 1 mg / kg and 3 mg / kg using two different chemistries (N1MPU and 5MeOU). WT mice were used as an internal control. Human-specific OTC levels were measured by MRM, and urinary orotate was measured in each sample and normalized to creatinine. PK / PD is plotted in Figure 10. PK / PD analysis demonstrates a compound-specific correlation between protein expression levels and reduction in urinary orotate. Construct 1799.7 demonstrates a high PK / PD correlation. [Example]

[0176] Fractions of spf / ash mice in in vivo samples treated with selected mRNAs. spf / ash mice were intravenously injected with either PBS or lipid-formulated OTC-mRNA at 1 mg / kg and 3 mg / kg. WT mice were used as an internal control. Sample fractionation was performed on liver samples, separating cytosolic and mitochondrial fractions. OTC levels were measured by WB using human-specific (hOTC) and cross-reactive (crOTC) antibodies (Figure 11). Cyclooxygenase IV (CoxIV) was used as a mitochondrial control. OTC protein expression levels were measured by near-infrared fluorescence imaging and normalized to total protein. WB analysis shows the difference in OTC expression levels in the mitochondrial and cytosolic fractions when 2016 and 2260 mRNAs were administered to spf / ash mice. 2260 mRNA encodes a protein with a modified signal peptide, as described herein. These results suggest that both compounds can efficiently target mitochondria. [Example]

[0177] Plots of mitochondrial and cytosolic fractions of spf / ash mouse samples treated with mRNA constructs 2016 and 2260. Spf / ash mice were injected IV with either PBS or lipid-formulated OTC-mRNA at 3 mg / kg. WT mice were used as an internal control. Sample fractionation was performed on liver samples, separating the cytosolic and mitochondrial fractions. OTC levels were measured by Western blot using a human-specific antibody. OTC protein expression levels were measured by a near-infrared fluorescence imaging system, and both fractions, normalized to total protein, were plotted (Figure 12). The protein expression level plot shown in Figure 11 (Example 12) suggests that although both compounds, 2016 and 2260, deliver similar protein levels in the cytosol, 2260 delivers more human OTC than 2016 in the mitochondria. 2260 contains a modified mitochondrial signaling peptide sequence of the present invention.

[0178] The patent and scientific literature referred to herein establishes knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are incorporated by reference. All other published references, documents, manuscripts, and scientific literature cited herein are incorporated by reference.

[0179] While the present disclosure has been shown and described in detail with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the disclosure as encompassed by the appended claims. It is also to be understood that the embodiments described herein are not mutually exclusive, and that features of various embodiments may be combined in whole or in part in accordance with the present disclosure. TIFF2025172749000027.tif232164 TIFF2025172749000028.tif232164 TIFF2025172749000029.tif232164 TIFF2025172749000030.tif232164 TIFF2025172749000031.tif232164 TIFF2025172749000032.tif232164 TIFF2025172749000033.tif232164 TIFF2025172749000034.tif232164 TIFF2025172749000035.tif232164 TIFF2025172749000036.tif232164 TIFF2025172749000037.tif232164 TIFF2025172749000038.tif232164 TIFF2025172749000039.tif232164 TIFF2025172749000040.tif232164 TIFF2025172749000041.tif232164 TIFF2025172749000042.tif232164 TIFF2025172749000043.tif232164 TIFF2025172749000044.tif232164 TIFF2025172749000045.tif232164 TIFF2025172749000046.tif232164 TIFF2025172749000047.tif232164 TIFF2025172749000048.tif232164 TIFF2025172749000049.tif232164 TIFF2025172749000050.tif232164 TIFF2025172749000051.tif232164 TIFF2025172749000052.tif232164 TIFF2025172749000053.tif232164 TIFF2025172749000054.tif232164 TIFF2025172749000055.tif232164 TIFF2025172749000056.tif232164 TIFF2025172749000057.tif232164 TIFF2025172749000058.tif232164 TIFF2025172749000059.tif232164 TIFF2025172749000060.tif232164 TIFF2025172749000061.tif232164 TIFF2025172749000062.tif232164 TIFF2025172749000063.tif232164 TIFF2025172749000064.tif232164 TIFF2025172749000065.tif232164 TIFF2025172749000066.tif232164 TIFF2025172749000067.tif232164 TIFF2025172749000068.tif232164 TIFF2025172749000069.tif232164 TIFF2025172749000070.tif232164 TIFF2025172749000071.tif232164 TIFF2025172749000072.tif232164 TIFF2025172749000073.tif232164 TIFF2025172749000074.tif232164 TIFF2025172749000075.tif232164 TIFF2025172749000076.tif232164 TIFF2025172749000077.tif232164 TIFF2025172749000078.tif232164 TIFF2025172749000079.tif232164 TIFF2025172749000080.tif232164 TIFF2025172749000081.tif232164 TIFF2025172749000082.tif232164 TIFF2025172749000083.tif232164 TIFF2025172749000084.tif232164 TIFF2025172749000085.tif232164 TIFF2025172749000086.tif232164 TIFF2025172749000087.tif232164 TIFF2025172749000088.tif232164 TIFF2025172749000089.tif232164 TIFF2025172749000090.tif232164 TIFF2025172749000091.tif232164 TIFF2025172749000092.tif232164 TIFF2025172749000093.tif232164 TIFF2025172749000094.tif232164 TIFF2025172749000095.tif232164 TIFF2025172749000096.tif232164 TIFF2025172749000097.tif232164 TIFF2025172749000098.tif232164 TIFF2025172749000099.tif232164 TIFF2025172749000100.tif232164 TIFF2025172749000101.tif232164 TIFF2025172749000102.tif232164 TIFF2025172749000103.tif232164 TIFF2025172749000104.tif232164 TIFF2025172749000105.tif232164 TIFF2025172749000106.tif232164 TIFF2025172749000107.tif232164 TIFF2025172749000108.tif232164 TIFF2025172749000109.tif232164 TIFF2025172749000110.tif232164 TIFF2025172749000111.tif232164 TIFF2025172749000112.tif232164 TIFF2025172749000113.tif232164 TIFF2025172749000114.tif232164 TIFF2025172749000115.tif232164 TIFF2025172749000116.tif232164 TIFF2025172749000117.tif232164 TIFF2025172749000118.tif232164 TIFF2025172749000119.tif232164 TIFF2025172749000120.tif232164 TIFF2025172749000121.tif232164 TIFF2025172749000122.tif232164 TIFF2025172749000123.tif232164 TIFF2025172749000124.tif232164 TIFF2025172749000125.tif232164 TIFF2025172749000126.tif232164 TIFF2025172749000127.tif232164 TIFF2025172749000128.tif232164 TIFF2025172749000129.tif232164 TIFF2025172749000130.tif232164 TIFF2025172749000131.tif232164 TIFF2025172749000132.tif232164 TIFF2025172749000133.tif232164 TIFF2025172749000134.tif232164 TIFF2025172749000135.tif232164 TIFF2025172749000136.tif232164

Claims

1. A modified protein having an amino acid sequence derived from the amino acid sequence of a human wild-type protein, wherein the amino acid sequence of the human wild-type protein has been modified to remove one or more ubiquitination sites identified as being present in the amino acid sequence of the human wild-type protein but not present in the homologous non-human animal wild-type protein.

2. The modified protein of claim 1 , wherein the homologous non-human animal wild-type protein is a mouse protein.

3. 3. The modified protein of claim 1 or 2, wherein one ubiquitination site has been removed from the amino acid sequence of the human wild-type protein.

4. 3. The modified protein of claim 1 or 2, wherein two ubiquitination sites have been removed from the amino acid sequence of the human wild-type protein.

5. 3. The modified protein of claim 1 or 2, wherein one or more ubiquitination sites are removed by altering the amino acids at the ubiquitination sites.

6. 3. The modified protein of claim 1 or 2, wherein the one or more ubiquitination sites are characterized by the presence of one or more lysine and non-lysine residues.

7. 3. The modified protein of claim 1 or 2, wherein the amino acid residues at one or more ubiquitination sites have been changed to arginine residues.

8. A modified protein having an amino acid sequence derived from the amino acid sequence of a wild-type protein having a signal peptide located at its terminal end, wherein the amino acid sequence of the signal peptide is modified by changing the amino acid at position +1 or +2, or by adding a new amino acid at position +1 or +2.

9. The modified protein of claim 8 , wherein the signal peptide is located at the N-terminus.

10. 10. The modified protein of claim 8 or 9, wherein the signal peptide directs the translocation of the wild-type protein for extracellular export.

11. The modified protein of claim 8 or 9, wherein the signal peptide directs the translocation of the wild-type protein to an organelle selected from the group consisting of mitochondria, nuclei, lysosomes, peroxisomes, endoplasmic reticulum, Golgi apparatus, and plasma membrane.

12. 10. The modified protein of claim 8 or 9, wherein the signal peptide directs the translocation of the wild-type protein to an internal portion of an intracellular organelle.

13. The modified protein of claim 11 or 12, wherein the intracellular organelle is a mitochondrion.

14. 14. The modified protein of any one of claims 8 to 13, wherein the signal peptide is modified by changing the amino acid at position +1 or +2.

15. 15. The modified protein of claim 14, wherein the amino acid at position +1 or +2 is changed to a stabilizing amino acid selected from the group consisting of alanine, glycine, methionine, serine, threonine, valine, and proline.

16. 14. A modified protein according to any one of claims 8 to 13, wherein the signal peptide is modified by adding a new amino acid at position +1 or +2.

17. 17. The modified protein of claim 16, wherein the amino acid added at the +1 or +2 position is a stabilizing amino acid selected from the group consisting of alanine, glycine, methionine, serine, threonine, valine, and proline.

18. a modified protein having an amino acid sequence derived from the amino acid sequence of a human wild-type protein, the human wild-type protein having a signal peptide located at its terminal end; i) the amino acid sequence of the signal peptide is modified by changing the amino acid at position +1 or +2, or by adding a new amino acid at position +1 or +2; ii) the amino acid sequence of the human wild-type protein has been modified to remove one or more ubiquitination sites identified as being present in the amino acid sequence of the human wild-type protein but not present in the wild-type protein of the homologous non-human animal; Modified proteins.

19. 19. The modified protein of claim 18, wherein the homologous non-human animal wild-type protein is a mouse protein.

20. 20. The modified protein of claim 18 or 19, wherein one ubiquitination site has been removed from the amino acid sequence of the human wild-type protein.

21. 20. The modified protein of claim 18 or 19, wherein two ubiquitination sites have been removed from the amino acid sequence of the human wild-type protein.

22. 20. The modified protein of claim 18 or 19, wherein one or more ubiquitination sites are removed by altering the amino acids at the ubiquitination sites.

23. 20. The modified protein of claim 18 or 19, wherein one or more ubiquitination sites are characterized by the presence of a lysine residue.

24. 23. The modified protein of claim 22, wherein the amino acid residues at one or more ubiquitination sites have been changed to arginine residues.

25. 25. The modified protein of any one of claims 18 to 24, wherein the signal peptide is located at the N-terminus.

26. 26. The modified protein of claim 25, wherein the signal peptide directs translocation of the human wild-type protein for extracellular export.

27. 26. The modified protein of claim 25, wherein the signal peptide directs translocation of the human wild-type protein to an organelle selected from the group consisting of mitochondria, nuclei, lysosomes, peroxisomes, endoplasmic reticulum, Golgi apparatus, and plasma membrane.

28. 26. The modified protein of claim 25, wherein the signal peptide directs translocation of the human wild-type protein to an internal portion of an organelle.

29. 29. The modified protein of claim 28, wherein the organelle is a mitochondrion.

30. 30. The modified protein of any one of claims 25 to 29, wherein the signal peptide is modified by changing the amino acid at position +1 or +2.

31. 31. The modified protein of claim 30, wherein the amino acid at position +1 or +2 is changed to a stabilizing amino acid selected from the group consisting of alanine, glycine, methionine, serine, threonine, valine, and proline.

32. 30. The modified protein of any one of claims 25 to 29, wherein the signal peptide is modified by adding an amino acid at the +1 or +2 position.

33. 33. The modified protein of claim 32, wherein the amino acid added at the +1 or +2 position is a stabilizing amino acid selected from the group consisting of alanine, glycine, methionine, serine, threonine, valine, and proline.

34. 10. The modified protein according to any one of the preceding claims, wherein the in vivo half-life of the modified protein is increased compared to the in vivo half-life of the human wild-type protein.

35. Human wild-type proteins include OTC, ASL, PAH, ABCB4, ABCB11, PAH, AGL, CFTR, MUT, PCCA, PCCB, ASS1, FAH, HMBS, ATP7B, PFIC2, LDLR, G6PC, AGX T, FXN, PAL, BCKDHA, BCKDHB, DBT, UGT1A1, SLC25A13, CD46, CFH, CFI, FIX, FVII, FVIII, C2, C3, C5, GCHD, CBS, MPI, LNL, SERPI NG1, UROC1, SMPD1, GLA, GAA, GRHPR, ATP8B1, SERPINC1, PROS1, GBA, ACADVL, HFE, BCKDA, CDG1B, SERPINA1, BMPR2, ENG, ACVR1 , SMAD4, BMPR9, HBB, FLCN, HSP1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, PLDN, AP3D1, BRAF, NF-1, SLC34A2, FBN1, CO L1A1, COL1A2, COL1A3, COL5A1, COL5A2, ADAMTS2, PLOD1, TNXB, ABCA3, SP-B, SP-C, GBA, NPC1, NPC2, FOXF1, NKX2-1, SFTPB, SF TPC, ABCA3, CSF2RA, SFTPD, MUC5B, BMPR2, EIF2AK4, CSF2RB, DNAH5, DNAI1, DNAH11, AKR1D1, AMACR, ATP8B1, CYP7A1, FOXC2, G 10. The modified protein of any one of the preceding claims, selected from the group consisting of ATA2, GHR, HSD3B7, IGFALS, IKBKG, JAG1, KIF11, NOTCH1, NOTCH2, NR1H4, SOX18, TJP2, P53, P73, P63, VIPAS39, VPS33B, EPO, ARG1, CPS1, NAGS, NOS, KRAS, OX40L, IL12, VEGF-A, MMA, TTR, PCSK9, AT, and ALAS1.

36. A polynucleotide comprising a sequence encoding a modified peptide according to any one of the preceding claims.

37. 37. The polynucleotide of claim 36, wherein the polynucleotide is DNA.

38. 37. The polynucleotide of claim 36, wherein the polynucleotide is messenger RNA (mRNA).

39. 39. The polynucleotide of claim 38, wherein the mRNA comprises an open reading frame encoding the modified protein.

40. 40. The polynucleotide of claim 39, wherein the open reading frame is a codon-optimized open reading frame.

41. 40. The polynucleotide of claim 39, wherein the open reading frame sequence is optimized to have the theoretical minimum number of uridines possible to encode a modified protein.

42. 42. The polynucleotide of any one of claims 38 to 41, wherein the mRNA comprises a 5' cap, a 5' untranslated region (UTR), a 3' UTR, an open reading frame encoding a modified protein, and a polyA tail.

43. mRNA is selected from the group consisting of 5-hydroxycytidine, 5-methylcytidine, 5-hydroxymethylcytidine, 5-carboxycytidine, 5-formylcytidine, 5-methoxycytidine, 5-propynylcytidine, 2-thiocytidine; 5-hydroxyuridine, 5-methyluridine, 5,6-dihydro-5-methyluridine, 2'-O-methyluridine, 2'-O-methyl-5-methyluridine, 2'-fluoro-2'-deoxyuridine, 2'-amino-2'-deoxyuridine, 2'-azido-2'-deoxyuridine, 4-thiouridine, 5-hydroxymethyluridine, 5-carboxyuridine, 5-carboxymethylester uridine, 5-formyluridine, 5-methoxyuridine, 5-propynyluridine, 5-bromouridine, 5-iodouridine, 5-fluorouridine; pseudouridine, 2'-O-methyl-pseudouridine, N １ -hydroxypseudouridine, N １ -methylpseudouridine, 2'-O-methyl-N １ -methylpseudouridine, N １ -Ethylpseudouridine, N １ -hydroxymethylpseudouridine, and alauridine; N ６ 43. The polynucleotide of any one of claims 38 to 42, comprising one or more chemically modified nucleotides selected from the group consisting of 6-O-methyladenosine, 2-aminoadenosine, 3-methyladenosine, 7-deazaadenosine, 8-oxoadenosine, inosine; thienoguanosine, 7-deazaguanosine, 8-oxoguanine, and 6-O-methylguanine.

44. Chemically modified nucleotides are N １ 42. The polynucleotide of any one of claims 38 to 41, wherein the polynucleotide is -methylpseudouridine.

45. 42. The polynucleotide of any one of claims 38 to 41, wherein the chemically modified nucleotide is 5-methoxyuridine.

46. Chemically modified nucleotides include pseudouridine and N １ -methylpseudouridine. The polynucleotide of any one of claims 38 to 41.

47. Chemically modified nucleotides include 5-methylcytidine and N １ -methylpseudouridine. The polynucleotide of any one of claims 38 to 41.

48. Chemically modified nucleotides include 5-methoxyuridine and N １ -methylpseudouridine. The polynucleotide of any one of claims 38 to 41.

49. Chemically modified nucleotides include 5-methoxyuridine, 5-methylcytidine and N-methyl- １ -methylpseudouridine. The polynucleotide of any one of claims 38 to 41.

50. 50. A polynucleotide according to any one of claims 38 to 49, wherein the translation efficiency of the polynucleotide is increased by at least 50% compared to an mRNA encoding the human wild-type protein.

51. 50. A polynucleotide according to any one of claims 38 to 49, wherein the translation efficiency of the polynucleotide is increased by at least three-fold compared to an mRNA encoding the human wild-type protein.

52. 52. The polynucleotide of any one of claims 38 to 51, comprising from 200 to 5,000 nucleotides.

53. 53. The polynucleotide of any one of claims 38 to 52, wherein chemically modified nucleotides constitute 1 to 99% of the nucleotides.

54. 54. The polynucleotide of any one of claims 38 to 53, wherein chemically modified nucleotides constitute 50 to 99% of the nucleotides.

55. 55. The polynucleotide of any one of claims 38 to 54, comprising a translation enhancer.

56. 56. A composition comprising one or more polynucleotides of any one of claims 38 to 55 and a pharmaceutically acceptable carrier.

57. 57. The composition of claim 56, wherein the carrier comprises a transfection reagent, a nanoparticle, or a liposome.

58. 58. The composition of claim 56 or 57 for use in medical therapy.

59. 58. A composition according to claim 56 or 57 for use in the treatment of the human body.

60. 58. A composition according to claim 56 or 57 for preparing or manufacturing a medicament for ameliorating, preventing, delaying the onset of, or treating a disease or condition associated with a deficiency of the human wild-type protein.

61. A method for ameliorating, preventing, delaying the onset of, or treating a disease or condition associated with a deficiency in a human wild-type protein in a subject identified as suffering from the deficiency, comprising administering to the subject a composition of any one of the preceding claims.

62. 62. The method of claim 61, wherein the administration is intravenous, subcutaneous, pulmonary, intramuscular, intraperitoneal, transdermal, oral, nasal, or by inhalation.

63. 63. The method of claim 61 or 62, wherein administration is once, twice, three times, or four times daily, weekly, biweekly, or monthly.

64. 64. The method of any one of claims 61 to 63, wherein administration comprises an effective dose of 0.01 to 10 mg / kg.

65. 65. The method of any one of claims 61 to 64, wherein administration increases expression of the modified protein in the liver, serum, lung, plasma, kidney, spleen, eye, heart, muscle, brain, cerebrospinal fluid, or lymph node of the subject.

66. 61. A kit for expressing a modified human protein in vivo, comprising a 0.1 to 500 mg dose of one or more polynucleotides of any one of claims 38 to 55, or a composition of any one of claims 56 to 60, and a device for administering the dose.

67. 67. The kit of claim 66, wherein the device is an injection needle, an intravenous needle, a droplet device, or an inhalation device.

68. 1. A method of modifying a protein of interest, wherein the protein of interest is a human wild-type protein, i) identifying ubiquitination sites in the amino acid sequence of the human wild-type protein that are not present in the amino acid sequence of the homologous non-human animal wild-type protein; ii) removing at least one of the ubiquitination sites identified in step (i) from the amino acid sequence of the human wild-type protein to provide a modified protein of interest; A method comprising:

69. 69. The method of claim 68, wherein one ubiquitination site is removed from the amino acid sequence of the human wild-type protein.

70. 69. The method of claim 68, wherein two ubiquitination sites are removed from the amino acid sequence of the human wild-type protein.

71. 71. The method of any one of claims 68 to 70, wherein the homologous non-human animal wild-type protein is a mouse protein.

72. 72. The method of any one of claims 68 to 71, wherein the removal of step (ii) comprises replacing at least one amino acid residue of the ubiquitination site.

73. 72. The method of any one of claims 68 to 71, wherein the removal of step (ii) comprises replacing at least one lysine residue of the ubiquitination site with an arginine residue.

74. 74. The method of any one of claims 68 to 73, wherein the human wild-type protein comprises a signal peptide at the terminal portion, and the method further comprises modifying the amino acid sequence of the signal peptide by changing the amino acid at the +1 or +2 position, or by adding an amino acid at the +1 or +2 position.

75. 75. The method of claim 74, wherein the signal peptide is located at the N-terminus.

76. 76. The method of claim 74 or 75, wherein the signal peptide directs translocation of the human wild-type protein for extracellular export.

77. 76. The method of claim 74 or 75, wherein the signal peptide directs translocation of the human wild-type protein to an organelle selected from the group consisting of mitochondria, nuclei, lysosomes, peroxisomes, endoplasmic reticulum, Golgi apparatus, and plasma membrane.

78. 76. The method of claim 74 or 75, wherein the signal peptide directs the translocation of the human wild-type protein to an internal portion of the organelle.

79. 79. The method of claim 78, wherein the organelle is a mitochondrion.

80. 80. The method of any one of claims 74 to 79, wherein modifying the amino acid sequence of the signal peptide comprises altering the amino acid at position +1 or +2.

81. 81. The method of claim 80, wherein the amino acid at position +1 or +2 is changed to a stabilizing amino acid selected from the group consisting of alanine, glycine, methionine, serine, threonine, valine, and proline.

82. 80. The method of any one of claims 74 to 79, wherein modifying the amino acid sequence of the signal peptide comprises adding an amino acid at the +1 or +2 position.

83. 83. The method of claim 82, wherein the amino acid added at the +1 or +2 position is a stabilizing amino acid selected from the group consisting of alanine, glycine, methionine, serine, threonine, valine, and proline.

84. 84. The method of any one of claims 74 to 83, wherein the in vivo half-life of the modified protein is increased compared to the in vivo half-life of the human wild-type protein.

85. Human wild-type proteins include OTC, ASL, PAH, ABCB4, ABCB11, PAH, AGL, CFTR, MUT, PCCA, PCCB, ASS1, FAH, HMBS, ATP7B, PFIC2, LDLR, G6PC, AGX T, FXN, PAL, BCKDHA, BCKDHB, DBT, UGT1A1, SLC25A13, CD46, CFH, CFI, FIX, FVII, FVIII, C2, C3, C5, GCHD, CBS, MPI, LNL, SERPI NG1, UROC1, SMPD1, GLA, GAA, GRHPR, ATP8B1, SERPINC1, PROS1, GBA, ACADVL, HFE, BCKDA, CDG1B, SERPINA1, BMPR2, ENG, ACVR1 , SMAD4, BMPR9, HBB, FLCN, HSP1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, PLDN, AP3D1, BRAF, NF-1, SLC34A2, FBN1, C OL1A1, COL1A2, COL1A3, COL5A1, COL5A2, ADAMTS2, PLOD1, TNXB, ABCA3, SP-B, SP-C, GBA, NPC1, NPC2, FOXF1, NKX2-1, SFTPB, S FTPC, ABCA3, CSF2RA, SFTPD, MUC5B, BMPR2, EIF2AK4, CSF2RB, DNAH5, DNAI1, DNAH11, AKR1D1, AMACR, ATP8B1, CYP7A1, FOXC2, 84. The method of any one of claims 74 to 83, wherein the target protein is selected from the group consisting of GATA2, GHR, HSD3B7, IGFALS, IKBKG, JAG1, KIF11, NOTCH1, NOTCH2, NR1H4, SOX18, TJP2, P53, P73, P63, VIPAS39, VPS33B, EPO, ARG1, CPS1, NAGS, NOS, KRAS, OX40L, IL12, VEGF-A, MMA, TTR, PCSK9, AT, and ALAS1.

86. 85. The method of any one of claims 74 to 84, further comprising preparing a polynucleotide encoding the modified protein.

87. 87. The method of claim 86, wherein the polynucleotide is messenger RNA (mRNA).

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