Methods of treating CLRN1-associated hearing loss and / or vision loss

Abstract

To provide compositions that include a single nucleic acid vector or two different nucleic acid vectors, and to provide the use of these compositions to treat hearing loss and / or vision loss in a subject.SOLUTION: The present invention relates to a composition including at least two different nucleic acid vectors, where each of the at least two different vectors includes a coding sequence that encodes a different portion of a CLRN1 protein, generates a sequence encoding an active CLRN1 protein (e.g., a full-length CLRN1 protein) in a mammalian cell by using the coding sequence, and thereby can treat CLRN1-associated hearing loss and / or vision loss in a subject in need thereof. The invention also relates to compositions including a single nucleic acid vector that includes a coding sequence for a first and / or second isoform of CLRN1 protein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 689,660, filed June 25, 2018. No. 6,239,999, filed on May 1, 2003, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure generally relates to a method for treating hearing loss, vision loss, or both in a human subject. The present invention relates to the use of nucleic acids. [Background technology]

[0003] Current treatments for hearing loss primarily include hearing amplification for mild to severe hearing loss; and cochlear implantation for severe to profound hearing loss. There remains a long-recognized need for agents and methods to prevent or reverse are.

[0004] Hearing loss can be conductive (originating from the ear canal or middle ear), sensorineural (originating from the inner ear or auditory nerve), or Most forms of syndromic hearing loss are due to a disorder in the inner ear. Permanent hearing loss caused by damage to the structure (sensorineural hearing loss), but some This form may be accompanied by changes in the middle ear (conductive hearing loss). Most cases are caused by abnormalities in the hair cells of the organ of Corti in the cochlea (poor hair cell function). Hair cells may be abnormal at birth or may be damaged during an individual's lifetime. They may also be subjected to noise-induced trauma (e.g., as a result of noise trauma or infection). Summary of the Invention [Means for solving the problem]

[0005] The present invention relates to a composition comprising at least two different nucleic acid vectors, Each of the three vectors contains a coding sequence encoding a different portion of the CLRN1 protein. and a column that can be used to detect active CLRN1 protein (e.g., complete CLRN1 protein) in mammalian cells. and generating a sequence encoding the CLRN1 protein (long CLRN1 protein), thereby providing a therapeutic target for The present invention can treat CLRN1-associated hearing loss and / or vision loss in a subject. The present invention also provides a method for producing a polypeptide comprising the first and / or second isoforms of the CLRN1 protein. The present invention also relates to a composition comprising a single nucleic acid vector containing the code sequence.

[0006] Provided herein are compositions comprising at least two different nucleic acid vectors, At least two different vectors each encode a different portion of the CLRN1 protein. Each of the encoded sequences comprises a coding sequence, the coding sequences being at least 30 amino acid residues in length. and the amino acid sequence of each of the encoded portions is optionally The amino acid sequences of the at least two different bases may partially overlap with each other. Any single vector in the vectors encodes the full-length CLRN1 protein. and at least one of the coding sequences is located between two consecutive sites in the CLRN1 genomic DNA. a nucleotide sequence spanning two consecutive exons and lacking intronic sequences between the two consecutive exons the at least two different vectors containing the nucleotide sequences when introduced into mammalian cells. undergo homologous recombination with each other, thereby encoding the full-length CLRN1 protein A recombinant nucleic acid is formed. Some embodiments of any of the compositions provided herein In one embodiment, each of the at least two different vectors contains a first sequence of the CLRN1 protein. The compositions provided herein include coding sequences that encode different portions of the isoforms. In some embodiments of any of the above, the first isoform of the CLRN1 protein The form comprises a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments of any of the compositions, the first eye of the CLRN1 protein The isoform comprises SEQ ID NO: 3. A portion of any of the compositions provided herein In one embodiment, the first isoform of the CLRN1 protein is selected from the group consisting of SEQ ID NO: 3 to In some embodiments of any of the compositions provided herein, the at least One of the two different nucleic acid vectors encodes a second isoform of the CLRN1 protein. Any of the compositions provided herein further comprises a sequence encoding a form. In some embodiments, the second isoform of the CLRN1 protein is set forth in SEQ ID NO:5 Any of the compositions provided herein comprises a sequence that is at least 95% identical to In some embodiments, the second isoform of the CLRN1 protein has SEQ ID NO: In some embodiments of any of the compositions provided herein, the C The second isoform of the LRN1 protein consists of SEQ ID NO: 5. In some embodiments of any of the compositions described above, the at least two different vectors Each of the sequences encodes a different portion of the second isoform of the CLRN1 protein. In some embodiments of any of the compositions provided herein, the composition comprises a coding sequence. The second isoform of the CLRN1 protein has at least 95% identity with SEQ ID NO:5. Some embodiments of any of the compositions provided herein include sequences that are identical. In the present specification, the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. In some embodiments of any of the compositions provided herein, the CLRN1 protein The second isoform of consists of SEQ ID NO: 5. In some embodiments of any of the above, one of the at least two different nucleic acid vectors The gene encoding the first isoform of the CLRN1 protein is further included. In some embodiments of any of the compositions provided herein, the CLRN1 protein The first isoform of the protein comprises a sequence that is at least 95% identical to SEQ ID NO:3. In some embodiments of any of the compositions provided herein, the CLRN1 tag The first isoform of the protein comprises SEQ ID NO: 3. Compositions provided herein In some embodiments of any of the above, the first isoform of the CLRN1 protein is The sequence consists of SEQ ID NO:3.

[0007] In some embodiments of any of the compositions provided herein, the at least 2 At least one of the two vectors contains a 5' untranslated region (UTR), a 3' UTR, In some embodiments of any of the compositions provided herein, In other words, the 5'UTR is a sequence of at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the The 5'UTR comprises at least 20 contiguous nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the 5′U TR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12 In some embodiments of any of the compositions provided herein, the 5'UTR is , comprising at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the 5'UTR comprises the sequence The compositions described herein include sequences that are at least 80% identical to sequence number 12. In some embodiments of any of the above, the 3'UTR comprises a sequence from anywhere within SEQ ID NO: 15. Any of the compositions described herein comprises at least 10 consecutive nucleotides. In some embodiments, the 3'UTR comprises at least one sequence from anywhere within SEQ ID NO:15. Any of the compositions provided herein comprises 20 consecutive nucleotides. In some embodiments, the 3'UTR comprises at least 5' of any sequence within SEQ ID NO: 15. 0 consecutive nucleotides. In embodiments, the 3'UTR comprises at least 80 amino acids from anywhere within SEQ ID NO: 15. Some embodiments of any of the compositions provided herein include contiguous nucleotides. In some embodiments, the 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO:15.

[0008] In some embodiments of any of the compositions provided herein, the at least 2 Each of the different vectors can be a plasmid, transposon, cosmid, artificial chromosome, or or a viral vector. In embodiments, each of the at least two different vectors is a human artificial chromosome (HAC), Yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), or P1-derived artificial chromosomes (P In some embodiments of any of the compositions provided herein, Each of the at least two different vectors may be an adeno-associated virus (AAV) vector, an adenovirus vector, or an adenovirus vector. Choose from denoviral, lentiviral, or retroviral vectors A viral vector selected from the group consisting of any of the compositions provided herein. In this embodiment, each of the at least two different vectors is an AAV vector.

[0009] In some embodiments of any of the compositions provided herein, the encoded The amino acid sequence of any one of the encoded portions may be different from that of a different one of the encoded portions. The amino acid sequence of any of the compositions provided herein does not overlap. In embodiments, the amino acid sequence of each of the encoded portions is The amino acid sequence of the composition provided herein partially overlaps with a different portion of the amino acid sequence of the composition provided herein. In some embodiments, the overlapping amino acid sequences are from about 30 amino acid residues to about 2 The length of any of the compositions provided herein is 0.2 amino acid residues. In embodiments, the vector comprises two different vectors, Each contains a different segment of an intron, which is located in the CLRN1 genomic DNA. A comprises the nucleotide sequence of an intron present in A, and the two different intron segments The sequences of the two fragments overlap by at least 100 nucleotides. In some embodiments of any of these, the sequences of the two different intron segments are They overlap by 00 nucleotides to approximately 800 nucleotides.

[0010] In some embodiments of any of the compositions provided herein, the at least 2 The entire nucleotide sequence of each of the different vectors ranges from about 500 nucleotides to about 10, 000 nucleotides in length. In one embodiment, the entire nucleotide sequence of each of the at least two different vectors is The compositions provided herein are between 500 nucleotides and 5,000 nucleotides in length. In some embodiments of any of the compositions, the number of different vectors in the composition is two or more. In some embodiments of any of the compositions provided herein, the two different The first vector of the vectors encodes the N-terminal portion of the CLRN1 protein. Some embodiments of any of the compositions provided herein include a coding sequence for The N-terminal portion of the CLRN1 protein is 30 to 202 amino acids long. In some embodiments of any of the compositions provided herein, the CLR The N-terminal portion of the N1 protein is 60 to 170 amino acids in length. In some embodiments of any of the compositions provided herein, the first vector comprises 5 'Further comprising a UTR sequence. In one embodiment, the 5'UTR comprises at least 10 consecutive sequences from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, In other words, the 5'UTR is a sequence of at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the The 5'UTR comprises at least 50 contiguous nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the 5′U TR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12 In some embodiments of any of the compositions provided herein, the 5'UTR is , comprising a sequence that is at least 80% identical to SEQ ID NO: 12. In some embodiments of any of the above, the first vector comprises a promoter and a Kozak vector. Any of the compositions provided herein further comprises one or both of the following sequences: In some embodiments, the first vector comprises an inducible promoter, a constitutive promoter, or promoters that are specific for the target gene, or tissue-specific promoters. In some embodiments of any of the compositions, the second of the two different vectors The vector contains a coding sequence that encodes the C-terminal portion of the CLRN1 protein. In some embodiments of any of the compositions provided herein, the CLRN1 protein The C-terminal portion of the polypeptide is 30 to 202 amino acids in length. In some embodiments of any of the compositions, the C-terminal portion of the CLRN1 protein The amino acid sequence is between 60 and 170 amino acids in length. In some embodiments of any of the above, the second vector comprises a polyadenylation signal sequence. In some embodiments of any of the compositions provided herein, the first The vectors of the second aspect further comprise a 3'UTR sequence. In some embodiments, the 3'UTR comprises at least one sequence from anywhere within SEQ ID NO: 15. Any of the compositions provided herein comprises at least 10 consecutive nucleotides. In some embodiments, the 3'UTR comprises at least one sequence from anywhere within SEQ ID NO:15. 20 consecutive nucleotides. In this embodiment, the 3'UTR comprises at least 50 amino acids from anywhere within SEQ ID NO: 15. Some embodiments of any of the compositions provided herein include In one embodiment, the 3'UTR comprises at least 80 consecutive amino acids from anywhere within SEQ ID NO: 15. In some embodiments of any of the compositions provided herein, wherein the 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO:15.

[0011] Also provided herein are compositions comprising a single nucleic acid vector, the vector comprising: ) a first coding sequence encoding a first isoform of the CLRN1 protein; and ii) a second coding sequence encoding a second isoform of the CLRN1 protein; wherein one or both of the first and second coding sequences are C It spans two consecutive exons of the LRN1 genomic DNA and contains the two consecutive intros. The combinations provided herein include nucleotide sequences lacking intron sequences between the sequences. In some embodiments of any of the compositions, the single nucleic acid vector comprises the first coding The compositions provided herein contain the sequence and do not contain the second coding sequence. In some embodiments of any of the above, the single nucleic acid vector contains the second coding sequence. The first coding sequence is not contained in any one of the compositions provided herein. In some embodiments, the single nucleic acid vector contains the first coding sequence and the second coding sequence. In some embodiments of any of the compositions provided herein, The first isoform of the CLRN1 protein has at least 95% identity with SEQ ID NO: 3. % identical to any of the compositions provided herein. In one embodiment, the first isoform of the CLRN1 protein comprises SEQ ID NO: 3. In some embodiments of any of the compositions provided herein, the CLRN1 protein The first isoform of the protein consists of SEQ ID NO: 3. In some embodiments of any of these, the second isoform of the CLRN1 protein comprises a sequence that is at least 95% identical to SEQ ID NO: 5. Compositions provided herein In some embodiments of any of the above, the second isoform of the CLRN1 protein is The composition comprises SEQ ID NO: 5. Some embodiments of any of the compositions provided herein In one embodiment, the second isoform of the CLRN1 protein consists of SEQ ID NO:5.

[0012] In some embodiments of any of the compositions provided herein, the single nucleic acid vector The vector further comprises a 5' untranslated region (UTR), a 3' UTR, or both. In some embodiments of any of the compositions provided herein, the 5'UTR is selected from the group consisting of SEQ ID NO: nucleotides from any position within the range of 1 to 12. In some embodiments of any of the compositions described above, the 5'UTR is selected from the group consisting of SEQ ID NO: 12 The present invention also provides a method for the preparation of a nucleic acid sequence comprising at least 20 consecutive nucleotides from any part of the sequence provided herein. In some embodiments of any of the compositions, the 5'UTR is any of SEQ ID NO: 12 The compositions provided herein comprise at least 50 consecutive nucleotides from In some embodiments of any of the above, the 5'UTR is any position within SEQ ID NO: 12. Among the compositions provided herein, the present invention comprises at least 80 contiguous nucleotides from In some embodiments of any of the above, the 5'UTR is at least 80% identical to SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, In other words, the 3'UTR is a sequence of at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 15. In some embodiments of any of the compositions provided herein, the The 3'UTR comprises at least 20 contiguous nucleotides from anywhere within SEQ ID NO: 15. In some embodiments of any of the compositions provided herein, the 3′U TR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 15 In some embodiments of any of the compositions provided herein, the 3'UTR is , comprising at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 15. In some embodiments of any of the compositions provided herein, the 3'UTR comprises the sequence Contains a sequence that is at least 80% identical to number 15.

[0013] In some embodiments of any of the compositions provided herein, the single nucleic acid vector Vectors may be plasmids, transposons, cosmids, artificial chromosomes, or viral vectors. In some embodiments of any of the compositions provided herein, the single Nucleic acid vectors include human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), and bacterial artificial chromosomes (BACs). The combinations provided herein are chromosomes derived from artificial chromosomes (BACs), or P1-derived artificial chromosomes (PACs). In some embodiments of any of the compositions, the single nucleic acid vector is an adeno-associated virus. vectors, such as AAV vectors, adenoviral vectors, lentiviral vectors, or lentiviral vectors. The viral vector is selected from the group consisting of viral vectors, viral vectors, and viral vectors. In some embodiments of any of the compositions, the single nucleic acid vector is an AAV vector In some embodiments of any of the compositions provided herein, the single The nucleic acid vector further comprises one or both of a promoter and a Kozak sequence. In some embodiments of any of the compositions provided herein, the first vector promoters that are inducible, constitutive, or tissue-specific promoters. In some embodiments of any of the compositions provided herein, The single nucleic acid vector further comprises a polyadenylation signal sequence. Some embodiments of any of the compositions described further comprise a pharmaceutically acceptable excipient. include.

[0014] Also provided herein are kits containing any of the compositions provided herein. Some embodiments of any of the kits provided herein may include the Pre-filled syringes containing or including any of the compositions described are also provided. include.

[0015] Also provided herein are methods for administering to the mammalian cochlea a therapeutically effective amount of a composition provided herein. Also provided are methods comprising introducing any of the methods provided herein. In some embodiments of any of these, the mammal is a human. In some embodiments of any of the methods, the mammal has a defective CLRN1 gene. Previously identified as having children.

[0016] Also described herein is a method for increasing the expression of full-length CLRN1 protein in mammalian cells. Also provided are methods of administering any of the compositions provided herein to the mammal. Some embodiments of any of the methods provided herein include introducing the gene into a cell. In some embodiments, the mammalian cell is a cochlear inner hair cell or an outer cochlear hair cell. In some embodiments of any of the methods described above, the mammalian cell is a retinal cell. In some embodiments of any of the methods provided herein, the mammalian cell is a human In some embodiments of any of the methods provided herein, the mammalian cell is a mammalian cell. Mammalian cells have previously been determined to have a defective CLRN1 gene.

[0017] Also described herein are inner hair cells, outer hair cells, or both in the mammalian cochlea. Also provided is a method for increasing expression of full-length CLRN1 protein, the method comprising: introducing a therapeutically effective amount of any of the compositions provided herein into the cochlea of Also described herein is the expression of full-length CLRN1 protein in the mammalian eye. Also provided is a method of increasing the number of inflammatory cytokines present in a mammalian eye, the method comprising administering to the mammal a therapeutically effective amount of the compounds provided herein. The method includes administering any of the compositions provided herein intraocularly. In some embodiments of any of the above, the mammal has a defective CLRN1 gene. It has been previously identified as having the following properties: In embodiments, the mammal is a human.

[0018] Also described herein are methods for detecting hearing loss in subjects identified as having a defective CLRN1 gene. Also provided are methods for treating loss of strength, the methods comprising administering a therapeutically effective amount of a composition provided herein. The present invention also includes administering to the subject a defective cochlea any of the following: Also provided are methods of treating vision loss in a subject identified as having the CLRN1 gene. The method comprises administering to the subject a therapeutically effective amount of any of the compositions provided herein. Some embodiments of any of the methods provided herein include administering to the eye. In the method provided herein, the subject has Usher syndrome type III. In some embodiments of any of the methods provided herein, the subject is a human. Some embodiments of any of these may further comprise administering to the subject a therapeutically effective amount of steroid hormone (SAH) to the subject, the therapeutically effective amount of steroid hormone (SAH) to the subject. It further includes determining that the patient has the N1 gene.

[0019] Also provided herein are compositions comprising two different nucleic acid vectors, wherein the two different The first of the nucleic acid vectors comprises a promoter and a 3' end of the promoter. a first coding sequence encoding the N-terminal portion of the CLRN1 protein, located adjacent to and a splice donor sequence located at the 3' end of the first coding sequence, The second of the two different nucleic acid vectors comprises a splice acceptor sequence and of the CLRN1 protein located at the 3' end of the splice acceptor sequence. a second coding sequence encoding a C-terminal portion and a and a polyadenylation signal sequence, each of said encoded segments comprising at least 30 amino acids. the amino acid sequences of the two encoded portions do not overlap with each other, Any single vector of the two different vectors contains the full-length CLRN1 protein. When introduced into mammalian cells, the splice donor sequence and the splice donor sequence do not encode a protein. Splicing occurs between the Rice acceptor sequence and the full-length CLR A recombinant nucleic acid encoding the N1 protein is formed. In some embodiments of any of these, the first coding sequence encodes the first amino acid sequence of the CLRN1 protein. The second coding sequence encodes the N-terminal portion of the first isoform, and the second coding sequence encodes the N-terminal portion of the first isoform. The present invention relates to a method for producing a CLRN1 protein comprising administering to a subject the method of the present invention ... In some embodiments of any of these, the first isoform of the CLRN1 protein The compositions provided herein include sequences that are at least 95% identical to SEQ ID NO: 3. In some embodiments of any of the above, the first isoform of the CLRN1 protein The form comprises SEQ ID NO: 3. Some embodiments of any of the compositions provided herein may be In an embodiment, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3 In some embodiments of any of the compositions provided herein, the second nucleic acid vector The first nucleic acid vector of the vector encodes a second isoform of the CLRN1 protein. A portion of any of the compositions provided herein further comprises a sequence encoding the nucleotide sequence. In this embodiment, the second isoform of the CLRN1 protein has a sequence similar to SEQ ID NO: 5 and at least one sequence similar to SEQ ID NO: 6. Any of the compositions provided herein includes sequences that are at least 95% identical. In some embodiments, the second isoform of the CLRN1 protein is set forth in SEQ ID NO:5 In some embodiments of any of the compositions provided herein, the CLR The second isoform of the N1 protein consists of SEQ ID NO:5.

[0020] In some embodiments of any of the compositions provided herein, the first code The sequence encodes the N-terminal portion of a second isoform of the CLRN1 protein, The coding sequence of this gene encodes the C-terminal portion of the second isoform CLRN1 protein. In some embodiments of any of the compositions provided herein, the CLRN1 The second isoform of the protein has a sequence that is at least 95% identical to SEQ ID NO:5. In some embodiments of any of the compositions provided herein, the CLR The second isoform of the N1 protein comprises SEQ ID NO: 5. In some embodiments of any of the compositions, the second eye of the CLRN1 protein The isoform consists of SEQ ID NO: 5. Any one of the compositions provided herein In some embodiments, the first nucleic acid vector or the second nucleic acid vector comprises the CLRN1 The present invention further includes a sequence encoding a first isoform of the protein. In some embodiments of any of the compositions, the first amino acid sequence of the CLRN1 protein is Isoforms include sequences that are at least 95% identical to SEQ ID NO: 3. In some embodiments of any of the compositions described above, the first Isoforms of include SEQ ID NO: 3. Any of the compositions provided herein In some embodiments, the first isoform of the CLRN1 protein is selected from the group consisting of SEQ ID NO: It consists of 3.

[0021] In some embodiments of any of the compositions provided herein, the first nucleic acid vector one or both of the vector and the second nucleic acid vector contain a 5' untranslated region (UTR) , 3'UTR, or both. In this embodiment, the 5'UTR comprises at least 10 amino acids from anywhere within SEQ ID NO: 12. Some embodiments of any of the compositions provided herein include In one embodiment, the 5'UTR comprises at least 20 consecutive amino acids from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, In other words, the 5'UTR is a sequence of at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the The 5'UTR comprises at least 80 contiguous nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the 5′U The TR comprises a sequence that is at least 80% identical to SEQ ID NO: 12. In some embodiments of any of the compositions, the 3'UTR is any of SEQ ID NO: 15 The compositions provided herein comprise at least 10 consecutive nucleotides from In some embodiments of any of the above, the 3'UTR is any position within SEQ ID NO: 15. Among the compositions provided herein, the composition comprises at least 20 contiguous nucleotides from In some embodiments of any of the above, the 3'UTR comprises a sequence from anywhere within SEQ ID NO: 15. Any of the compositions provided herein comprises at least 50 contiguous nucleotides. In some embodiments, the 3'UTR comprises at least one sequence from anywhere within SEQ ID NO:15. Any of the compositions provided herein comprises 80 consecutive nucleotides. In some embodiments, the 3'UTR comprises a sequence at least 80% identical to SEQ ID NO:15. Includes:

[0022] In some embodiments of any of the compositions provided herein, the first nucleic acid vector Each of the vector and the second nucleic acid vector may be a plasmid, a transposon, a cosmid, a human Any of the compositions provided herein is an engineered chromosome, or a viral vector. In some embodiments, each of the first nucleic acid vector and the second nucleic acid vector is a human Human artificial chromosomes (HAC), yeast artificial chromosomes (YAC), bacterial artificial chromosomes (BAC), and is a P1-derived artificial chromosome (PAC). Any of the compositions provided herein In some embodiments, the first nucleic acid vector and the second nucleic acid vector each comprise an adenovirus. AAV vectors, adenovirus vectors, lentivirus vectors or a retroviral vector. In some embodiments of any of the provided compositions, the first nucleic acid vector and the second nucleic acid vector Each of the two nucleic acid vectors is an AAV vector. In some embodiments of any of the above, at least one of the coding sequences is It spans two consecutive exons of genomic DNA and has an intervening sequence between the two consecutive exons. It contains a nucleotide sequence that lacks any nucleotide sequence.

[0023] Also provided herein are compositions comprising two different nucleic acid vectors, wherein the two different The first of the nucleic acid vectors comprises a promoter and a 3' end of the promoter. a first coding sequence encoding the N-terminal portion of the CLRN1 protein, located adjacent to a splice donor sequence located at the 3' end of the first coding sequence; a first detectable marker gene located 3' to the rice donor sequence, The second of the two different nucleic acid vectors comprises a second detectable marker gene and a splice acceptor sequence located 3' to the second detectable marker gene. and a CLRN1 protein located at the 3' end of the splice acceptor sequence. a second coding sequence encoding a C-terminal portion of the protein; and a and a polyadenylation signal sequence positioned therein, each of the encoded portions comprising at least The length of each of the encoded portions is at least 30 amino acid residues, and the amino acid sequences of the encoded portions overlap with each other. No single vector among the two different vectors contained the full-length CLRN1 gene. When introduced into mammalian cells, the splice donor sequence does not encode a protein. Splicing occurs between the splice acceptor sequence, thereby forming a full-length A recombinant nucleic acid encoding a CLRN1 protein is formed. In some embodiments of any of the above, the first coding sequence encodes a CLRN1 protein. The second coding sequence encodes the N-terminal portion of a first isoform of the protein, The isoform encodes the C-terminal portion of the CLRN1 protein. In some embodiments of any of the compositions, the first isoform of the CLRN1 protein The form comprises a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments of any of the compositions, the first amino acid sequence of the CLRN1 protein is Isoforms include SEQ ID NO: 3. Any one of the compositions provided herein In some embodiments, the first isoform of the CLRN1 protein is selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4. In some embodiments of any of the compositions provided herein, the second The first of the nucleic acid vectors contains a second isoform of the CLRN1 protein. Any of the compositions provided herein further comprises a sequence encoding a form. In some embodiments, the second isoform of the CLRN1 protein is selected from the group consisting of SEQ ID NO: 5. Any of the compositions provided herein includes a sequence that is at least 95% identical to In some embodiments, the second isoform of the CLRN1 protein has the sequence In some embodiments of any of the compositions provided herein, the The second isoform of the CLRN1 protein consists of SEQ ID NO: 5. In some embodiments of any of the provided compositions, the first coding sequence is a CLR a second coding sequence encoding the N-terminal portion of a second isoform of the N1 protein, the second coding sequence comprising , which encodes the C-terminal portion of the second isoform CLRN1 protein. In some embodiments of any of the provided compositions, the CLRN1 protein The second isoform comprises a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments of any of the compositions provided herein, the CLRN1 protein The second isoform of comprises SEQ ID NO: 5. In some embodiments of any of the above, the second isoform of the CLRN1 protein is: consists of SEQ ID NO: 5. In some embodiments of any of the compositions provided herein the first nucleic acid vector or the second nucleic acid vector is a nucleic acid encoding the first sequence of the CLRN1 protein The compositions provided herein further comprise a sequence encoding an isoform of 1. In some embodiments of any of the above, the first isoform of the CLRN1 protein is , comprising a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments of any of these, the first isoform of the CLRN1 protein The composition comprises SEQ ID NO: 3. Some embodiments of any of the compositions provided herein In one embodiment, the first isoform of the CLRN1 protein consists of SEQ ID NO:3.

[0024] In some embodiments of any of the compositions provided herein, the first nucleic acid vector one or both of the vector and the second nucleic acid vector contain a 5' untranslated region (UTR) , 3'UTR, or both. In this embodiment, the 5'UTR comprises at least 10 amino acids from anywhere within SEQ ID NO: 12. Some embodiments of any of the compositions provided herein include In one embodiment, the 5'UTR comprises at least 20 consecutive amino acids from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, In other words, the 5'UTR is a sequence of at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. Contains octide.

[0025] In some embodiments of any of the compositions provided herein, the 5'UTR , comprising at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the 5'UTR comprises the sequence Among the compositions provided herein are those comprising a sequence that is at least 80% identical to sequence number 12. In some embodiments of any of the above, the 3'UTR comprises a sequence from anywhere within SEQ ID NO: 15. Any of the compositions provided herein comprises at least 10 consecutive nucleotides. In some embodiments, the 3'UTR comprises at least one sequence from anywhere within SEQ ID NO:15. Any of the compositions provided herein comprises 20 consecutive nucleotides. In some embodiments, the 3'UTR comprises at least 5' of any sequence within SEQ ID NO: 15. 0 consecutive nucleotides. In embodiments, the 3'UTR comprises at least 80 amino acids from anywhere within SEQ ID NO: 15. Some embodiments of any of the compositions provided herein include contiguous nucleotides. In some embodiments, the 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO:15.

[0026] In some embodiments of any of the compositions provided herein, the first nucleic acid vector Each of the vector and the second nucleic acid vector may be a plasmid, a transposon, a cosmid, a human Any of the compositions provided herein is an engineered chromosome, or a viral vector. In some embodiments, each of the first nucleic acid vector and the second nucleic acid vector is a human Human artificial chromosomes (HAC), yeast artificial chromosomes (YAC), bacterial artificial chromosomes (BAC), and is a P1-derived artificial chromosome (PAC). Any of the compositions provided herein In some embodiments, the first nucleic acid vector and the second nucleic acid vector each comprise an adenovirus. AAV vectors, adenovirus vectors, lentivirus vectors or a retroviral vector. In some embodiments of any of the provided compositions, the first nucleic acid vector and the second nucleic acid vector Each of the two nucleic acid vectors is an AAV vector. In some embodiments of any of the above, at least one of the coding sequences is It spans two consecutive exons of genomic DNA and has an intervening sequence between the two consecutive exons. Among the compositions provided herein, there are nucleotide sequences that lack transtron sequences. In some embodiments of any of the above, the first or second detectable marker gene is It is potassium phosphatase.

[0027] Also provided herein are compositions comprising two different nucleic acid vectors, wherein the two different The first nucleic acid vector of the nucleic acid vectors comprises a promoter and a nucleic acid sequence encoding a target gene for the promoter. The first code fragment encodes the N-terminal portion of the CLRN1 protein, located 3' to the a splice donor sequence located at the 3' end of the first coding sequence; an F1 phage recombination induction region located 3' to the splice donor sequence; wherein the second nucleic acid vector of the two different nucleic acid vectors is an F1 phage recombinase vector. and a splice acceptor located 3' to the F1 phage recombination induction region. a CLRN1 tag located at the 3' end of the splice acceptor sequence. a second coding sequence encoding a C-terminal portion of the protein; and a 3'-terminal and a polyadenylation signal sequence located at each end of the two encoded portions. Each is at least 30 amino acid residues in length and has the amino acid sequence of the two encoded portions. The sequences of the two different vectors do not overlap with each other, and any single vector of the two different vectors It does not encode the full-length CLRN1 protein and, when introduced into mammalian cells, Splicing occurs between the splice donor sequence and the splice acceptor sequence, This results in the formation of a recombinant nucleic acid encoding the full-length CLRN1 protein. In some embodiments of any of the compositions provided herein, the first coding sequence comprises: A gene encoding the N-terminal portion of a first isoform of the CLRN1 protein, The sequence encodes the C-terminal portion of the first isoform CLRN1 protein. In some embodiments of any of the compositions provided herein, the CLRN1 protein The first isoform of interest comprises a sequence that is at least 95% identical to SEQ ID NO:3. In some embodiments of any of the compositions provided herein, the CLRN1 tandem The first isoform of the protein comprises SEQ ID NO: 3. In some embodiments of any of these, the first isoform of the CLRN1 protein The system consists of SEQ ID NO: 3. In one embodiment, the first nucleic acid vector of the second nucleic acid vector encodes the CLRN1 protein. The compositions provided herein further comprise a sequence encoding a second isoform of the protein. In some embodiments of any of the above, the second isoform of the CLRN1 protein is The form comprises a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments of any of the compositions, the second eye of the CLRN1 protein The isoform comprises SEQ ID NO: 5. A portion of any of the compositions provided herein In one embodiment, the second isoform of the CLRN1 protein is selected from the group consisting of SEQ ID NO: 5 and SEQ ID NO: 6. become.

[0028] In some embodiments of any of the compositions provided herein, the first code The sequence encodes the N-terminal portion of a second isoform of the CLRN1 protein, The coding sequence of this gene encodes the C-terminal portion of the second isoform CLRN1 protein. In some embodiments of any of the compositions provided herein, the CLRN1 The second isoform of the protein has a sequence that is at least 95% identical to SEQ ID NO:5. In some embodiments of any of the compositions provided herein, the CLR The second isoform of the N1 protein comprises SEQ ID NO: 5. In some embodiments of any of the compositions, the second eye of the CLRN1 protein The isoform consists of SEQ ID NO: 5. Any one of the compositions provided herein In some embodiments, the first nucleic acid vector or the second nucleic acid vector comprises the CLRN1 The present invention further includes a sequence encoding a first isoform of the protein. In some embodiments of any of the compositions, the first amino acid sequence of the CLRN1 protein is Isoforms include sequences that are at least 95% identical to SEQ ID NO: 3. In some embodiments of any of the compositions described above, the first Isoforms of include SEQ ID NO: 3. Any of the compositions provided herein In some embodiments, the first isoform of the CLRN1 protein is selected from the group consisting of SEQ ID NO: It consists of 3.

[0029] In some embodiments of any of the compositions provided herein, the first nucleic acid vector one or both of the vector and the second nucleic acid vector contain a 5' untranslated region (UTR) , 3'UTR, or both. In this embodiment, the 5'UTR comprises at least 10 amino acids from anywhere within SEQ ID NO: 12. Some embodiments of any of the compositions provided herein include In one embodiment, the 5'UTR comprises at least 20 consecutive amino acids from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, In other words, the 5'UTR is a sequence of at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the The 5'UTR comprises at least 80 contiguous nucleotides from anywhere within SEQ ID NO: 12. In some embodiments of any of the compositions provided herein, the 5′U The TR comprises a sequence that is at least 80% identical to SEQ ID NO: 12. In some embodiments of any of the compositions, the 3'UTR is any of SEQ ID NO: 15 The compositions provided herein comprise at least 10 consecutive nucleotides from In some embodiments of any of the above, the 3'UTR is any position within SEQ ID NO: 15. Among the compositions provided herein, the composition comprises at least 20 contiguous nucleotides from In some embodiments of any of the above, the 3'UTR comprises a sequence from anywhere within SEQ ID NO: 15. Any of the compositions provided herein comprises at least 50 contiguous nucleotides. In some embodiments, the 3'UTR comprises at least one sequence from anywhere within SEQ ID NO:15. Any of the compositions provided herein comprises 80 consecutive nucleotides. In some embodiments, the 3'UTR comprises a sequence at least 80% identical to SEQ ID NO:15. Includes:

[0030] In some embodiments of any of the compositions provided herein, the first nucleic acid vector Each of the vector and the second nucleic acid vector may be a plasmid, a transposon, a cosmid, a human Any of the compositions provided herein is an engineered chromosome, or a viral vector. In some embodiments, each of the first nucleic acid vector and the second nucleic acid vector is a human Human artificial chromosomes (HAC), yeast artificial chromosomes (YAC), bacterial artificial chromosomes (BAC), and is a P1-derived artificial chromosome (PAC). Any of the compositions provided herein In some embodiments, the first nucleic acid vector and the second nucleic acid vector each comprise an adenovirus. AAV vectors, adenovirus vectors, lentivirus vectors or a retroviral vector. In some embodiments of any of the provided compositions, the first nucleic acid vector and the second nucleic acid vector Each of the two nucleic acid vectors is an AAV vector. In some embodiments of any of the above, at least one of the coding sequences is It spans two consecutive exons of genomic DNA and has an intervening sequence between the two consecutive exons. It contains a nucleotide sequence that lacks any nucleotide sequence.

[0031] Also provided herein are kits containing any of the compositions provided herein. Some embodiments of any of the kits provided herein include The present invention further includes a pre-filled syringe containing the

[0032] Also provided herein are methods for administering to the mammalian cochlea a therapeutically effective amount of a composition provided herein. Also provided are methods comprising introducing any of the methods provided herein. In some embodiments of any of these, the mammal is a human. In some embodiments of any of the methods, the mammal has a defective CLRN1 gene. Previously identified as having children.

[0033] Also described herein is a method for increasing the expression of full-length CLRN1 protein in mammalian cells. Also provided are methods of administering any of the compositions provided herein to the mammal. Some embodiments of any of the methods provided herein include introducing the gene into a cell. In some embodiments, the mammalian cell is a cochlear inner hair cell or an outer cochlear hair cell. In some embodiments of any of the methods described above, the mammalian cell is a retinal cell. In some embodiments of any of the methods provided herein, the mammalian cell is a human In some embodiments of any of the methods provided herein, the mammalian cell is a mammalian cell. Mammalian cells have previously been determined to have a defective CLRN1 gene.

[0034] Also described herein are inner hair cells, outer hair cells, or both in the mammalian cochlea. Also provided is a method for increasing expression of full-length CLRN1 protein, the method comprising: introducing a therapeutically effective amount of any of the compositions described herein into the cochlea of Also described herein is the expression of full-length CLRN1 protein in the mammalian eye. Also provided is a method of increasing the number of inflammatory bowel diseases, the method comprising administering to the mammalian eye a therapeutically effective amount of the compounds provided herein. The method includes administering any of the compositions provided herein intraocularly. In some embodiments of any of the above, the mammal has a defective CLRN1 gene. It has been previously identified as having the following properties: In embodiments, the mammal is a human.

[0035] Also described herein are methods for detecting hearing loss in subjects identified as having a defective CLRN1 gene. Also provided are methods for treating loss of strength, the methods comprising administering a therapeutically effective amount of a composition provided herein. The present invention also includes administering to the subject a defective cochlea any of the following: Also provided are methods of treating vision loss in a subject identified as having the CLRN1 gene. The method comprises administering to the subject a therapeutically effective amount of any of the compositions provided herein. Some embodiments of any of the methods provided herein include administering to the eye. In the method provided herein, the subject has Usher syndrome type III. In some embodiments of any of the methods provided herein, the subject is a human. Some embodiments of any of these may further comprise administering to the subject a therapeutically effective amount of steroid hormone (SAH) to the subject, the therapeutically effective amount of steroid hormone (SAH) to the subject. It further includes determining that the patient has the N1 gene.

[0036] The articles "a" and "an" refer to one or more than one (i.e., For example, "an element" refers to one element and more than one. It encompasses many more elements than

[0037] The term "mutation in the CLRN1 gene" refers to a mutation in the CLRN1 gene compared to the wild-type CLRN1 protein. One or more amino acid deletions, one or more amino acid substitutions, and one or more or the production of a CLRN1 protein having one or more of the multiple amino acid insertions. and / or the encoded CLRN1 in mammalian cells without mutations The expressed levels of the encoded CLRN1 protein in mammalian cells compared with Modifications in the wild-type CLRN1 gene that result in a decrease in the expressed levels of the protein In some embodiments, the mutation refers to one or more amino acids (e.g., 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , or 20 amino acids) In some embodiments, the mutation may result in a frameshift in the CLRN1 gene. The term "frameshift" is used in the art to describe a shift in the reading frame of a coding sequence. It is known to encompass any mutation in the coding sequence that results in a gamete shift. In some embodiments, frameshifting can result in a non-functional protein. In this embodiment, the point mutation is a nonsense mutation (i.e., a mismatch in an exon of a gene). Nonsense mutations can be functional or non-functional. This results in the production of truncated proteins (compared to the corresponding wild-type proteins) that may or may not be present. In some embodiments, the mutation may occur in CLRN1 mRNA or CLRN1 protein. loss of expression (or reduced levels) of the protein, or both mRNA and protein In some embodiments, the mutation may result in one or more mutations compared to the wild-type CLRN1 protein. or an altered CLRN1 protein with loss or reduction of multiple biological activities (functions). This can result in protein production.

[0038] In some embodiments, the mutation is one or more nucleotides in the CLRN1 gene. In some embodiments, the mutation is an insertion in the regulatory sequence of the CLRN1 gene, i.e., In some embodiments, the mutation in the regulatory sequence is in a portion of the gene that is not the regulatory sequence. , which may be in the promoter or enhancer region and prevent proper transcription of the CLRN1 gene. The term "conservative mutation" refers to a mutation that occurs at the site of mutation (due to codon degeneracy). refers to a mutation that does not change the amino acid encoded by

[0039] Modifications can be made by any method known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions can be introduced into a nucleotide sequence by conventional techniques. A substitution is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having side chains are defined in the art. The family consists of amino acids with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains ( aspartic acid and glutamic acid), polar uncharged side chains (e.g., glycine, aspartic acid, Paragine, glutamine, serine, threonine, tyrosine, cysteine, and tryptophan non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, and methionine), beta-branched side chains (e.g., threonine, valine, and and isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, It contains amino acids with the following structure: α-, α-, β-, β- and β-histidine.

[0040] Unless otherwise specified, "nucleotide sequences encoding amino acid sequences" include sequences of each other. All nucleotide sequences that are degenerate versions and therefore encode the same amino acid sequence are Included.

[0041] The term "endogenous" refers to any material from within an organism, cell, or tissue.

[0042] The term "exogenous" refers to materials that originate from the same organism, cell, or tissue into which they are introduced. Not produced or derived from an organism, cell, or tissue, or introduced from outside the organism, cell, or tissue or any material originating from outside thereof.

[0043] The term "isolated" means changed or removed from the natural state. For example, nucleic acids or peptides that are naturally present in living animals. A peptide is not "isolated," but is partially or completely separated from the coexisting materials of its natural state. The same nucleic acid or peptide separated from the other is "isolated." The protein may be present in a substantially purified form or may be present in a native environment, such as a host cell. It can exist in environments other than the border.

[0044] "Transfected," "transformed," or "transduced" The term "transfect" refers to the process by which exogenous nucleic acid is transferred or introduced into a cell. A mammalian cell that has been "transformed" or "transduced" with exogenous nucleic acid A mammalian cell that has been transfected, transformed, or transduced.

[0045] The term "expression" refers to the transcription and / or transfer of a particular nucleotide sequence encoding a protein. Or refers to translation.

[0046] The term "transient expression" refers to the expression of unintegrated coding sequences for a short, fixed period of time (e.g. Transient expression in cells (e.g., mammalian cells) The coding sequences expressed in the . . . are lost during multiple cell divisions.

[0047] The term "subject" is intended to include any mammal. In some embodiments, The subject may be a rodent (e.g., rat or mouse), rabbit, sheep, goat, pig, dog, In some embodiments, the subject is a cat, a non-human primate, or a human. or has or is at risk of having vision loss. , previously identified as having a mutation in the CLRN1 gene. The subject is identified as having a mutation in the CLRN1 gene and has hearing loss and In some embodiments, the subject has been diagnosed with hearing loss and / or vision loss. has been identified as having vision loss.

[0048] Treatment can be achieved by treating a condition (e.g., hearing loss or vision loss) in a subject (e.g., a human). a reduction in one or more of the number, severity, and frequency of one or more symptoms of In some embodiments, a therapeutically effective amount of a composition is an amount that is sufficient to treat an active ingredient. CLRN1 protein (e.g., wild-type full-length CLRN1 protein, or a protein with the desired activity) an increase in the expression level of a CLRN1 protein variant having the In some embodiments, a therapeutically effective amount The composition expresses active CLRN1 protein ( For example, increased expression levels of wild-type full-length CLRN1 protein or active variants In some embodiments, a therapeutically effective amount of the composition may result in the following in a target cell: Active CLRN1 protein (e.g., wild-type full-length CLRN1 protein, or active BASF protein) increased expression levels of one or more of the CLRN1 proteins Increased activity of (e.g., level(s) in the subject before treatment, in the CLRN1 gene level(s) in subjects with mutations in the (compared to a reference level, such as the level(s) in a subject or population of subjects with This can result in:

[0049] The terms "nucleic acid" or "polynucleotide" refer to either single-stranded or double-stranded forms. Deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), or a combination thereof Unless otherwise specified, the term refers to a combination of nucleotides that have similar binding properties to a reference nucleotide. Nucleic acids containing known analogues of natural nucleotides, including those having the following structure, unless otherwise indicated: Insofar as a particular nucleic acid sequence is used, it also implicitly refers to the complementary sequence as well as the sequence explicitly indicated. In some embodiments of any of the nucleic acids described herein, the nucleic acid comprises: In some embodiments of any of the nucleic acids described herein, the nucleic acid is DNA. is RNA.

[0050] The term "active CLRN1 protein" refers to a mammalian protein that is an otherwise wild-type mammal. Both encode the full-length CLRN1 protein in the auditory hair cells or eye cells of animals and replaces the wild-type allele of the gene in the auditory hair cells or eye cells of the mammal. When expressed in a mammal, the mammal has a normal expression level similar to that of a similar mammal that is completely wild type. DNA that results in a person having hearing or vision levels similar to the hearing or vision levels Non-limiting examples of active CLRN1 proteins is a full-length CLRN1 protein (e.g., a full-length CLRN1 protein described herein). (one of the proteins).

[0051] For example, an active CLRN1 protein may contain from one amino acid substitution to about 100 amino acid substitutions. substitutions, 1 amino acid substitution to about 95 amino acid substitutions, 1 amino acid substitution to about 90 amino acid substitutions Amino acid substitutions, 1 amino acid substitution to about 85 amino acid substitutions, 1 amino acid substitution to about 8 0 amino acid substitutions, 1 amino acid substitution to approximately 75 amino acid substitutions, 1 amino acid substitution substitutions of 1 to about 70 amino acids, substitutions of 1 to about 65 amino acids, substitutions of 1 amino acid substitutions up to about 60 amino acid substitutions, 1 amino acid substitution to about 55 amino acid substitutions, 1 amino acid substitution to approximately 50 amino acid substitutions, 1 amino acid substitution to approximately 45 amino acid substitutions Amino acid substitutions, 1 to approximately 40 amino acid substitutions, 1 to approximately 35 amino acid substitutions 1 amino acid substitution ~ 30 amino acid substitutions, 1 amino acid substitution ~ Approximately 25 amino acid substitutions, 1 amino acid substitution to approximately 20 amino acid substitutions, 1 amino acid substitution Amino acid substitutions up to about 15 amino acid substitutions, 1 amino acid substitution to about 10 amino acid substitutions, 1 to about 9 amino acid substitutions, 1 to about 8 amino acid substitutions, 1 to about 7 amino acid substitutions, 1 to about 6 amino acid substitutions substitution, 1 amino acid substitution to about 5 amino acid substitutions, 1 amino acid substitution to about 4 amino acid substitutions amino acid substitution, 1 amino acid substitution to about 3 amino acid substitutions, about 2 amino acid substitutions to about 100 100 amino acid substitutions, about 2 amino acid substitutions to about 95 amino acid substitutions, about 2 amino acids substitutions up to about 90 amino acid substitutions, about 2 amino acid substitutions to about 85 amino acid substitutions, about 2 10 to about 80 amino acid substitutions, about 2 to about 75 amino acid substitutions amino acid substitutions, about 2 amino acid substitutions to about 70 amino acid substitutions, about 2 amino acid substitutions to about 6 5 amino acid substitutions, approximately 2 amino acid substitutions to approximately 60 amino acid substitutions, approximately 2 amino acid substitutions Approximately 55 amino acid substitutions, approximately 2 amino acid substitutions to approximately 50 amino acid substitutions, approximately 2 amino acid substitutions to approximately 45 amino acid substitutions, approximately 2 amino acid substitutions to approximately 40 amino acid substitutions amino acid substitutions, about 2 amino acid substitutions to about 35 amino acid substitutions, about 2 amino acid substitutions to about 30 amino acid substitutions, approximately 2 amino acid substitutions to approximately 25 amino acid substitutions, approximately 2 amino acid substitutions amino acid substitutions to about 20 amino acid substitutions, about 2 amino acid substitutions to about 15 amino acid substitutions, Approximately 2 to 10 amino acid substitutions, approximately 2 to 9 amino acid substitutions amino acid substitutions, about 2 to about 8 amino acid substitutions, about 2 to about 7 amino acid substitutions 1 amino acid substitution, about 2 amino acid substitutions to about 6 amino acid substitutions, about 2 amino acid substitutions about 2 to about 4 amino acid substitutions, about 3 to about 5 amino acid substitutions, ...4 amino acid substitutions, about 3 to about 5 amino acid substitutions, about 2 to about 4 amino acid substitutions, about 3 to about 4 amino acid substitutions, about 3 to about 4 amino acid substitutions, about 3 to about 4 amino acid substitutions, about 3 to about 4 amino acid substitutions, about 3 to about 4 amino acid substitutions, about 3 Amino acid substitutions up to about 100 amino acid substitutions, about 3 amino acid substitutions up to about 95 amino acid substitutions substitutions, about 3 to about 90 amino acid substitutions, about 3 to about 85 amino acid substitutions 100 amino acid substitutions, about 3 amino acid substitutions to about 80 amino acid substitutions, about 3 amino acid substitutions ~ about 75 amino acid substitutions, ~ about 3 amino acid substitutions ~ about 70 amino acid substitutions, ~ about 3 ~ 65 amino acid substitutions, ~ 3 amino acid substitutions ~ 60 amino acid substitutions substitutions, about 3 amino acid substitutions to about 55 amino acid substitutions, about 3 amino acid substitutions to about 50 45 amino acid substitutions, about 3 amino acid substitutions to about 45 amino acid substitutions, about 3 amino acid substitutions substitutions up to about 40 amino acid substitutions, about 3 amino acid substitutions to about 35 amino acid substitutions, about 3 10 to about 30 amino acid substitutions, about 3 to about 25 amino acid substitutions amino acid substitutions, about 3 amino acid substitutions to about 20 amino acid substitutions, about 3 amino acid substitutions to about 1 5 amino acid substitutions, about 3 amino acid substitutions to about 10 amino acid substitutions, about 3 amino acid substitutions Approximately 9 amino acid substitutions, approximately 3 amino acid substitutions, approximately 8 amino acid substitutions, approximately 3 ~ about 7 amino acid substitutions, ~ about 3 amino acid substitutions ~ about 6 amino acid substitutions , about 3 to about 5 amino acid substitutions, about 4 to about 100 amino acid substitutions Amino acid substitutions, approximately 4 amino acid substitutions to approximately 95 amino acid substitutions, approximately 4 amino acid substitutions ~ about 90 amino acid substitutions, about 4 amino acid substitutions ~ about 85 amino acid substitutions, about 4 Amino acid substitutions up to about 80 amino acid substitutions, about 4 amino acid substitutions to about 75 amino acid substitutions substitutions, about 4 to about 70 amino acid substitutions, about 4 to about 65 amino acid substitutions 100 amino acid substitutions, about 4 amino acid substitutions to about 60 amino acid substitutions, about 4 amino acid substitutions Approximately 55 amino acid substitutions, approximately 4 amino acid substitutions, approximately 50 amino acid substitutions, approximately 4 ~ about 45 amino acid substitutions, ~ about 4 amino acid substitutions ~ about 40 amino acid substitutions substitutions, about 4 amino acid substitutions to about 35 amino acid substitutions, about 4 amino acid substitutions to about 30 10 amino acid substitutions, about 4 amino acid substitutions to about 25 amino acid substitutions, about 4 amino acid substitutions substitutions up to about 20 amino acid substitutions, about 4 amino acid substitutions to about 15 amino acid substitutions, about 4 10 to 10 amino acid substitutions, about 4 to 9 amino acid substitutions substitutions, about 4 amino acid substitutions to about 8 amino acid substitutions, about 4 amino acid substitutions to about 7 amino acid substitutions Amino acid substitutions: about 4 amino acid substitutions ~ about 6 amino acid substitutions: about 5 amino acid substitutions ~ Approximately 100 amino acid substitutions, approximately 5 amino acid substitutions to approximately 95 amino acid substitutions, approximately 5 Amino acid substitutions up to about 90 amino acid substitutions, about 5 amino acid substitutions to about 85 amino acid substitutions substitutions, about 5 to about 80 amino acid substitutions, about 5 to about 75 amino acid substitutions 5 amino acid substitutions to 70 amino acid substitutions, about 5 amino acid substitutions Approximately 65 amino acid substitutions, approximately 5 amino acid substitutions, approximately 60 amino acid substitutions, approximately 5 ~ about 55 amino acid substitutions, ~ about 5 amino acid substitutions ~ about 50 amino acid substitutions substitutions, about 5 amino acid substitutions to about 45 amino acid substitutions, about 5 amino acid substitutions to about 40 5 amino acid substitutions to 35 amino acid substitutions, about 5 amino acid substitutions substitutions up to about 30 amino acid substitutions, about 5 amino acid substitutions to about 25 amino acid substitutions, about 5 10 to about 20 amino acid substitutions, about 5 to about 15 amino acid substitutions amino acid substitutions, about 5 to about 10 amino acid substitutions, about 5 to about 9 amino acid substitutions about 5 amino acid substitutions to about 8 amino acid substitutions, about 5 amino acid substitutions substitutions of about 7 amino acids, substitutions of about 6 amino acids to about 100 amino acids, substitutions of about 6 ~ 95 amino acid substitutions, ~ 6 amino acid substitutions ~ 90 amino acid substitutions substitutions, about 6 amino acid substitutions to about 85 amino acid substitutions, about 6 amino acid substitutions to about 80 10 amino acid substitutions, about 6 amino acid substitutions to about 75 amino acid substitutions, about 6 amino acids substitutions up to about 70 amino acid substitutions, about 6 amino acid substitutions to about 65 amino acid substitutions, about 6 10 to about 60 amino acid substitutions, about 6 to about 55 amino acid substitutions amino acid substitutions, about 6 amino acid substitutions to about 50 amino acid substitutions, about 6 amino acid substitutions to about 4 5 amino acid substitutions, about 6 amino acid substitutions to about 40 amino acid substitutions, about 6 amino acid substitutions Approximately 35 amino acid substitutions, approximately 6 amino acid substitutions to approximately 30 amino acid substitutions, approximately 6 amino acid substitutions to approximately 25 amino acid substitutions, approximately 6 amino acid substitutions to approximately 20 amino acid substitutions amino acid substitutions, about 6 amino acid substitutions to about 15 amino acid substitutions, about 6 amino acid substitutions to about 10 amino acid substitutions, about 6 amino acid substitutions to about 9 amino acid substitutions, about 6 amino acid substitutions amino acid substitutions to about 8 amino acid substitutions, about 7 amino acid substitutions to about 100 amino acid substitutions, about 7 amino acid substitutions to approximately 95 amino acid substitutions, approximately 7 amino acid substitutions to approximately 90 amino acid substitutions amino acid substitutions, about 7 amino acid substitutions to about 85 amino acid substitutions, about 7 amino acid substitutions to about 80 amino acid substitutions, approximately 7 amino acid substitutions ~ approximately 75 amino acid substitutions, approximately 7 amino acid substitutions 7 to about 70 amino acid substitutions, about 7 to about 65 amino acid substitutions, Approximately 7 amino acid substitutions to approximately 60 amino acid substitutions, approximately 7 amino acid substitutions to approximately 55 amino acid substitutions Amino acid substitutions, approximately 7 amino acid substitutions ~ Approximately 50 amino acid substitutions, approximately 7 amino acid substitutions ~ Approximately 45 amino acid substitutions, approximately 7 amino acid substitutions to approximately 40 amino acid substitutions, approximately 7 amino acid substitutions Amino acid substitutions up to approximately 35 amino acid substitutions, approximately 7 amino acid substitutions to approximately 30 amino acid substitutions , about 7 to about 25 amino acid substitutions, about 7 to about 20 amino acid substitutions Amino acid substitutions, approximately 7 amino acid substitutions to approximately 15 amino acid substitutions, approximately 7 amino acid substitutions ~ about 10 amino acid substitutions, about 7 amino acid substitutions ~ about 9 amino acid substitutions, about 8 amino acid substitutions Amino acid substitutions up to about 100 amino acid substitutions, about 8 amino acid substitutions to about 95 amino acid substitutions substitutions, about 8 to about 90 amino acid substitutions, about 8 to about 85 amino acid substitutions 8 amino acid substitutions to 80 amino acid substitutions, about 8 amino acid substitutions ~ about 75 amino acid substitutions, ~ about 8 amino acid substitutions, ~ about 70 amino acid substitutions, ~ about 8 ~ 65 amino acid substitutions, ~ 8 amino acid substitutions ~ 60 amino acid substitutions substitutions, about 8 amino acid substitutions to about 55 amino acid substitutions, about 8 amino acid substitutions to about 50 10 amino acid substitutions, about 8 amino acid substitutions to about 45 amino acid substitutions, about 8 amino acids substitutions up to about 40 amino acid substitutions, about 8 amino acid substitutions to about 35 amino acid substitutions, about 8 10 to about 30 amino acid substitutions, about 8 to about 25 amino acid substitutions amino acid substitutions, about 8 amino acid substitutions to about 20 amino acid substitutions, about 8 amino acid substitutions to about 1 5 amino acid substitutions, approximately 8 amino acid substitutions to approximately 10 amino acid substitutions, approximately 10 amino acid substitutions Approximately 100 amino acid substitutions, approximately 10 amino acid substitutions, approximately 95 amino acid substitutions substitutions, about 10 to about 90 amino acid substitutions, about 10 to about 8 amino acid substitutions 5 amino acid substitutions, approximately 10 amino acid substitutions to approximately 80 amino acid substitutions, approximately 10 amino acid substitutions Amino acid substitutions up to about 75 amino acid substitutions, about 10 amino acid substitutions up to about 70 amino acid substitutions substitutions, about 10 to about 65 amino acid substitutions, about 10 to about 6 0 amino acid substitutions, about 10 amino acid substitutions to about 55 amino acid substitutions, about 10 amino acid substitutions Amino acid substitutions up to about 50 amino acid substitutions, about 10 amino acid substitutions up to about 45 amino acid substitutions substitutions, about 10 to about 40 amino acid substitutions, about 10 to about 3 5 amino acid substitutions, approximately 10 amino acid substitutions to approximately 30 amino acid substitutions, approximately 10 amino acid substitutions Amino acid substitutions up to about 25 amino acid substitutions, about 10 amino acid substitutions to about 20 amino acid substitutions substitutions, about 10 to about 15 amino acid substitutions, about 15 to about 1 00 amino acid substitutions, about 15 amino acid substitutions to about 95 amino acid substitutions, about 15 Amino acid substitutions: up to approximately 90 amino acid substitutions, and from approximately 15 amino acid substitutions to approximately 85 amino acids substitutions, about 15 amino acid substitutions to about 80 amino acid substitutions, about 15 amino acid substitutions to about 75 amino acid substitutions, approximately 15 amino acid substitutions to approximately 70 amino acid substitutions, approximately 15 Amino acid substitutions: up to approximately 65 amino acid substitutions, and from approximately 15 amino acid substitutions to approximately 60 amino acids substitutions, about 15 amino acid substitutions to about 55 amino acid substitutions, about 15 amino acid substitutions to about 50 amino acid substitutions, about 15 amino acid substitutions to about 45 amino acid substitutions, about 15 Amino acid substitutions: up to approximately 40 amino acid substitutions, and from approximately 15 amino acid substitutions to approximately 35 amino acids substitutions, about 15 amino acid substitutions to about 30 amino acid substitutions, about 15 amino acid substitutions to about 25 amino acid substitutions, about 15 amino acid substitutions to about 20 amino acid substitutions, about 20 Amino acid substitutions: up to approximately 100 amino acid substitutions, and from approximately 20 amino acid substitutions to approximately 95 amino acid substitutions. Approximately 20 amino acid substitutions ~ Approximately 90 amino acid substitutions ~ Approximately 20 amino acid substitutions ~ Approximately 85 amino acid substitutions, approximately 20 amino acid substitutions to approximately 80 amino acid substitutions, approximately 20 10 to about 75 amino acid substitutions, about 20 to about 70 amino acid substitutions acid substitutions, about 20 amino acid substitutions to about 65 amino acid substitutions, about 20 amino acid substitutions to about 60 amino acid substitutions, approximately 20 amino acid substitutions to approximately 55 amino acid substitutions, approximately 20 Amino acid substitutions up to approximately 50 amino acid substitutions, approximately 20 amino acid substitutions to approximately 45 amino acids substitutions, about 20 amino acid substitutions to about 40 amino acid substitutions, about 20 amino acid substitutions to about 35 amino acid substitutions, approximately 20 amino acid substitutions to approximately 30 amino acid substitutions, approximately 20 Amino acid substitutions up to about 25 amino acid substitutions, about 25 amino acid substitutions up to about 100 amino acid substitutions Approximately 25 amino acid substitutions ~ Approximately 95 amino acid substitutions ~ Approximately 25 amino acid substitutions ~ Approximately 90 amino acid substitutions, approximately 25 amino acid substitutions to approximately 85 amino acid substitutions, approximately 25 100 to about 80 amino acid substitutions, about 25 to about 75 amino acid substitutions Approximately 25 amino acid substitutions ~ Approximately 70 amino acid substitutions ~ Approximately 25 amino acid substitutions ~ Approximately 65 amino acid substitutions, approximately 25 amino acid substitutions to approximately 60 amino acid substitutions, approximately 25 10 to about 55 amino acid substitutions, about 25 to about 50 amino acid substitutions Approximately 25 amino acid substitutions ~ Approximately 45 amino acid substitutions ~ Approximately 25 amino acid substitutions ~ Approximately 40 amino acid substitutions, approximately 25 amino acid substitutions to approximately 35 amino acid substitutions, approximately 25 100 to 300 amino acid substitutions, 30 to 100 amino acid substitutions Approximately 30 amino acid substitutions ~ Approximately 95 amino acid substitutions, Approximately 30 amino acid substitutions ~ about 90 amino acid substitutions, about 30 amino acid substitutions ~ about 85 amino acid substitutions, about 30 100 to about 80 amino acid substitutions, about 30 to about 75 amino acid substitutions Approximately 30 amino acid substitutions ~ Approximately 70 amino acid substitutions, Approximately 30 amino acid substitutions ~ about 65 amino acid substitutions, about 30 amino acid substitutions ~ about 60 amino acid substitutions, about 30 100 to about 55 amino acid substitutions, about 30 to about 50 amino acid substitutions amino acid substitutions, approximately 30 amino acid substitutions to approximately 45 amino acid substitutions, approximately 30 amino acid substitutions ~ about 40 amino acid substitutions, about 30 amino acid substitutions ~ about 35 amino acid substitutions, about 35 100 to 100 amino acid substitutions, 35 to 95 amino acid substitutions Amino acid substitutions, approximately 35 amino acid substitutions to approximately 90 amino acid substitutions, approximately 35 amino acid substitutions about 85 amino acid substitutions, about 35 amino acid substitutions to about 80 amino acid substitutions, about 3 5 amino acid substitutions to approximately 75 amino acid substitutions, approximately 35 amino acid substitutions to approximately 70 amino acid substitutions amino acid substitutions, about 35 amino acid substitutions to about 65 amino acid substitutions, about 35 amino acid substitutions about 60 amino acid substitutions, about 35 amino acid substitutions to about 55 amino acid substitutions, about 3 5 amino acid substitutions to approximately 50 amino acid substitutions, approximately 35 amino acid substitutions to approximately 45 amino acid substitutions amino acid substitutions, about 35 amino acid substitutions to about 40 amino acid substitutions, about 40 amino acid substitutions substitutions of about 100 amino acids, substitutions of about 40 amino acids to about 95 amino acids, substitutions of about 40 to approximately 90 amino acid substitutions, approximately 40 to approximately 85 amino acid substitutions Amino acid substitutions, approximately 40 amino acid substitutions to approximately 80 amino acid substitutions, approximately 40 amino acids substitutions up to about 75 amino acid substitutions, about 40 amino acid substitutions to about 70 amino acid substitutions, about 40 amino acid substitutions to approximately 65 amino acid substitutions, approximately 40 amino acid substitutions to approximately 60 Amino acid substitutions, approximately 40 amino acid substitutions to approximately 55 amino acid substitutions, approximately 40 amino acids substitutions up to about 50 amino acid substitutions, about 40 amino acid substitutions to about 45 amino acid substitutions, about 45 to approximately 100 amino acid substitutions, approximately 45 to approximately 95 amino acid substitutions about 45 amino acid substitutions to about 90 amino acid substitutions, about 45 amino acid substitutions amino acid substitutions to about 85 amino acid substitutions, about 45 amino acid substitutions to about 80 amino acid substitutions, Approximately 45 to 75 amino acid substitutions, approximately 45 to 70 amino acid substitutions about 45 amino acid substitutions to about 65 amino acid substitutions, about 45 amino acid substitutions amino acid substitutions to about 60 amino acid substitutions, about 45 amino acid substitutions to about 55 amino acid substitutions, Approximately 45 to 50 amino acid substitutions, approximately 50 to 100 amino acid substitutions 50 amino acid substitutions to 95 amino acid substitutions, approximately 50 amino acid substitutions Approximately 90 amino acid substitutions, approximately 50 amino acid substitutions to approximately 85 amino acid substitutions , about 50 to about 80 amino acid substitutions, about 50 to about 75 amino acid substitutions 50 amino acid substitutions to 70 amino acid substitutions, approximately 50 amino acid substitutions Approximately 65 amino acid substitutions, approximately 50 amino acid substitutions to approximately 60 amino acid substitutions , about 50 to about 55 amino acid substitutions, about 60 to about 10 0 amino acid substitutions, approximately 60 amino acid substitutions to approximately 95 amino acid substitutions, approximately 60 amino acid substitutions Amino acid substitutions up to approximately 90 amino acid substitutions, and approximately 60 amino acid substitutions up to approximately 85 amino acid substitutions. substitutions, about 60 to about 80 amino acid substitutions, about 60 to about 7 5 amino acid substitutions, approximately 60 amino acid substitutions to approximately 70 amino acid substitutions, approximately 60 amino acid substitutions Amino acid substitutions: Approximately 65 amino acid substitutions, approximately 70 amino acid substitutions: Approximately 100 amino acid substitutions substitutions, about 70 amino acid substitutions to about 95 amino acid substitutions, about 70 amino acid substitutions to about 90 amino acid substitutions, approximately 70 amino acid substitutions to approximately 85 amino acid substitutions, approximately 70 Amino acid substitutions: up to approximately 80 amino acid substitutions, and approximately 70 to approximately 75 amino acid substitutions. Substitutions, approximately 80 amino acid substitutions ~ Approximately 100 amino acid substitutions, approximately 80 amino acid substitutions ~ Approximately 95 amino acid substitutions, approximately 80 amino acid substitutions to approximately 90 amino acid substitutions, approximately 80 100 to 85 amino acid substitutions, 90 to 100 amino acid substitutions amino acid substitutions, about 90 amino acid substitutions to about 95 amino acid substitutions, or about 95 amino acid substitutions wild-type full-length CLRN1 protein (e.g., wild-type CLRN1) containing approximately 100 amino acids It may comprise the sequence of the human full-length CLRN1 protein.

[0052] Those skilled in the art will recognize that the sequences of wild-type CLRN1 proteins from different species are not conserved. Amino acids can be mutated without loss of activity, while wild-type Conserved amino acids among CLRN1 proteins may be involved in their activity. is high (for amino acids that are not conserved between different species), so should not be mutated Let's understand that.

[0053] An active CLRN1 protein may be, for example, from about 1 amino acid to about 100 amino acids, 1 amino acid to about 95 amino acids, about 1 amino acid to about 90 amino acids, about 1 1 to about 85 amino acids, about 1 to about 80 amino acids, about 1 amino acids to about 75 amino acids, about 1 amino acid to about 70 amino acids, about 1 amino acid Acid ~ Approximately 65 amino acids, approximately 1 amino acid ~ Approximately 60 amino acids, approximately 1 amino acid ~ About 55 amino acids, about 1 amino acid to about 50 amino acids, about 1 amino acid to about 4 amino acids 5 amino acids, about 1 amino acid to about 40 amino acids, about 1 amino acid to about 35 amino acids amino acids, about 1 amino acid to about 30 amino acids, about 1 amino acid to about 25 amino acids amino acids, about 1 amino acid to about 20 amino acids, about 1 amino acid to about 15 amino acids Acid, about 1 amino acid to about 10 amino acids, about 1 amino acid to about 9 amino acids, about 1 amino acid to about 8 amino acids, about 1 amino acid to about 7 amino acids, about 1 amino acid amino acids ~ about 6 amino acids, about 1 amino acid ~ about 5 amino acids, about 1 amino acid About 4 amino acids, about 1 amino acid to about 3 amino acids, about 2 amino acids to about 100 amino acids, about 2 amino acids to about 95 amino acids, about 2 amino acids to about 90 amino acids Amino acids, from about 2 amino acids to about 85 amino acids, from about 2 amino acids to about 80 amino acids amino acids, about 2 amino acids to about 75 amino acids, about 2 amino acids to about 70 amino acids , about 2 amino acids to about 65 amino acids, about 2 amino acids to about 60 amino acids, about 2 amino acids to about 55 amino acids, about 2 amino acids to about 50 amino acids, about 2 10 to about 45 amino acids, about 2 to about 40 amino acids, about 2 amino acids to about 35 amino acids, about 2 amino acids to about 30 amino acids, about 2 amino acids Acids ~ Approximately 25 amino acids, approximately 2 amino acids ~ Approximately 20 amino acids, approximately 2 amino acids ~ About 15 amino acids, about 2 to about 10 amino acids, about 2 to about 9 amino acids 1 amino acid, about 2 amino acids to about 8 amino acids, about 2 amino acids to about 7 amino acids amino acids, about 2 amino acids to about 6 amino acids, about 2 amino acids to about 5 amino acids, about 2 amino acids to about 4 amino acids, about 3 amino acids to about 100 amino acids, about 3 0 to about 95 amino acids, about 3 to about 90 amino acids, about 3 amino acids ~ about 85 amino acids, about 3 amino acids ~ about 80 amino acids, about 3 amino acids Acids ~ Approximately 75 amino acids, approximately 3 amino acids ~ Approximately 70 amino acids, approximately 3 amino acids ~ About 65 amino acids, about 3 amino acids to about 60 amino acids, about 3 amino acids to about 5 5 amino acids, about 3 amino acids to about 50 amino acids, about 3 amino acids to about 45 amino acids amino acids, about 3 amino acids to about 40 amino acids, about 3 amino acids to about 35 amino acids amino acids, about 3 amino acids to about 30 amino acids, about 3 amino acids to about 25 amino acids acids, about 3 amino acids to about 20 amino acids, about 3 amino acids to about 15 amino acids, About 3 amino acids to about 10 amino acids, about 3 amino acids to about 9 amino acids, about 3 1 to about 8 amino acids, about 3 to about 7 amino acids, about 3 amino acids About 6 amino acids, about 3 amino acids to about 5 amino acids, about 4 amino acids to about 1 00 amino acids, about 4 amino acids to about 95 amino acids, about 4 amino acids to about 90 amino acids, about 4 amino acids to about 85 amino acids, about 4 amino acids to about 80 amino acids Amino acids, about 4 amino acids to about 75 amino acids, about 4 amino acids to about 70 amino acids amino acids, about 4 amino acids to about 65 amino acids, about 4 amino acids to about 60 amino acids , about 4 amino acids to about 55 amino acids, about 4 amino acids to about 50 amino acids, about 4 amino acids to about 45 amino acids, about 4 amino acids to about 40 amino acids, about 4 10 to about 35 amino acids, about 4 to about 30 amino acids, about 4 amino acids to about 25 amino acids, about 4 amino acids to about 20 amino acids, about 4 amino acids Acid ~ about 15 amino acids, about 4 amino acids ~ about 10 amino acids, about 4 amino acids About 9 amino acids, about 4 to about 8 amino acids, about 4 to about 7 amino acids Amino acids, about 4 amino acids to about 6 amino acids, about 5 amino acids to about 100 amino acids amino acids, about 5 amino acids to about 95 amino acids, about 5 amino acids to about 90 amino acids , about 5 amino acids to about 85 amino acids, about 5 amino acids to about 80 amino acids, about 5 amino acids to about 75 amino acids, about 5 amino acids to about 70 amino acids, about 5 10 to about 65 amino acids, about 5 to about 60 amino acids, about 5 amino acids to about 55 amino acids, about 5 amino acids to about 50 amino acids, about 5 amino acids Acids ~ Approximately 45 amino acids, approximately 5 amino acids ~ Approximately 40 amino acids, approximately 5 amino acids ~ About 35 amino acids, about 5 amino acids to about 30 amino acids, about 5 amino acids to about 2 5 amino acids, about 5 to about 20 amino acids, about 5 to about 15 amino acids about 5 to about 10 amino acids, about 5 to about 9 amino acids amino acids, about 5 amino acids to about 8 amino acids, about 5 amino acids to about 7 amino acids, about 6 amino acids to about 100 amino acids, about 6 amino acids to about 95 amino acids, about 6 10 to about 90 amino acids, about 6 to about 85 amino acids, about 6 Amino acids ~ about 80 amino acids, about 6 amino acids ~ about 75 amino acids, about 6 amino acids 6 amino acids to about 70 amino acids, about 6 amino acids to about 65 amino acids, about 6 amino acids ~ about 60 amino acids, ~ about 6 amino acids ~ about 55 amino acids, ~ about 6 amino acids ~ about 50 amino acids, about 6 amino acids to about 45 amino acids, about 6 amino acids to about 40 amino acids, about 6 amino acids to about 35 amino acids, about 6 amino acids to about 30 amino acids Amino acids, about 6 amino acids to about 25 amino acids, about 6 amino acids to about 20 amino acids amino acids, about 6 amino acids to about 15 amino acids, about 6 amino acids to about 10 amino acids , about 6 amino acids to about 9 amino acids, about 6 amino acids to about 8 amino acids, about 7 100 amino acids, 700 amino acids, 950 amino acids, 700 amino acids, Amino acids ~ about 90 amino acids, about 7 amino acids ~ about 85 amino acids, about 7 amino acids 80 amino acids, 7 amino acids, 75 amino acids, 7 amino acids ~ about 70 amino acids, ~ about 7 amino acids ~ about 65 amino acids, ~ about 7 amino acids ~ about 60 amino acids, about 7 amino acids to about 55 amino acids, about 7 amino acids to about 50 7 to 45 amino acids, 7 to 40 amino acids Amino acids, about 7 amino acids to about 35 amino acids, about 7 amino acids to about 30 amino acids amino acids, about 7 amino acids to about 25 amino acids, about 7 amino acids to about 20 amino acids , about 7 amino acids to about 15 amino acids, about 7 amino acids to about 10 amino acids, about 7 amino acids to about 9 amino acids, about 8 amino acids to about 100 amino acids, about 8 8 to about 95 amino acids, about 8 to about 90 amino acids, about 8 amino acids ~ about 85 amino acids, about 8 amino acids ~ about 80 amino acids, about 8 amino acids Acids ~ Approximately 75 amino acids, approximately 8 amino acids ~ Approximately 70 amino acids, approximately 8 amino acids ~ About 65 amino acids, about 8 amino acids to about 60 amino acids, about 8 amino acids to about 5 5 amino acids, about 8 amino acids to about 50 amino acids, about 8 amino acids to about 45 amino acids amino acids, about 8 amino acids to about 40 amino acids, about 8 amino acids to about 35 amino acids amino acids, about 8 amino acids to about 30 amino acids, about 8 amino acids to about 25 amino acids acids, about 8 amino acids to about 20 amino acids, about 8 amino acids to about 15 amino acids, about 8 amino acids to about 10 amino acids, about 10 amino acids to about 100 amino acids, about 10 amino acids to about 95 amino acids, about 10 amino acids to about 90 amino acids, about 10 amino acids to about 85 amino acids, about 10 amino acids to about 80 amino acids, about 10 amino acids to about 75 amino acids, about 10 amino acids to about 70 amino acids, about 10 amino acids to about 65 amino acids, about 10 amino acids to about 60 amino acids, about 10 amino acids to about 55 amino acids, about 10 amino acids to about 50 amino acids, about 10 amino acids to about 45 amino acids, about 10 amino acids to about 40 amino acids, about 10 amino acids to about 35 amino acids, about 10 amino acids to about 30 amino acids, about 10 amino acids to about 25 amino acids, about 10 amino acids to about 20 amino acids, About 10 to 15 amino acids, about 15 to 100 amino acids , about 15 amino acids to about 95 amino acids, about 15 amino acids to about 90 amino acids , about 15 amino acids to about 85 amino acids, about 15 amino acids to about 80 amino acids , about 15 amino acids to about 75 amino acids, about 15 amino acids to about 70 amino acids , about 15 amino acids to about 65 amino acids, about 15 amino acids to about 60 amino acids , about 15 amino acids to about 55 amino acids, about 15 amino acids to about 50 amino acids , about 15 amino acids to about 45 amino acids, about 15 amino acids to about 40 amino acids , about 15 amino acids to about 35 amino acids, about 15 amino acids to about 30 amino acids , about 15 to about 25 amino acids, about 15 to about 20 amino acids , about 20 amino acids to about 100 amino acids, about 20 amino acids to about 95 amino acids Acids, about 20 amino acids to about 90 amino acids, about 20 amino acids to about 85 amino acids Acids, about 20 amino acids to about 80 amino acids, about 20 amino acids to about 75 amino acids Acids, about 20 amino acids to about 70 amino acids, about 20 amino acids to about 65 amino acids Acids, about 20 amino acids to about 60 amino acids, about 20 amino acids to about 55 amino acids Acids, about 20 amino acids to about 50 amino acids, about 20 amino acids to about 45 amino acids Acids, about 20 amino acids to about 40 amino acids, about 20 amino acids to about 35 amino acids Acids, about 20 amino acids to about 30 amino acids, about 20 amino acids to about 25 amino acids amino acids, about 25 amino acids to about 100 amino acids, about 25 amino acids to about 95 amino acids amino acids, about 25 amino acids to about 90 amino acids, about 25 amino acids to about 85 amino acids amino acids, about 25 amino acids to about 80 amino acids, about 25 amino acids to about 75 amino acids amino acids, about 25 amino acids to about 70 amino acids, about 25 amino acids to about 65 amino acids amino acids, about 25 amino acids to about 60 amino acids, about 25 amino acids to about 55 amino acids amino acids, about 25 amino acids to about 50 amino acids, about 25 amino acids to about 45 amino acids amino acids, about 25 amino acids to about 40 amino acids, about 25 amino acids to about 35 amino acids amino acids, about 25 amino acids to about 30 amino acids, about 30 amino acids to about 100 amino acids amino acids, about 30 amino acids to about 95 amino acids, about 30 amino acids to about 90 amino acids amino acids, about 30 amino acids to about 85 amino acids, about 30 amino acids to about 80 amino acids amino acids, about 30 amino acids to about 75 amino acids, about 30 amino acids to about 70 amino acids amino acids, about 30 amino acids to about 65 amino acids, about 30 amino acids to about 60 amino acids amino acids, about 30 amino acids to about 55 amino acids, about 30 amino acids to about 50 amino acids amino acids, about 30 amino acids to about 45 amino acids, about 30 amino acids to about 40 amino acids amino acids, about 30 amino acids to about 35 amino acids, about 35 amino acids to about 50 amino acids amino acids, about 35 amino acids to about 45 amino acids, about 35 amino acids to about 40 amino acids amino acids, about 40 amino acids to about 100 amino acids, about 40 amino acids to about 95 amino acids a amino acids, about 40 amino acids to about 90 amino acids, about 40 amino acids to about 85 amino acids amino acids, about 40 amino acids to about 80 amino acids, about 40 amino acids to about 75 amino acids amino acids, about 40 amino acids to about 70 amino acids, about 40 amino acids to about 65 amino acids amino acids, about 40 amino acids to about 60 amino acids, about 40 amino acids to about 55 amino acids amino acids, about 40 amino acids to about 50 amino acids, about 40 amino acids to about 45 amino acids amino acids, about 45 amino acids to about 50 amino acids, about 50 amino acids to about 100 amino acids Amino acids, about 50 amino acids to about 95 amino acids, about 50 amino acids to about 90 amino acids Amino acids, about 50 amino acids to about 85 amino acids, about 50 amino acids to about 80 amino acids Amino acids, about 50 amino acids to about 75 amino acids, about 50 amino acids to about 70 amino acids Amino acids, about 50 amino acids to about 65 amino acids, about 50 amino acids to about 60 amino acids wild-type full-length C, or a deletion of about 50 to about 55 amino acids It may comprise the sequence of a LRN1 protein (e.g., a wild-type human full-length CLRN1 protein). A mutant in which two or more amino acids are deleted from the sequence of the wild-type full-length CLRN1 protein. In some embodiments, at least two of the two or more deleted amino acids are the same as the wild-type complete amino acid. It is possible that the sequence of the full-length CLRN1 protein is contiguous. In other embodiments where two or more amino acids are deleted from the sequence of the RN1 protein, the two Some or all of the deleted amino acids are present in the wild-type full-length CLRN1 protein. Those skilled in the art will appreciate that wild-type full-length CLRNs from different species are not contiguous in sequence. 1 Amino acids that are not conserved among proteins can be deleted without losing activity. While it can be used to identify the CLNRN1 protein, it is conserved among wild-type full-length CLNRN1 proteins from different species. The amino acids present in the ribosomal nucleotides are likely to be involved in the activity (amino acids that are not conserved among different species). Understand that the ATP content of ATP is higher than that of ATP and therefore should not be deleted.

[0054] In some instances, an active CLRN1 protein may comprise, for example, a sequence of 1 amino acid to about 100 amino acids. Amino acids, 1 amino acid to about 95 amino acids, 1 amino acid to about 90 amino acids , 1 amino acid to about 85 amino acids, 1 amino acid to about 80 amino acids, 1 Amino acids up to about 75 amino acids, 1 amino acid up to about 70 amino acids, 1 amino acid ~ about 65 amino acids, 1 amino acid ~ about 60 amino acids, 1 amino acid ~ about 55 1 amino acid to about 50 amino acids, 1 amino acid to about 45 amino acids 1 amino acid to about 40 amino acids, 1 amino acid to about 35 amino acids, 1 10 to about 30 amino acids, 1 to about 25 amino acids, 1 amino acid 1 amino acid to about 20 amino acids, 1 amino acid to about 15 amino acids, 1 amino acid to about 10 amino acids, 1 amino acid to about 9 amino acids, 1 amino acid to about 8 amino acids 1 amino acid to about 7 amino acids, 1 amino acid to about 6 amino acids, 1 Amino acids up to about 5 amino acids, 1 amino acid to about 4 amino acids, 1 amino acid to about 3 amino acids, about 2 amino acids to about 100 amino acids, about 2 amino acids to about 95 amino acids, about 2 amino acids to about 90 amino acids, about 2 amino acids to about 85 amino acids Amino acids, about 2 amino acids to about 80 amino acids, about 2 amino acids to about 75 amino acids amino acids, about 2 amino acids to about 70 amino acids, about 2 amino acids to about 65 amino acids , about 2 amino acids to about 60 amino acids, about 2 amino acids to about 55 amino acids, about 2 amino acids to about 50 amino acids, about 2 amino acids to about 45 amino acids, about 2 10 to about 40 amino acids, about 2 to about 35 amino acids, about 2 amino acids to about 30 amino acids, about 2 amino acids to about 25 amino acids, about 2 amino acids Acids ~ about 20 amino acids, about 2 amino acids ~ about 15 amino acids, about 2 amino acids ~ About 10 amino acids, about 2 to about 9 amino acids, about 2 to about 8 amino acids about 2 to about 7 amino acids, about 2 to about 6 amino acids Acid, about 2 amino acids to about 5 amino acids, about 2 amino acids to about 4 amino acids, about 3 100 amino acids, about 3 amino acids to about 95 amino acids, about 3 100 to about 90 amino acids, about 3 to about 85 amino acids, about 3 amino acids ~ about 80 amino acids, about 3 amino acids ~ about 75 amino acids, about 3 amino acids Acids ~ Approximately 70 amino acids, approximately 3 amino acids ~ Approximately 65 amino acids, approximately 3 amino acids ~ About 60 amino acids, about 3 amino acids to about 55 amino acids, about 3 amino acids to about 5 0 amino acids, about 3 amino acids to about 45 amino acids, about 3 amino acids to about 40 amino acids amino acids, about 3 amino acids to about 35 amino acids, about 3 amino acids to about 30 amino acids amino acids, about 3 amino acids to about 25 amino acids, about 3 amino acids to about 20 amino acids acids, about 3 amino acids to about 15 amino acids, about 3 amino acids to about 10 amino acids, About 3 to about 9 amino acids, about 3 to about 8 amino acids, about 3 Amino acids up to about 7 amino acids, about 3 amino acids to about 6 amino acids, about 3 amino acids ~ about 5 amino acids, ~ about 4 amino acids to about 100 amino acids, ~ about 4 amino acids to about 95 amino acids, about 4 amino acids to about 90 amino acids, about 4 amino acids to about 85 amino acids, about 4 amino acids to about 80 amino acids, about 4 amino acids to about 75 amino acids Amino acids, about 4 amino acids to about 70 amino acids, about 4 amino acids to about 65 amino acids amino acids, about 4 amino acids to about 60 amino acids, about 4 amino acids to about 55 amino acids , about 4 amino acids to about 50 amino acids, about 4 amino acids to about 45 amino acids, about 4 amino acids to about 40 amino acids, about 4 amino acids to about 35 amino acids, about 4 10 to about 30 amino acids, about 4 to about 25 amino acids, about 4 amino acids to about 20 amino acids, about 4 amino acids to about 15 amino acids, about 4 amino acids Acids to about 10 amino acids, about 4 amino acids to about 9 amino acids, about 4 amino acids to about 8 amino acids, about 4 amino acids to about 7 amino acids, about 4 amino acids to about 6 amino acids amino acids, about 5 amino acids to about 100 amino acids, about 5 amino acids to about 95 amino acids amino acids, about 5 amino acids to about 90 amino acids, about 5 amino acids to about 85 amino acids , about 5 amino acids to about 80 amino acids, about 5 amino acids to about 75 amino acids, about 5 amino acids to about 70 amino acids, about 5 amino acids to about 65 amino acids, about 5 10 to about 60 amino acids, about 5 to about 55 amino acids, about 5 amino acids to about 50 amino acids, about 5 amino acids to about 45 amino acids, about 5 amino acids Acids ~ Approximately 40 amino acids, approximately 5 amino acids ~ Approximately 35 amino acids, approximately 5 amino acids ~ About 30 amino acids, about 5 amino acids to about 25 amino acids, about 5 amino acids to about 2 0 amino acids, about 5 to about 15 amino acids, about 5 to about 10 amino acids about 5 to about 9 amino acids, about 5 to about 8 amino acids amino acids, about 5 amino acids to about 7 amino acids, about 6 amino acids to about 100 amino acids, About 6 amino acids to about 95 amino acids, about 6 amino acids to about 90 amino acids, about 6 10 to about 85 amino acids, about 6 to about 80 amino acids, about 6 Amino acids ~ about 75 amino acids, about 6 amino acids ~ about 70 amino acids, about 6 amino acids 65 amino acids, 60 amino acids, 6 ~ about 55 amino acids, ~ about 6 amino acids ~ about 50 amino acids, ~ about 6 amino acids ~ about 45 amino acids, about 6 amino acids to about 40 amino acids, about 6 amino acids to about 35 amino acids, about 6 amino acids to about 30 amino acids, about 6 amino acids to about 25 amino acids Amino acids, about 6 amino acids to about 20 amino acids, about 6 amino acids to about 15 amino acids amino acids, about 6 amino acids to about 10 amino acids, about 6 amino acids to about 9 amino acids, About 6 amino acids to about 8 amino acids, about 7 amino acids to about 100 amino acids, about 7 10 to about 95 amino acids, about 7 to about 90 amino acids, about 7 Amino acids ~ about 85 amino acids, about 7 amino acids ~ about 80 amino acids, about 7 amino acids 75 amino acids, 7 amino acids, 70 amino acids, 7 amino acids ~ about 65 amino acids, ~ about 7 amino acids ~ about 60 amino acids, ~ about 7 amino acids ~ about 55 amino acids, about 7 amino acids to about 50 amino acids, about 7 amino acids to about 45 7 to 40 amino acids, 7 to 35 amino acids Amino acids, about 7 amino acids to about 30 amino acids, about 7 amino acids to about 25 amino acids amino acids, about 7 amino acids to about 20 amino acids, about 7 amino acids to about 15 amino acids , about 7 amino acids to about 10 amino acids, about 7 amino acids to about 9 amino acids, about 8 100 amino acids, 800 amino acids, 95 amino acids, 800 amino acids, 100 to about 90 amino acids, about 8 to about 85 amino acids, about 8 amino acids ~ about 80 amino acids, about 8 amino acids ~ about 75 amino acids, about 8 amino acids Acids ~ Approximately 70 amino acids, approximately 8 amino acids ~ Approximately 65 amino acids, approximately 8 amino acids ~ About 60 amino acids, about 8 amino acids to about 55 amino acids, about 8 amino acids to about 5 0 amino acids, about 8 amino acids to about 45 amino acids, about 8 amino acids to about 40 amino acids amino acids, about 8 amino acids to about 35 amino acids, about 8 amino acids to about 30 amino acids amino acids, about 8 amino acids to about 25 amino acids, about 8 amino acids to about 20 amino acids acid, about 8 amino acids to about 15 amino acids, about 8 amino acids to about 10 amino acids, About 10 to 100 amino acids, about 10 to 95 amino acids , about 10 amino acids to about 90 amino acids, about 10 amino acids to about 85 amino acids , about 10 amino acids to about 80 amino acids, about 10 amino acids to about 75 amino acids , about 10 amino acids to about 70 amino acids, about 10 amino acids to about 65 amino acids , about 10 amino acids to about 60 amino acids, about 10 amino acids to about 55 amino acids , about 10 amino acids to about 50 amino acids, about 10 amino acids to about 45 amino acids , about 10 to about 40 amino acids, about 10 to about 35 amino acids , about 10 to about 30 amino acids, about 10 to about 25 amino acids , about 10 to about 20 amino acids, about 10 to about 15 amino acids , about 20 amino acids to about 100 amino acids, about 20 amino acids to about 95 amino acids Acids, about 20 amino acids to about 90 amino acids, about 20 amino acids to about 85 amino acids Acids, about 20 amino acids to about 80 amino acids, about 20 amino acids to about 75 amino acids Acids, about 20 amino acids to about 70 amino acids, about 20 amino acids to about 65 amino acids Acids, about 20 amino acids to about 60 amino acids, about 20 amino acids to about 55 amino acids Acids, about 20 amino acids to about 50 amino acids, about 20 amino acids to about 45 amino acids Acids, about 20 amino acids to about 40 amino acids, about 20 amino acids to about 35 amino acids Acids, about 20 amino acids to about 30 amino acids, about 20 amino acids to about 25 amino acids Acids, about 30 amino acids to about 100 amino acids, about 30 amino acids to about 95 amino acids amino acids, about 30 amino acids to about 90 amino acids, about 30 amino acids to about 85 amino acids amino acids, about 30 amino acids to about 80 amino acids, about 30 amino acids to about 75 amino acids amino acids, about 30 amino acids to about 70 amino acids, about 30 amino acids to about 65 amino acids amino acids, about 30 amino acids to about 60 amino acids, about 30 amino acids to about 55 amino acids amino acids, about 30 amino acids to about 50 amino acids, about 30 amino acids to about 45 amino acids amino acids, about 30 to about 40 amino acids, about 30 to about 35 amino acids amino acids, about 40 amino acids to about 100 amino acids, about 40 amino acids to about 95 amino acids amino acids, about 40 amino acids to about 90 amino acids, about 40 amino acids to about 85 amino acids amino acids, about 40 amino acids to about 80 amino acids, about 40 amino acids to about 75 amino acids amino acids, about 40 amino acids to about 70 amino acids, about 40 amino acids to about 65 amino acids amino acids, about 40 amino acids to about 60 amino acids, about 40 amino acids to about 55 amino acids amino acids, about 40 amino acids to about 50 amino acids, about 40 amino acids to about 45 amino acids amino acids, about 50 amino acids to about 100 amino acids, about 50 amino acids to about 95 amino acids Amino acids, about 50 amino acids to about 90 amino acids, about 50 amino acids to about 85 amino acids Amino acids, about 50 amino acids to about 80 amino acids, about 50 amino acids to about 75 amino acids Amino acids, about 50 amino acids to about 70 amino acids, about 50 amino acids to about 65 amino acids Amino acids, about 50 amino acids to about 60 amino acids, about 50 amino acids to about 55 amino acids Amino acids, about 60 amino acids to about 100 amino acids, about 60 amino acids to about 95 amino acids amino acids, about 60 amino acids to about 90 amino acids, about 60 amino acids to about 85 amino acids amino acids, about 60 amino acids to about 80 amino acids, about 60 amino acids to about 75 amino acids amino acids, about 60 to about 70 amino acids, about 60 to about 65 amino acids amino acids, about 70 to about 100 amino acids, about 70 to about 95 amino acids 70 to 90 amino acids, 70 to 85 amino acids 70 to 80 amino acids, 70 to 75 amino acids amino acids, about 80 amino acids to about 100 amino acids, about 80 amino acids to about 9 5 80 to 90 amino acids, 80 to 85 amino acids 90 to 100 amino acids, 90 to 9 5 amino acids, or about 95 to about 100 amino acids from its N-terminus and / or 1 amino acid to 100 amino acids (or a wild-type nucleotide sequence having a C-terminus removed from it (any of the subranges of this range listed below) It may comprise the sequence of the full-length CLRN1 protein.

[0055] In some embodiments, an active CLRN1 protein may contain, for example, between 1 amino acid and 50 amino acids. amino acids, 1 amino acid to 45 amino acids, 1 amino acid to 40 amino acids, 1 amino acid ~ 35 amino acids, 1 amino acid ~ 30 amino acids, 1 amino acid Acid ~ 25 amino acids, 1 amino acid ~ 20 amino acids, 1 amino acid ~ 15 amino acids Amino acids, 1 amino acid to 10 amino acids, 1 amino acid to 9 amino acids, 1 1 to 8 amino acids, 1 to 7 amino acids, 1 to 6 amino acids of amino acids, 1 amino acid to 5 amino acids, 1 amino acid to 4 amino acids, 1 ~3 amino acids, ~2 amino acids, ~50 amino acids, ~2 amino acids ~45 amino acids, about 2 amino acids ~40 amino acids, about 2 amino acids ~35 amino acids, about 2 amino acids to 30 amino acids, about 2 amino acids to 25 amino acids Acids, about 2 amino acids to 20 amino acids, about 2 amino acids to 15 amino acids, about 2 10 amino acids, 2 amino acids, 9 amino acids, 2 amino acids About 2 amino acids to 8 amino acids, about 2 amino acids to 7 amino acids, about 2 amino acids to 6 amino acids amino acids, about 2 amino acids to 5 amino acids, about 2 amino acids to 4 amino acids, about 3 3 to 50 amino acids, approximately 3 to 45 amino acids, approximately 3 40 amino acids, approximately 3 amino acids, 35 amino acids, approximately 3 amino acids, 3 0 amino acids, about 3 amino acids to 25 amino acids, about 3 amino acids to 20 amino acids amino acids, about 3 amino acids to 15 amino acids, about 3 amino acids to 10 amino acids, About 3 to 9 amino acids, about 3 to 8 amino acids, about 3 amino acids About 3 to 6 amino acids, about 3 to 5 amino acids Amino acids, about 4 amino acids to 50 amino acids, about 4 amino acids to 45 amino acids , about 4 amino acids to 40 amino acids, about 4 amino acids to 35 amino acids, about 4 4 amino acids ~ 30 amino acids, about 4 amino acids ~ 25 amino acids, about 4 amino acids Acids ~ 20 amino acids, about 4 amino acids ~ 15 amino acids, about 4 amino acids ~ 10 amino acids, about 4 to 9 amino acids, about 4 to 8 amino acids , about 4 amino acids to 7 amino acids, about 4 amino acids to 6 amino acids, about 5 amino acids 50 amino acids, approximately 5 amino acids 45 amino acids, approximately 5 amino acids 40 amino acids, about 5 amino acids to 35 amino acids, about 5 amino acids to 30 amino acids Amino acids, about 5 amino acids to 25 amino acids, about 5 amino acids to 20 amino acids , about 5 amino acids to 15 amino acids, about 5 amino acids to 10 amino acids, about 5 9 amino acids, about 5 amino acids, 8 amino acids, about 5 amino acids 7 amino acids, about 6 amino acids to 50 amino acids, about 6 amino acids to 45 amino acids amino acids, about 6 amino acids to 40 amino acids, about 6 amino acids to 35 amino acids, Approximately 6 amino acids to 30 amino acids, approximately 6 amino acids to 25 amino acids, approximately 6 Amino acids ~ 20 amino acids, about 6 amino acids ~ 15 amino acids, about 6 amino acids ~10 amino acids, ~6 amino acids ~9 amino acids, ~6 amino acids ~8 amino acids amino acids, about 7 amino acids to 50 amino acids, about 7 amino acids to 45 amino acids, Approximately 7 amino acids to 40 amino acids, approximately 7 amino acids to 35 amino acids, approximately 7 Amino acids ~ 30 amino acids, about 7 amino acids ~ 25 amino acids, about 7 amino acids ~20 amino acids, ~15 amino acids, ~10 amino acids amino acids, about 7 amino acids to 9 amino acids, about 8 amino acids to 50 amino acids , about 8 amino acids to 45 amino acids, about 8 amino acids, 40 amino acids, about 8 Amino acids ~ 35 amino acids, about 8 amino acids ~ 30 amino acids, about 8 amino acids ~25 amino acids, ~20 amino acids, ~15 amino acids amino acids, about 8 amino acids to 10 amino acids, about 10 amino acids to 50 amino acids amino acids, about 10 amino acids to 45 amino acids, about 10 amino acids to 40 amino acids , about 10 amino acids to 35 amino acids, about 10 amino acids to 30 amino acids, about 10 amino acids to 25 amino acids, approximately 10 amino acids to 20 amino acids, approximately 10 15 to 50 amino acids, approx. 15 to 15 amino acids, approx. Amino acids ~ 45 amino acids, about 15 amino acids ~ 40 amino acids, about 15 amino acids ~35 amino acids, ~30 amino acids, ~15 amino acids ~25 amino acids, ~15 amino acids ~20 amino acids, ~20 amino acids ~5 0 amino acids, approximately 20 amino acids to 45 amino acids, approximately 20 amino acids to 40 amino acids amino acids, about 20 amino acids to 35 amino acids, about 20 amino acids to 30 amino acids amino acids, about 20 amino acids to 25 amino acids, about 25 amino acids to 50 amino acids Acids, about 25 amino acids to 45 amino acids, about 25 amino acids to 40 amino acids, Approximately 25 to 35 amino acids, approximately 25 to 30 amino acids, approximately 3 0 amino acids to 50 amino acids, approximately 30 amino acids to 45 amino acids, approximately 30 100-40 amino acids, approx. 30-35 amino acids, approx. 35 amino acids amino acids ~ 50 amino acids, about 35 amino acids ~ 45 amino acids, about 35 amino acids Acids ~ 40 amino acids, about 40 amino acids ~ 50 amino acids, about 40 amino acids ~ 45 amino acids, or about 45 amino acids to about 50 amino acids, are inserted; The sequence of the wild-type full-length CLRN1 protein may include the single amino acid sequence. ~50 amino acids (or any subrange thereof) from the sequence of the wild-type full-length protein In some cases, the sequence may be inserted as a continuous sequence of 1 to 50 amino acids (or (or any subrange thereof) may be expressed as multiple non-contiguous positions in the sequence of the wild-type full-length protein. As will be understood in the art, the 1 amino acid to 50 amino acids The acid is located in a part of the wild-type full-length protein sequence that is not well conserved among species. It can be inserted.

[0056] Unless otherwise defined, all technical and scientific terms used herein are intended to be used by the present invention. has the same meaning as that generally understood by a person skilled in the art to which it pertains. Methods and materials for use are described herein, but other suitable methods and materials known in the art may also be used. These materials, methods, and examples are provided for illustrative purposes only. All publications, patent applications, and other references mentioned herein are intended to be illustrative and not limiting. , patents, sequences, database entries, and other references are incorporated by reference in their entireties. In case of conflict, the present specification, including definitions, will control.

[0057] Other features and advantages of the present invention will become apparent from the following detailed description and figures, as well as from the accompanying drawings. This will be clear from the claims. The present invention provides, for example, the following items. (Item 1) 1. A composition comprising at least two different nucleic acid vectors, Each of the at least two different vectors carries a different portion of the CLRN1 protein. each of said encoded portions comprises a coding sequence encoding at least 30 amino acids the length of each of the encoded portions is 2000-20 ... The amino acid sequence of the encoded portion may partially overlap with the amino acid sequence of a different portion of the encoded portion, Any single vector of the at least two different vectors may contain a full-length CL It does not encode the RN1 protein, At least one of the coding sequences is located between two consecutive sequences of CLRN1 genomic DNA. A nucleic acid sequence spanning two consecutive exons and lacking intronic sequences between the two exons. comprising a nucleotide sequence, When introduced into a mammalian cell, the at least two different vectors undergo homologous recombination with each other. thereby forming a recombinant nucleic acid encoding the full-length CLRN1 protein. The composition. (Item 2) Each of the at least two different vectors contains a first antigen of the CLRN1 protein. 2. The composition of claim 1, comprising coding sequences encoding different portions of an isoform. (Item 3) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 3. The composition of claim 2, comprising a sequence that is 5% identical. (Item 4) Item 3. The first isoform of the CLRN1 protein comprises SEQ ID NO: 3. The composition described in (Item 5) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 4. The composition according to claim 4. (Item 6) One of the at least two different nucleic acid vectors encodes the CLRN1 protein 3. The composition of claim 2, further comprising a sequence encoding a second isoform of (Item 7) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 7. The composition of item 6, comprising a sequence that is 5% identical. (Item 8) Item 7. The second isoform of the CLRN1 protein comprises SEQ ID NO: 5. The composition described in (Item 9) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 8. The composition described in 8. (Item 10) Each of the at least two different vectors contains a second antigen of the CLRN1 protein. 2. The composition of claim 1, comprising coding sequences encoding different portions of an isoform. (Item 11) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 11. The composition of claim 10, comprising a sequence that is 5% identical. (Item 12) Item 1, wherein the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. 1. The composition described in 1. (Item 13) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 13. The composition according to claim 12. (Item 14) One of the at least two different nucleic acid vectors encodes the CLRN1 protein Item 14. The composition of item 13, further comprising a sequence encoding a first isoform of: (Item 15) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 15. The composition of claim 14, comprising a sequence that is 5% identical. (Item 16) Item 1, wherein the first isoform of the CLRN1 protein comprises SEQ ID NO: 3. 5. The composition described in 5. (Item 17) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 16. The composition described in 16. (Item 18) At least one of the at least two different vectors has a 5' untranslated region (U 18. The composition of any one of items 1 to 17, comprising a 3'UTR, a 3'UTR, or both. (Item 19) The 5'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 19. The composition according to item 18, comprising an oxalate. (Item 20) The 5'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 12. 20. The composition according to item 19, comprising an oxalate. (Item 21) The 5'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. 21. The composition according to item 20, comprising an oxalate. (Item 22) The 5'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12. 22. The composition according to item 21, comprising an oxalate. (Item 23) Item 18. The 5'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 12. The composition described in (Item 24) The 3'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 19. The composition according to item 18, comprising an oxalate. (Item 25) The 3'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 15. 25. The composition according to item 24, comprising an oxalate. (Item 26) The 3'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 15. 26. The composition according to item 25, comprising an oxalate. (Item 27) The 3'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 15. 27. The composition according to item 26, comprising an oxalate. (Item 28) Item 18. The 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 15. The composition described in (Item 29) Each of the at least two different vectors may be a plasmid, a transposon, a cosmi 2. The composition of item 1, wherein the composition is a vector, an artificial chromosome, or a viral vector. (Item 30) Each of the at least two different vectors may be a human artificial chromosome (HAC), a yeast artificial chromosome (YAC), or a yeast artificial chromosome (YAC). YAC, bacterial artificial chromosome (BAC), or P1-derived artificial chromosome (PAC) Item 1. The composition according to item 1. (Item 31) Each of the at least two different vectors is an adeno-associated virus (AAV) vector. -, adenoviral vector, lentiviral vector, or retroviral vector The composition of item 1, wherein the viral vector is selected from the group consisting of: (Item 32) Item 32. The method according to item 31, wherein each of the at least two different vectors is an AAV vector. The composition described above. (Item 33) The amino acid sequence of any of the encoded portions may be 32. The amino acid sequence of any one of items 1 to 32 does not overlap with a different part of the amino acid sequence of the The composition described above. (Item 34) The amino acid sequence of each of the encoded portions is different from that of the encoded portions. 33. The composition according to any one of items 1 to 32, wherein the amino acid sequence of the fragment partially overlaps with that of the fragment. (Item 35) The overlapping amino acid sequences are about 30 to about 202 amino acid residues in length. Item 35. The composition according to item 34. (Item 36) The vector comprises two different vectors, each of the two different vectors comprising: and different segments of an intron, the intron being present in the CLRN1 genomic DNA. the nucleotide sequence of the intron present in said two different intron segments; 33. The method of any one of items 1 to 32, wherein the sequences overlap by at least 100 nucleotides. composition. (Item 37) The sequences of the two different intron segments are from 100 nucleotides to about 800 nucleotides. 37. The composition of claim 36, wherein the composition overlaps with leiotide. (Item 38) The entire nucleotide sequence of each of the at least two different vectors is about 500 nucleotides. 37. The nucleic acid sequence of claim 1, wherein the nucleic acid sequence is about 10,000 nucleotides in length. The composition described above. (Item 39) The entire nucleotide sequence of each of the at least two different vectors is 500 nucleotides. 39. The composition of item 38, wherein the length of the composition is between 5,000 nucleotides and 5,000 nucleotides. (Item 40) 40. The method according to any one of items 1 to 39, wherein the number of different vectors in the composition is two. Composition of. (Item 41) The first of the two different vectors contains the N of the CLRN1 protein 41. The composition of claim 40, comprising a coding sequence encoding a terminal portion. (Item 42) The N-terminal portion of the CLRN1 protein has a length of 30 amino acids to 202 amino acids. Item 42. The composition according to item 41, wherein (Item 43) The N-terminal portion of the CLRN1 protein has a length of 60 to 170 amino acids. Item 42. The composition according to item 41, wherein (Item 44) 42. The composition of claim 41, wherein the first vector further comprises a 5'UTR sequence. (Item 45) The 5'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 12. 45. The composition according to item 44, comprising an oxalate. (Item 46) The 5'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 12. 46. ​​The composition according to item 45, comprising an oxalate. (Item 47) The 5'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. 47. The composition according to item 46, comprising an oxalate. (Item 48) The 5'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12. 48. The composition according to item 47, comprising an oxalate. (Item 49) Item 44. The 5'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 12. The composition described in (Item 50) The first vector contains one or both of a promoter and a Kozak sequence. 50. The composition according to any one of items 41 to 49, comprising: (Item 51) The first vector may comprise an inducible promoter, a constitutive promoter, or a tissue-specific promoter. 51. The composition of item 50, comprising a promoter that is a promoter. (Item 52) The second of the two different vectors contains the C of the CLRN1 protein. 52. The composition according to any one of items 40 to 51, comprising a coding sequence encoding a terminal portion. . (Item 53) The C-terminal portion of the CLRN1 protein has a length of 30 amino acids to 202 amino acids. Item 53. The composition according to item 52, wherein (Item 54) The C-terminal portion of the CLRN1 protein has a length of 60 to 170 amino acids. Item 54. The composition according to item 53, wherein (Item 55) 55. The method of claim 52, wherein the second vector further comprises a polyadenylation signal sequence. The composition according to any one of claims 1 to 4. (Item 56) 56. Any one of items 52 to 55, wherein the second vector further comprises a 3'UTR sequence. The composition described in (Item 57) The 3'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 15. 57. The composition according to item 56, comprising an oxalate. (Item 58) The 3'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 15. 58. The composition according to item 57, comprising an oxalate. (Item 59) The 3'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 15. 59. The composition of claim 58, comprising an oxalate. (Item 60) The 3'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 59. The composition of item 59, comprising an oxalate. (Item 61) Item 56. The 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 15. The composition described in (Item 62) A composition comprising a single nucleic acid vector, said vector comprising: (i) a nucleic acid encoding a CLRN1 protein; (ii) a first coding sequence encoding a first isoform of a protein; and one or both of the second coding sequences encoding a second isoform of the protein; Including, One or both of the first and second coding sequences is a sequence of the CLRN1 genomic DNA A sequence spanning two consecutive exons and having an intron sequence between the two consecutive introns. The composition comprising a nucleotide sequence lacking a sequence. (Item 63) The single nucleic acid vector contains the first coding sequence and the second coding sequence 63. The composition of item 62, which does not contain (Item 64) The single nucleic acid vector contains the second coding sequence and the first coding sequence 63. The composition of item 62, which does not contain (Item 65) The single nucleic acid vector contains both the first coding sequence and the second coding sequence. 63. The composition according to item 62, comprising (Item 66) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 66. The composition of any one of items 62, 63, and 65, comprising a sequence that is 5% identical. (Item 67) Item 6. The first isoform of the CLRN1 protein comprises SEQ ID NO: 3. 6. The composition according to claim 6. (Item 68) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 67. The composition according to claim 67. (Item 69) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 66. The composition of any one of items 62, 64, and 65, comprising a sequence that is 5% identical. (Item 70) Item 6. The second isoform of the CLRN1 protein comprises SEQ ID NO: 5. 9. The composition according to claim 9. (Item 71) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 70. The composition described in 70. (Item 72) The single nucleic acid vector further comprises a 5' untranslated region (UTR), a 3' UTR, or both. The composition according to any one of items 62 to 71, further comprising: (Item 73) The 5'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 12. 73. The composition according to item 72, comprising an oxalate. (Item 74) The 5'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 12. 74. The composition according to item 73, comprising an oxalate. (Item 75) The 5'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. 75. The composition according to item 74, comprising an oxalate. (Item 76) The 5'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12. 76. The composition of claim 75, comprising an oxalate. (Item 77) Item 72. The 5'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 12. The composition described in (Item 78) The 3'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 15. 73. The composition according to item 72, comprising an oxalate. (Item 79) The 3'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 15. 79. The composition according to item 78, comprising an oxalate. (Item 80) The 3'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 15. 80. The composition of claim 79, comprising an oxalate. (Item 81) The 3'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 15. 81. The composition according to item 80, comprising an oxalate. (Item 82) Item 72. The 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 15. The composition described in (Item 83) The single nucleic acid vector may be a plasmid, a transposon, a cosmid, an artificial chromosome, or 63. The composition of item 62, which is a vector or a viral vector. (Item 84) The single nucleic acid vector may be a human artificial chromosome (HAC), a yeast artificial chromosome (YAC), Bacterial artificial chromosomes (BACs) or P1-derived artificial chromosomes (PACs), as described in item 62. The composition described above. (Item 85) The single nucleic acid vector may be an adeno-associated virus (AAV) vector, an adenovirus, a virus selected from a vector, a lentiviral vector, or a retroviral vector. 63. The composition of claim 62, which is a vector. (Item 86) 86. The composition of item 85, wherein the single nucleic acid vector is an AAV vector. (Item 87) The single nucleic acid vector contains one or both of a promoter and a Kozak sequence. 63. The composition of claim 62, further comprising: (Item 88) The first vector may comprise an inducible promoter, a constitutive promoter, or a tissue-specific promoter. 88. The composition of item 87, comprising a promoter that is a promoter. (Item 89) 88. The nucleic acid vector according to item 87, wherein the single nucleic acid vector further comprises a polyadenylation signal sequence. The composition described above. (Item 90) 89. The composition according to any one of items 1 to 89, further comprising a pharmaceutically acceptable excipient. . (Item 91) A kit comprising the composition according to any one of items 1 to 90. (Item 92) 92. The kit of item 91, further comprising a pre-filled syringe containing the composition. (Item 93) A therapeutically effective amount of the composition according to any one of items 1 to 90 is introduced into the cochlea of ​​a mammal. A method, comprising: (Item 94) Item 94. The method of item 93, wherein the mammal is a human. (Item 95) the mammal has previously been identified as having a defective CLRN1 gene. 93. The method according to claim 94, wherein (Item 96) A method for increasing expression of a full-length CLRN1 protein in a mammalian cell, comprising: 100. The method of claim 100, further comprising introducing the composition according to any one of items 1 to 90 into the mammalian cell. method. (Item 97) 97. The method of claim 96, wherein the mammalian cell is a cochlear inner hair cell or an outer cochlear hair cell. . (Item 98) 97. The method of item 96, wherein the mammalian cell is a retinal cell. (Item 99) 99. The method according to any one of items 96 to 98, wherein the mammalian cells are human cells. (Item 100) the mammalian cell has previously been determined to have a defective CLRN1 gene. 99. A method according to any one of items 96 to 99. (Item 101) Full-length CLRN1 transcription factors are expressed in inner hair cells, outer hair cells, or both in the mammalian cochlea. 1. A method for increasing expression of a protein, comprising: administering to the cochlea of ​​the mammal a therapeutically effective amount of the composition according to any one of items 1 to 90. The method further comprising introducing an agent. (Item 102) 1. A method for increasing expression of a full-length CLRN1 protein in a mammalian eye, comprising: a therapeutically effective amount of the composition according to any one of items 1 to 90, to the eye of the mammal; The method comprises administering intraocularly (Item 103) the mammal has previously been identified as having a defective CLRN1 gene. 101 or 102. (Item 104) 105. The method according to any one of items 101 to 104, wherein the mammal is a human. (Item 105) Methods for treating hearing loss in subjects identified as having a defective CLRN1 gene It is a law, A therapeutically effective amount of the composition according to any one of items 1 to 90 is administered to the cochlea of ​​the subject. The method comprising administering. (Item 106) Methods for treating vision loss in subjects identified as having a defective CLRN1 gene It is a law, administering a therapeutically effective amount of the composition according to any one of items 1 to 90 to the eye of the subject; The method comprising: (Item 107) 107. The method according to item 105 or 106, wherein the subject has Usher syndrome type III. Law. (Item 108) 108. The method according to any one of items 105 to 107, wherein the subject is a human. (Item 109) Prior to the administering step, determining that the subject has a defective CLRN1 gene. 109. The method according to any one of items 105 to 108, further comprising: (Item 110) 1. A composition comprising two different nucleic acid vectors, a first nucleic acid vector of the two different nucleic acid vectors comprising a promoter and the A gene encoding the N-terminal portion of the CLRN1 protein located 3' of the promoter a first coding sequence comprising a splice sequence located at the 3' end of the first coding sequence; and a donor sequence, The second nucleic acid vector of the two different nucleic acid vectors contains a splice acceptor. a CLRN sequence located at the 3' end of the splice acceptor sequence; a second coding sequence encoding the C-terminal portion of the first protein, and a sequence preceding the second coding sequence; and a polyadenylation signal sequence at the 3' end, each of said encoded portions is at least 30 amino acid residues in length, The amino acid sequences of the encoded portions of the two different vectors do not overlap with each other, None of the vectors encodes the full-length CLRN1 protein, When introduced into a mammalian cell, the splice donor sequence and the splice acceptor sequence splicing occurs between the -sequence, thereby generating the full-length CLRN1 protein. The composition, wherein a recombinant nucleic acid encoding the composition is formed. (Item 111) the first coding sequence is an N-terminal portion of a first isoform of the CLRN1 protein; wherein said second coding sequence encodes said first isoform of CLRN1 protein. 111. The composition of claim 110, wherein the C-terminal portion of the (Item 112) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 112. The composition of claim 111, comprising a sequence that is 5% identical. (Item 113) Item 1, wherein the first isoform of the CLRN1 protein comprises SEQ ID NO: 3. 13. The composition according to claim 12. (Item 114) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 113. The composition according to claim 113. (Item 115) The first nucleic acid vector of the second nucleic acid vector encodes the CLRN1 protein. 112. The composition of claim 111, further comprising a sequence encoding a second isoform of the protein. (Item 116) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 116. The composition of claim 115, comprising a sequence that is 5% identical. (Item 117) Item 1, wherein the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. 16. The composition according to claim 16. (Item 118) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 117. The composition according to claim 117. (Item 119) the first coding sequence is an N-terminal portion of a second isoform of the CLRN1 protein; wherein said second coding sequence encodes said second isoform of CLRN1 protein. 111. The composition of claim 110, wherein the C-terminal portion of the (Item 120) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 120. The composition of claim 119, comprising a sequence that is 5% identical. (Item 121) Item 1, wherein the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. 20. The composition described in 20. (Item 122) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 121. The composition according to claim 121. (Item 123) the first nucleic acid vector or the second nucleic acid vector is a nucleic acid encoding the CLRN1 protein 120. The composition of claim 119, further comprising a sequence encoding a first isoform of: (Item 124) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 124. The composition of claim 123, comprising a sequence that is 5% identical. (Item 125) Item 1, wherein the first isoform of the CLRN1 protein comprises SEQ ID NO: 3. 24. The composition described in 24. (Item 126) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 125. The composition according to claim 125. (Item 127) One or both of the first nucleic acid vector and the second nucleic acid vector comprises a 5' Any of items 110-126, including untranslated regions (UTR), 3'UTR, or both 2. The composition described in item 1. (Item 128) The 5'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 128. The composition according to item 127, comprising an oxalate. (Item 129) The 5'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 129. The composition according to item 128, comprising an oxalate. (Item 130) The 5'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 129. The composition of item 129, comprising an oxalate. (Item 131) The 5'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 131. The composition according to item 130, comprising an oxalate. (Item 132) Item 12. The 5'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 12. 7. The composition described in 7. (Item 133) The 3'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 128. The composition according to item 127, comprising an oxalate. (Item 134) The 3'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 134. The composition according to item 133, comprising an oxalate. (Item 135) The 3'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 135. The composition according to item 134, comprising an oxalate. (Item 136) The 3'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 136. The composition according to item 135, comprising an oxalate. (Item 137) Item 12. The 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 15. 7. The composition described in 7. (Item 138) Each of the first nucleic acid vector and the second nucleic acid vector is a plasmid, a trans Items 110 to 137, which are posons, cosmids, artificial chromosomes, or viral vectors The composition according to any one of claims 1 to 4. (Item 139) Each of the first nucleic acid vector and the second nucleic acid vector is a human artificial chromosome (HA C) Yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or P1-derived artificial staining 138. The composition according to any one of items 110 to 137, which is a protease inhibitor (PAC). (Item 140) Each of the first nucleic acid vector and the second nucleic acid vector is an adeno-associated virus ( AAV (adenoviral vector), adenoviral vector, lentiviral vector, or retroviral vector 137. Any of items 110 to 137, wherein the viral vector is selected from the group consisting of viral vectors. 2. The composition described in item 1. (Item 141) Each of the first nucleic acid vector and the second nucleic acid vector is an AAV vector. 141. The composition according to item 140. (Item 142) At least one of the coding sequences is located between two consecutive sequences of CLRN1 genomic DNA. A nucleic acid sequence spanning two consecutive exons and lacking intronic sequences between the two exons. 142. The composition according to any one of items 110 to 141, comprising a nucleotide sequence. (Item 143) 1. A composition comprising two different nucleic acid vectors, a first nucleic acid vector of the two different nucleic acid vectors comprising a promoter and the A gene encoding the N-terminal portion of the CLRN1 protein located 3' of the promoter a first coding sequence comprising a splice sequence located at the 3' end of the first coding sequence; a splice donor sequence and a first detectable target located 3' to the splice donor sequence. a leader gene, A second of the two different nucleic acid vectors contains a second detectable marker. a gene and a splice amplified fragment located 3' of the second detectable marker gene a splice acceptor sequence and a splice acceptor sequence located at the 3' end of the splice acceptor sequence, a second coding sequence encoding a C-terminal portion of the CLRN1 protein; a polyadenylation signal sequence located at the 3' end of the sequence; Each of the encoded portions is at least 30 amino acid residues in length, The amino acid sequences of the transferred parts do not overlap with each other, and None of the vectors encodes the full-length CLRN1 protein. When introduced into a mammalian cell, the splice donor sequence and the splice acceptor sequence splicing occurs between the -sequence, thereby generating the full-length CLRN1 protein. The composition, wherein a recombinant nucleic acid encoding the composition is formed. (Item 144) the first coding sequence is an N-terminal portion of a first isoform of the CLRN1 protein; wherein said second coding sequence encodes said first isoform of CLRN1 protein. Item 144. The composition of item 143, wherein the composition encodes a C-terminal portion of the (Item 145) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 145. The composition of claim 144, comprising a sequence that is 5% identical. (Item 146) Item 1, wherein the first isoform of the CLRN1 protein comprises SEQ ID NO: 3. 45. The composition described in (Item 147) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 146. The composition according to claim 146. (Item 148) The first nucleic acid vector of the second nucleic acid vector encodes the CLRN1 protein. 145. The composition of claim 144, further comprising a sequence encoding a second isoform of the protein. (Item 149) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 149. The composition of claim 148, comprising a sequence that is 5% identical. (Item 150) Item 1, wherein the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. 49. The composition according to claim 49. (Item 151) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 150. The composition according to claim 150. (Item 152) the first coding sequence is an N-terminal portion of a second isoform of the CLRN1 protein; wherein said second coding sequence encodes said second isoform of CLRN1 protein. Item 144. The composition of item 143, wherein the composition encodes a C-terminal portion of the (Item 153) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 153. The composition of claim 152, comprising a sequence that is 5% identical. (Item 154) Item 1, wherein the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. 53. The composition described in 53. (Item 155) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 154. The composition according to claim 154. (Item 156) the first nucleic acid vector or the second nucleic acid vector is a nucleic acid encoding the CLRN1 protein Item 153. The composition of item 152, further comprising a sequence encoding a first isoform of (Item 157) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 157. The composition of claim 156, comprising a sequence that is 5% identical. (Item 158) Item 1, wherein the first isoform of the CLRN1 protein comprises SEQ ID NO: 3. 57. The composition described in 57. (Item 159) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 158. The composition according to claim 158. (Item 160) One or both of the first nucleic acid vector and the second nucleic acid vector comprises a 5' Any of items 143-159, including untranslated regions (UTR), 3'UTR, or both 2. The composition described in item 1. (Item 161) The 5'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 161. The composition according to item 160, comprising an oxalate. (Item 162) The 5'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 162. The composition according to item 161, comprising an oxalate. (Item 163) The 5'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 163. The composition according to item 162, comprising an oxalate. (Item 164) The 5'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 164. The composition according to item 163, comprising an oxalate. (Item 165) Item 16. The 5'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 12. 1. The composition described in 0. (Item 166) The 3'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 161. The composition according to item 160, comprising an oxalate. (Item 167) The 3'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 167. The composition according to item 166, comprising an oxalate. (Item 168) The 3'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 168. The composition according to item 167, comprising an oxalate. (Item 169) The 3'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 169. The composition according to item 168, comprising an oxalate. (Item 170) Item 16. The 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 15. 1. The composition described in 0. (Item 171) Each of the first nucleic acid vector and the second nucleic acid vector is a plasmid, a trans Items 143 to 170, which are posons, cosmids, artificial chromosomes, or viral vectors The composition according to any one of claims 1 to 4. (Item 172) Each of the first nucleic acid vector and the second nucleic acid vector is a human artificial chromosome (HA C) Yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or P1-derived artificial staining 171. The composition according to any one of items 143 to 170, which is a protease inhibitor (PAC). (Item 173) Each of the first nucleic acid vector and the second nucleic acid vector is an adeno-associated virus ( AAV (adenoviral vector), adenoviral vector, lentiviral vector, or retroviral vector 170. Any of items 143 to 170, wherein the viral vector is selected from the group consisting of viral vectors. 2. The composition described in item 1. (Item 174) Each of the first nucleic acid vector and the second nucleic acid vector is an AAV vector. 174. The composition according to item 173. (Item 175) At least one of the coding sequences is located between two consecutive sequences of CLRN1 genomic DNA. A nucleic acid sequence spanning two consecutive exons and lacking intronic sequences between the two exons. 175. The composition according to any one of items 143 to 174, comprising a nucleotide sequence. (Item 176) The first or second detectable marker gene is alkaline phosphatase. The composition according to any one of items 143 to 175. (Item 177) 1. A composition comprising two different nucleic acid vectors, a first nucleic acid vector of the two different nucleic acid vectors comprising a promoter and the The N-terminal portion of the CLRN1 protein is located 3' to the promoter. a first coding sequence that encodes a nucleotide sequence and a sequence located at the 3' end of the first coding sequence; a splice donor sequence and an F1 located 3' to the splice donor sequence a phage recombinogenic region; The second of the two different nucleic acid vectors is an F1 phage recombinase vector. a guide region and a splice access region located 3' to the F1 phage recombination induction region a splice acceptor sequence and a CL located at the 3' end of the splice acceptor sequence. a second coding sequence encoding a C-terminal portion of the RN1 protein; and and a polyadenylation signal sequence located at the 3' end of Each of the two encoded portions is at least 30 amino acid residues in length, The amino acid sequences of the two encoded portions do not overlap with each other, and the two different vectors None of the vectors encodes the full-length CLRN1 protein, When introduced into a mammalian cell, the splice donor sequence and the splice acceptor sequence splicing occurs between the -sequence, thereby generating the full-length CLRN1 protein. The composition, wherein a recombinant nucleic acid encoding the composition is formed. (Item 178) the first coding sequence is an N-terminal portion of a first isoform of the CLRN1 protein; wherein said second coding sequence encodes said first isoform of CLRN1 protein. Item 178. The composition of item 177, wherein the composition encodes a C-terminal portion of the (Item 179) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 179. The composition of claim 178, comprising a sequence which is 5% identical. (Item 180) Item 1, wherein the first isoform of the CLRN1 protein comprises SEQ ID NO: 3. 79. The composition according to claim 79. (Item 181) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 180. The composition according to claim 180. (Item 182) The first nucleic acid vector of the second nucleic acid vector encodes the CLRN1 protein. 179. The composition of claim 178, further comprising a sequence encoding a second isoform of the protein. (Item 183) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 183. The composition of claim 182, comprising a sequence which is 5% identical. (Item 184) Item 1, wherein the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. 83. The composition described in 83. (Item 185) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 184. The composition according to claim 184. (Item 186) the first coding sequence is an N-terminal portion of a second isoform of the CLRN1 protein; wherein said second coding sequence encodes said second isoform of CLRN1 protein. Item 178. The composition of item 177, wherein the composition encodes a C-terminal portion of the (Item 187) the second isoform of the CLRN1 protein is a sequence identical to that of SEQ ID NO: 5 and at least 9 187. The composition of claim 186, comprising a sequence which is 5% identical. (Item 188) Item 1, wherein the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. 87. The composition according to claim 87. (Item 189) the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. 188. The composition according to claim 188. (Item 190) the first nucleic acid vector or the second nucleic acid vector is a nucleic acid encoding the CLRN1 protein 187. The composition of claim 186, further comprising a sequence encoding a first isoform of (Item 191) The first isoform of the CLRN1 protein has a sequence identical to that of SEQ ID NO: 3 and at least 9 191. The composition of claim 190, comprising a sequence that is 5% identical. (Item 192) Item 1, wherein the first isoform of the CLRN1 protein comprises SEQ ID NO: 3. 91. The composition described in 91. (Item 193) the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. 192. The composition according to claim 192. (Item 194) One or both of the first nucleic acid vector and the second nucleic acid vector comprises a 5' Any of items 177-193, including untranslated regions (UTR), 3'UTR, or both 2. The composition described in item 1. (Item 195) The 5'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 195. The composition according to item 194, comprising an oxalate. (Item 196) The 5'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 196. The composition according to item 195, comprising an oxalate. (Item 197) The 5'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 12. 197. The composition according to item 196, comprising an oxalate. (Item 198) The 5'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 12. Item 197. The composition according to item 197, comprising an oxalate. (Item 199) Item 19. The 5'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 12. 4. The composition according to claim 4. (Item 200) The 3'UTR comprises at least 10 consecutive nucleotides from anywhere within SEQ ID NO: 15. Item 195. The composition according to item 194, comprising an oxalate. (Item 201) The 3'UTR comprises at least 20 consecutive nucleotides from anywhere within SEQ ID NO: 15. 201. The composition according to item 200, comprising an oxalate. (Item 202) The 3'UTR comprises at least 50 consecutive nucleotides from anywhere within SEQ ID NO: 15. 202. The composition according to item 201, comprising an oxalate. (Item 203) The 3'UTR comprises at least 80 consecutive nucleotides from anywhere within SEQ ID NO: 15. 203. The composition according to item 202, comprising an oxalate. (Item 204) Item 19. The 3'UTR comprises a sequence that is at least 80% identical to SEQ ID NO: 15. 4. The composition according to claim 4. (Item 205) Each of the first nucleic acid vector and the second nucleic acid vector is a plasmid, a trans 177 to 204, which are posons, cosmids, artificial chromosomes, or viral vectors. The composition according to any one of claims 1 to 4. (Item 206) Each of the first nucleic acid vector and the second nucleic acid vector is a human artificial chromosome (HA C) Yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or P1-derived artificial staining The composition according to any one of items 177 to 204, which is a protease inhibitor (PAC). (Item 207) Each of the first nucleic acid vector and the second nucleic acid vector is an adeno-associated virus ( AAV (adenoviral vector), adenoviral vector, lentiviral vector, or retroviral vector 205. Any of items 177 to 204, wherein the viral vector is selected from the group consisting of viral vectors. 2. The composition described in item 1. (Item 208) Each of the first nucleic acid vector and the second nucleic acid vector is an AAV vector. 208. The composition according to item 207. (Item 209) At least one of the coding sequences is located between two consecutive sequences of CLRN1 genomic DNA. A nucleic acid sequence spanning two consecutive exons and lacking intronic sequences between the two exons. 205. The composition of any one of items 177 to 204, comprising a nucleotide sequence. (Item 210) A kit comprising the composition according to any one of items 110 to 209. (Item 211) 211. The kit of item 210, further comprising a pre-filled syringe containing the composition. (Item 212) A therapeutically effective amount of the composition according to any one of items 110 to 209 is administered to the cochlea of ​​a mammal. 20. A method comprising: (Item 213) 213. The method of claim 212, wherein the mammal is a human. (Item 214) the mammal has previously been identified as having a defective CLRN1 gene. 214. The method according to claim 212 or 213. (Item 215) A method for increasing expression of a full-length CLRN1 protein in a mammalian cell, comprising: and introducing the composition according to any one of items 110 to 209 into the mammalian cell. , the method. (Item 216) 216. The method of claim 215, wherein the mammalian cells are cochlear inner hair cells or cochlear outer hair cells. Law. (Item 217) 216. The method of item 215, wherein the mammalian cell is a retinal cell. (Item 218) 218. The method according to any one of items 215 to 217, wherein the mammalian cells are human cells. (Item 219) the mammalian cell has previously been determined to have a defective CLRN1 gene. 219. The method according to any one of items 215 to 218. (Item 220) Full-length CLRN1 transcription factors are expressed in inner hair cells, outer hair cells, or both in the mammalian cochlea. 1. A method for increasing expression of a protein, comprising: A therapeutically effective amount of any one of items 110 to 209 is administered to the cochlea of ​​the mammal. The method comprising introducing a composition of formula (I) into the tissue. (Item 221) 1. A method for increasing expression of a full-length CLRN1 protein in a mammalian eye, comprising: A therapeutically effective amount of any one of items 110 to 209 is administered to the eye of the mammal. The method comprises administering the composition intraocularly. (Item 222) the mammal has previously been identified as having a defective CLRN1 gene. 220 or 221. (Item 223) 223. The method according to any one of items 220 to 222, wherein the mammal is a human. (Item 224) Methods for treating hearing loss in subjects identified as having a defective CLRN1 gene It is a law, A therapeutically effective amount of the composition according to any one of items 110 to 209 is administered to the cochlear cavity of the subject. The method comprises administering to a cow. (Item 225) Methods for treating vision loss in subjects identified as having a defective CLRN1 gene It is a law, A therapeutically effective amount of the composition according to any one of items 110 to 209 is administered to the eye of the subject. The method comprises administering to (Item 226) 226. The method according to item 224 or 225, wherein the subject has Usher syndrome type III. Law. (Item 227) 227. The method according to any one of items 224 to 226, wherein the subject is a human. (Item 228) Prior to the administering step, determining that the subject has a defective CLRN1 gene. 228. The method of any one of items 224 to 227, further comprising: [Brief explanation of the drawings]

[0058] [Figure 1] 1 is an exemplary schematic diagram of a genetic map of the CLRN-1 vector (SEQ ID NO: 40, 3397 base pairs (bp)) that can be used in any of the methods described herein. The vector contains AAV2 ITRs, a CMV enhancer (SEQ ID NO: 17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), a T2A sequence (SEQ ID NO: 31), CLRN1 isoform 2 (SEQ ID NO: 6), a bGH poly(A) signal (SEQ ID NO: 20), and the AAV2 ITRs. [Figure 2] 1 is an exemplary schematic diagram of a genetic map of the CLRN-2GFP vector (SEQ ID NO:41, 4177 bp) that can be used in any of the methods described herein. The vector contains AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 2 (SEQ ID NO:6), a T2A sequence (SEQ ID NO:31), eGFP (SEQ ID NO:32), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 3] 1 is an exemplary schematic diagram of a genetic map of the CLRN-3 vector (SEQ ID NO:42, 4607 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), 5'UTR-291, CLRN1 isoform 1 (SEQ ID NO:1), 3'UTR-1357 (SEQ ID NO:36), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 4] 1 is an exemplary schematic diagram of a genetic map of the CLRN-4 vector (SEQ ID NO:43, 4796 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 2 (SEQ ID NO:6), 3'UTR-1406 (SEQ ID NO:37), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 5]1 is an exemplary schematic diagram of the genetic map of the pITR-CBA-5'UTR-tGFP-3'UTR vector (5026 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO: 17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO: 16), 5'UTR-291, tGFP (SEQ ID NO: 19), 3'UTR-1595, a bGH poly(A) signal (SEQ ID NO: 20), and the AAV2 ITRs. [Figure 6] 1 is an exemplary schematic diagram of a genetic map of the CLRN-6eGFP vector (SEQ ID NO:44, 4756 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), eGFP (SEQ ID NO:32), 3'UTR-1406 (SEQ ID NO:37), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 7] 1 is an exemplary schematic diagram of the genetic map of the pITR-CBA-3'UTR-600A vector (3982 bp) that can be used in any of the methods described herein, which vector contains AAV2 ITRs, a CMV enhancer (SEQ ID NO: 17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 4), a T2A sequence (SEQ ID NO: 31), CLRN1 isoform 2 (SEQ ID NO: 6), 3'UTR-600 (SEQ ID NO: 27), a bGH poly(A) signal (SEQ ID NO: 20), and the AAV2 ITRs. [Figure 8]1 is an exemplary schematic diagram of a genetic map of the CLRN-8 vector (SEQ ID NO:46, 3982 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 2 (SEQ ID NO:6), 3'UTR-600B (SEQ ID NO:28), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 9] 1 is an exemplary schematic diagram of a genetic map of the CLRN-9 vector (SEQ ID NO:47, 3982 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 2 (SEQ ID NO:6), 3'UTR-600C (SEQ ID NO:29), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 10] 1 is an exemplary schematic diagram of a genetic map of the CLRN-0 vector (SEQ ID NO: 39, 4732 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO: 17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), 3'UTR 1773 (SEQ ID NO: 15), a bGH poly(A) signal (SEQ ID NO: 20), and the AAV2 ITRs. [Figure 11] 1 is an exemplary schematic diagram of a genetic map of the CLRN-7eGFP vector (SEQ ID NO:45, 3580 bp) that may be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), an eGFP sequence (SEQ ID NO:32), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 12] 1 is an exemplary schematic diagram of a genetic map of CLRN-10 (SEQ ID NO:48, 3511 bp) that can be used in any of the methods described herein. The vector contains AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:4), an HA sequence (SEQ ID NO:34), an FP sequence (SEQ ID NO:30), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 2 (SEQ ID NO:5), a 3×FLAG tag sequence (SEQ ID NO:35), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 13] 1 is an exemplary schematic diagram of a genetic map of the CLRN-10myc vector (SEQ ID NO:49, 3574 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), a myc sequence (SEQ ID NO:33), an FP sequence (SEQ ID NO:30), a T2A sequence (SEQ ID NO:31), a 3×FLAG tag sequence (SEQ ID NO:35), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 14] 1 is an exemplary schematic diagram of a genetic map of the CLRN-10NF vector (SEQ ID NO:50, 3499 bp) that can be used in any of the methods described herein. The vector contains AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), a T2A sequence (SEQ ID NO:31), an HA sequence (SEQ ID NO:34), CLRN-1 isoform 2 (SEQ ID NO:5), a 3×FLAG tag sequence (SEQ ID NO:35), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 15]1 is an exemplary schematic diagram of a genetic map of the CLRN-11 vector (SEQ ID NO:51, 4908 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), an HA sequence (SEQ ID NO:34), an FP sequence (SEQ ID NO:30), a T2A sequence (SEQ ID NO:31), CLRN-1 isoform 2 (SEQ ID NO:5), a 3×FLAG tag sequence (SEQ ID NO:35), a 3′UTR-1406 (SEQ ID NO:37), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 16] 1 is an exemplary schematic diagram of a genetic map of the CLRN-11myc vector (SEQ ID NO:52, 4971 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), a myc sequence (SEQ ID NO:33), an FP sequence (SEQ ID NO:30), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 2 (SEQ ID NO:5), a 3×FLAG tag sequence (SEQ ID NO:35), a 3′UTR-1406 (SEQ ID NO:37), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 17] 1 is an exemplary schematic diagram of a genetic map of the CLRN-11NF vector (SEQ ID NO:53, 4896 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 1 (SEQ ID NO:1), an HA sequence (SEQ ID NO:34), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 2 (SEQ ID NO:5), a 3×FLAG sequence (SEQ ID NO:33), a 3′UTR-1406 (SEQ ID NO:37), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 18]1 is an exemplary schematic diagram of a genetic map of the CLRN-12 vector (SEQ ID NO:54, 4640 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), a 5'UTR-291 sequence (SEQ ID NO:12), CLRN1 isoform 1 (SEQ ID NO:1), an HA sequence (SEQ ID NO:34), a 3'UTR-1357 (SEQ ID NO:36), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 19] 1 is an exemplary schematic diagram of a genetic map of the CLRN-13 vector (SEQ ID NO:55, 4291 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 4 (SEQ ID NO:7), a 3×FLAG tag sequence (SEQ ID NO:35), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 1 (SEQ ID NO:1), an HA sequence (SEQ ID NO:34), a 3′UTR-600 (SEQ ID NO:27), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 20] 1 is an exemplary schematic diagram of a genetic map of the CLRN-14 vector (SEQ ID NO:56, 4192 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 4 (SEQ ID NO:7), a T2A sequence (SEQ ID NO:31), CLRN1 isoform 1 (SEQ ID NO:1), 3'UTR-600 (SEQ ID NO:27), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 21]1 is an exemplary schematic diagram of a genetic map of the CLRN-15 vector (SEQ ID NO:57, 3505 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 4 (SEQ ID NO:7), a 3×FLAG tag sequence (SEQ ID NO:35), a 3′ UTR-600 (SEQ ID NO:27), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 22] 1 is an exemplary schematic diagram of a genetic map of the CLRN-16 vector (SEQ ID NO:58, 3439 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:16), CLRN1 isoform 4 (SEQ ID NO:7), 3'UTR-600 (SEQ ID NO:27), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 23] 1 is an exemplary schematic diagram of a genetic map of the CLRN-17 vector (SEQ ID NO:59, 130 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a sh-chimeric intron (SEQ ID NO:26), 5'UTR-291 (SEQ ID NO:12), CLRN1 isoform 1 (SEQ ID NO:1), an HA sequence (SEQ ID NO:34), 3'UTR-1773 (SEQ ID NO:15), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 24] 1 is an exemplary schematic diagram of a genetic map of the CLRN-18 vector (SEQ ID NO:60, 4277 bp) that can be used in any of the methods described herein. The vector contains the AAV2 ITRs, a CMV enhancer (SEQ ID NO:17), a chicken β-actin promoter, a chimeric intron (SEQ ID NO:26), CLRN1 isoform 1 (SEQ ID NO:1), 3'UTR-1773 (SEQ ID NO:15), a bGH poly(A) signal (SEQ ID NO:20), and the AAV2 ITRs. [Figure 25] Immunoblot images of CLRN1 protein levels from transfected HEK293FT cells 48 hours posttransfection using anti-HA and anti-FLAG antibodies. Column 1—PageRuler Plus Prestained; Column 2—CLRN-10 (denatured at 37°C); Column 3—CLRN-11 (denatured at 37°C); Column 4—CLRN-12 (denatured at 37°C); Column 5—negative control; Column 6—CLRN-10 (denatured at 56°C); Column 7—CLRN-11 (denatured at 56°C); Column 8—CLRN-12 (denatured at 56°C); Column 9—negative control. CLRN-1 isoform proteins are glycosylated proteins and often migrate as smear bands. [Figure 26] Immunoblot images of CLRN1 protein levels from transfected HEK293FT cells 48 hours post-transfection using anti-FLAG antibody. Column 1 - PageRuler Plus Prestained, column 2 - CLRN-10, column 3 - CLRN-11, column 4 - CLRN-12, column 5 - CLRN-13, column 6 - CLRN-15, column 7 - negative control. [Figure 27] Immunoblot images of CLRN1 protein levels from transfected HEK293FT cells 48 hours post-transfection using anti-FLAG antibody. Column 1 - PageRuler Plus Prestained, column 2 - CLRN-10, column 3 - CLRN-10NF, column 4 - CLRN-10myc, column 5 - CLRN-11NF, column 6 - CLRN-11myc, column 7 - negative control. All samples were kept at room temperature. [Figure 28] Immunoblot images of CLRN1 protein levels from transfected HEK293FT cells 48 hours post-transfection using an anti-myc antibody. Column 1—PageRuler Plus Prestained, column 2—CLRN-10, column 3—CLRN-10NF, column 4—CLRN-10myc, column 5—CLRN-11NF, column 6—CLRN-11myc, column 7—negative control. [Figure 29]Immunoblot images of CLRN1 protein levels from transfected HEK293FT cells 48 hours post-transfection using anti-HA and anti-FLAG antibodies. Column 1—PageRuler Plus Prestained, column 2—CLRN-13, column 3—CLRN-10, column 4—CLRN-10NF, column 5—CLRN-10myc, column 6—CLRN-11NF, column 7—CLRN-11myc, column 8—negative control. [Figure 30] 1 is an image of an immunoblot of CLRN1 isoform 1 protein levels from HEK239FT cells transfected with a plasmid described herein 48 hours post-transfection using an anti-CLRN (EKIANYKEGTYVYKTQSEKY, SEQ ID NO: 38) rabbit polyclonal antibody. Column 1—PageRuler Plus Prestained, column 2—CLRN-10, column 3—CLRN-1, column 4—CLRN-2, column 5—CLRN-3, column 6—CLRN-4, column 7—CLRN-8, column 8—CLRN-9, column 9—CLRN-10, column 10—CLRN-11, column 11—CLRN-12, column 12—CLRN-13, column 13—CLRN-14, column 14—CLRN-15, column 15—CLRN-16, column 16—negative control, column 17—negative control. [Figure 31]Immunoblot images of CLRN1 protein levels from transfected HEK293FT cells 48 hours posttransfection using anti-CLRN rabbit polyclonal antibody. Column 1—PageRuler Plus Prestained; Column 2—Anc80-CLRN-0; Column 3—Anc80-CLRN-0 + PNGase F; Column 4—Anc80-CLRN-3; Column 5—Anc80-CLRN-3 + PNGase F; Column 6—Anc80-CLRN-6eGFP; Column 7—Anc80-CLRN-6eGFP + PNGase F; Column 8—Anc80-CLRN-13; Column 9—Anc80-CLRN-13 + PNGase F; Column 10—No vector; Column 11—No vector + PNGase F. CLRN-1 isoform proteins are glycosylated proteins and often migrate as smeared bands (columns 2, 4, and 8). After treatment with PNGase F, the smeared bands disappeared and shifted to clear bands (lanes 3, 5, and 8). [Figure 32] 1 is a set of immunofluorescence images of AAVanc80-CLRN6eGFP-transduced HEK293FT cells imaged 24 and 48 hours after transfection at an MOI of 8.41E+04 and an MOI of 2.53E+05, respectively. [Figure 33] 1 is a bar graph showing the relative CLRN1 and GFP expression levels in HEK293FT cells transduced with AAVanc80-CLRN-6eGFP (at an MOI of 1.05E+05 and an MOI of 3.15E+05), AAVanc80-CLRN-0 (at an MOI of 8.23E+04 and an MOI of 2.47E+05), AAVanc80-CLRN-3 (at an MOI of 8.41E+04 and an MOI of 2.53E+04), and AAVanc80-CLRN-13 (at an MOI of 8.33E+04 and an MOI of 2.50E+05), respectively. [Figure 34]1 is a bar graph showing relative CLRN1 and GFP expression levels in P2 cochlear explants from WT mice infected for 16 hours with AAVanc80-CLRN-6eGFP (at an MOI of 2.0E+05), AAVanc80-CLRN-0 (at an MOI of 2.5E+05 and an MOI of 7.6E+0.5), AAVanc80-CLRN-3 (at an MOI of 2.0E+05 and an MOI of 6.03E+05), and AAVanc80-CLRN-13 (at an MOI of 2.0E+05 and an MOI of 6.0E+05), respectively. [Figure 35] A set of fluorescent images of P2 cochlear explants from WT mice infected for 72 hours with AAVanc80-CLRN-0 at 1.3E10 VG / cochlea, AAVanc80-CLRN-3 at 9.9E9 VG / cochlea, and AAVanc80-CLRN-13 at 1.0E10 VG / cochlea, showing Myo7a and DAPI staining. [Figure 36] FIG. 10 is a set of fluorescent images of P2 cochlear explants from WT mice infected with AAV Anc80.CAG.eGFP.3′UTR in 1E09 VG / cochlea for 72 hours, showing eGFP, Myo7a, and DAPI staining. DETAILED DESCRIPTION OF THE INVENTION

[0059] Defects in "clarin 1," a protein encoded by the CLRN1 gene Or mutations can cause hearing loss and vision loss. For example, mutations in CLRN1 , leading to Usher syndrome type III and retinitis pigmentosa.

[0060] Provided herein are compositions comprising at least two different nucleic acid vectors, At least two different vectors each encode a different portion of the CLRN1 protein. Each of the encoded sequences comprises a coding sequence, the coding sequences being at least 30 amino acid residues in length. and the amino acid sequence of each of the encoded portions is optionally The amino acid sequences of the at least two different bases may partially overlap with each other. Any single vector in the vectors encodes the full-length CLRN1 protein. and at least one of the coding sequences is located between two consecutive sites in the CLRN1 genomic DNA. a nucleotide sequence spanning two consecutive exons and lacking intronic sequences between the two consecutive exons the at least two different vectors containing the nucleotide sequences when introduced into mammalian cells. undergo homologous recombination with each other, thereby encoding the full-length CLRN1 protein A recombinant nucleic acid is formed.

[0061] Provided herein are compositions comprising a single nucleic acid vector, the vector comprising: (i) C a first coding sequence encoding a first isoform of the LRN1 protein; and (ii) ) a second coding sequence encoding a second isoform of the CLRN1 protein; one or both of the first and second coding sequences comprising a CLR It spans two consecutive exons of N1 genomic DNA and the two consecutive introns It contains a nucleotide sequence lacking any intron sequences between them.

[0062] Provided herein is a composition comprising two different nucleic acid vectors, wherein the two different nucleic acids The first nucleic acid vector of the nucleic acid vectors comprises a promoter and, on the 3' side of the promoter, a first coding sequence encoding the N-terminal portion of the CLRN1 protein, a splice donor sequence located at the 3' end of the first coding sequence, The second nucleic acid vector of the different nucleic acid vectors contains a splice acceptor sequence and a The C-terminus of the CLRN1 protein located at the 3' end of the price acceptor sequence a second coding sequence encoding a terminal portion and a polynucleotide at the 3' end of the second coding sequence; and an adenylation signal sequence, each of said encoded portions being at least 30 amino acids long. the amino acid sequences of the two encoded portions do not overlap with each other, and the two encoded portions Any single vector among the three vectors expresses the full-length CLRN1 protein. When introduced into mammalian cells, the splice donor sequence and the splice Splicing occurs between the acceptor sequence and the full-length CLRN1 A recombinant nucleic acid is formed that encodes the protein.

[0063] Provided herein is a composition comprising two different nucleic acid vectors, wherein the two different nucleic acids The first nucleic acid vector of the nucleic acid vectors comprises a promoter and, on the 3' side of the promoter, a first coding sequence encoding the N-terminal portion of the CLRN1 protein, a splice donor sequence located at the 3' end of the first coding sequence; and a first detectable marker gene located 3' to the donor sequence, The second nucleic acid vector of the different nucleic acid vector contains a second detectable marker gene and a splice acceptor sequence located 3' to the detectable marker gene of 2; of the CLRN1 protein located at the 3' end of the splice acceptor sequence. a second coding sequence encoding a C-terminal portion and a nucleotide sequence located at the 3' end of the second coding sequence; and a polyadenylation signal sequence attached thereto, each of said encoded portions comprising at least The length of each of the encoded portions is 30 amino acid residues, and the amino acid sequences of the encoded portions do not overlap with each other. Any single vector of the two different vectors contains the full-length CLRN1 protein. The splice donor sequence and the splice donor sequence do not encode a protein, and when introduced into mammalian cells, Splicing occurs between the splice acceptor sequence, thereby producing the full-length CL A recombinant nucleic acid encoding the RN1 protein is formed.

[0064] Also provided herein are compositions comprising two different nucleic acid vectors, wherein the two different The first nucleic acid vector of the nucleic acid vectors comprises a promoter and a nucleic acid sequence encoding a target gene for the promoter. The first code fragment encodes the N-terminal portion of the CLRN1 protein, located 3' to the a splice donor sequence located at the 3' end of the first coding sequence; an F1 phage recombination induction region located 3' to the splice donor sequence; wherein the second nucleic acid vector of the two different nucleic acid vectors comprises an F1 phage recombinase vector. and a splice acceptor located 3' to the F1 phage recombination induction region. a CLRN1 tag located at the 3' end of the splice acceptor sequence. a second coding sequence encoding a C-terminal portion of the protein; and a 3'-terminal and a polyadenylation signal sequence located at each end of the two encoded portions. Each is at least 30 amino acid residues in length and has the amino acid sequence of the two encoded portions. The sequences of the two different vectors do not overlap with each other, and any single vector of the two different vectors It does not encode the full-length CLRN1 protein and, when introduced into mammalian cells, Splicing occurs between the splice donor sequence and the splice acceptor sequence, This results in the formation of a recombinant nucleic acid encoding the full-length CLRN1 protein.

[0065] As used herein, a therapeutically effective amount of the compositions described herein is administered to the mammalian cochlea. The present invention provides a method for the preparation of a medicament for the treatment ...

[0066] Herein, we describe a method for increasing the expression of full-length CLRN1 protein in mammalian cells. A method is provided, the method comprising administering any of the compositions described herein to the mammalian cell. This includes introducing

[0067] As used herein, the term "cochlea" refers to the complete cell division of the inner hair cells, outer hair cells, or both in the mammalian cochlea. A method for increasing expression of long CLRN1 protein is provided, the method comprising: The method comprises administering to a cow a therapeutically effective amount of any of the compositions described herein. nothing.

[0068] Herein, increasing the expression of full-length CLRN1 protein in the mammalian eye A method is provided, the method comprising administering to the mammalian eye a therapeutically effective amount of a composition described herein. The present invention also includes administering any of the compositions intraocularly.

[0069] Provided herein is a method for treating hearing loss in a subject identified as having a defective CLRN1 gene. A method of treating rheumatoid arthritis is provided, the method comprising administering a therapeutically effective amount of a composition described herein. The method includes administering any of the above to the cochlea of ​​the subject.

[0070] Also provided herein are methods for treating ocular hyperplasia in subjects identified as having a defective CLRN1 gene. Also provided is a method of treating loss of strength, the method comprising administering a therapeutically effective amount of a composition described herein. The method includes administering to the eye of the subject any of the following:

[0071] Additional non-limiting aspects of the compositions, kits, and methods are described herein, including, but not limited to, They can be used in any combination without restriction.

[0072] CLRN1 The CLRN1 gene is involved in the function of hair cells in the inner ear (e.g., inner ear hair cells, outer ear hair cells) and the retina. It encodes "Cularin 1" (CLRN1), a protein expressed in the mouse.

[0073] The human CLRN1 gene is located on chromosome 3q25.1. It spans approximately 47 kilobases. It contains seven exons spanning (kb) (Vastinsalo et al. 2011) Eur J Hum Genet 19(1):30-35, NCBI accession no. No. NG_009168.1).

[0074] Various mutations in the CLRN1 gene cause Usher syndrome type III (e.g., Usher syndrome). M. schneider syndrome type IIIA (MIM number 606397) (e.g., Fields et al. (2002) Am J Hum Genet 71:607-617, and Joens uu et al. (2001) Am J Hum Genet 69:673-684 (2011) O (See Phthalmology 118:1444-1448) Mutations causing Usher syndrome type III predominantly occur in exon 3 of CLRN1. Usher syndrome type III deafness has been found in mice lacking CLRN1. (e.g., Geng et al. (2017) Sc i Rep 7(1):13480). Associated with Usher syndrome type III Exemplary CLRN1 mutations include T528G, M120K, M44K, N48K, and Includes C40G.

[0075] Exemplary CLRN1 mutations associated with retinitis pigmentosa include L154W and P31L. (e.g., Khan et al. (2011) Ophthalmology 1 18:1444-1448).

[0076] Additional exemplary mutations in the CLRN1 gene detected in subjects with hearing loss Methods for sequencing nucleic acids encoding CLRN1 are described, for example, in Fields et al. al. (2002) Am J Hum Genet 71:607-617, Joes uu et al. (2001) Am J Hum Genet 69:673-684 , Adato et al. (2002)Europ J Hum Genet 10: 339-350, Aller et al. (2004), Clin Genet 66 Methods for detecting mutations in genes are well known in the art. Non-limiting examples of such techniques include real-time polymerase chain reaction (RT -PCR), PCR, sequencing, Southern blotting, and Northern blotting. can be.

[0077] Exemplary human wild-type CLRN1 proteins are set forth in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO: 7. Non-limiting examples of nucleotide sequences that can be used include SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and is or comprises SEQ ID NO:8.

[0078] In some embodiments of any of the compositions described herein, CLRN1 tandem The protein should be at least 75% (e.g., at least 80%, at least 85%) identical to SEQ ID NO: 1. %, at least 90%, at least 91%, at least 92%, at least 93%, at least at least 94%, at least 95%, at least 96%, at least 97%, at least 9 8%, at least 99%) identical sequences.

[0079] In some embodiments of any of the compositions described herein, CLRN1 tandem The protein is at least 75% (e.g., at least 80%, at least 85%) identical to SEQ ID NO:3. %, at least 90%, at least 91%, at least 92%, at least 93%, at least at least 94%, at least 95%, at least 96%, at least 97%, at least 9 8%, at least 99%) identical sequences.

[0080] In some embodiments of any of the compositions described herein, CLRN1 tandem The protein is at least 75% (e.g., at least 80%, at least 85%) identical to SEQ ID NO:5. %, at least 90%, at least 91%, at least 92%, at least 93%, at least at least 94%, at least 95%, at least 96%, at least 97%, at least 9 8%, at least 99%) identical sequences.

[0081] In some embodiments of any of the compositions described herein, CLRN1 tandem The protein is at least 75% (e.g., at least 80%, at least 85%) identical to SEQ ID NO:7. %, at least 90%, at least 91%, at least 92%, at least 93%, at least at least 94%, at least 95%, at least 96%, at least 97%, at least 9 8%, at least 99%) identical sequences.

[0082] Human full-length wild-type CLRN1 protein isoform D (SEQ ID NO: 1) [ka]

[0083] Human wild-type CLRN1 isoform D cDNA (SEQ ID NO: 2) [ka]

[0084] Human full-length wild-type CLRN1 protein isoform A (SEQ ID NO: 3) [ka]

[0085] Human wild-type CLRN1 isoform A cDNA (SEQ ID NO: 4) [ka]

[0086] Human full-length wild-type CLRN1 protein isoform C (SEQ ID NO: 5) [ka]

[0087] Human wild-type CLRN1 isoform C cDNA (SEQ ID NO: 6) [ka]

[0088] Human full-length wild-type CLRN1 protein isoform E (SEQ ID NO: 7) [ka]

[0089] Human wild-type CLRN1 isoform E cDNA (SEQ ID NO: 8) [ka]

[0090] Human wild-type CLRN1 genomic sequence (SEQ ID NO: 9) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0091] A non-limiting example of a human wild-type CLRN1 genomic DNA sequence is SEQ ID NO: 9. The exons in No. 9 are nucleotides 1 to 544 (exon 1), nucleotide 28 nucleotides 764 to 29180 (exon 2), nucleotides 31239 to 31418 (exon exon 3), nucleotides 32481 to 32519 (exon 4), nucleotide 4479 Nucleotides 9 to 46433 (exon 5), 44799 to 44935 (exon 6) ), and nucleotides 46128 to 46837 (exon 7). Between each pair of these exons in SEQ ID NO: 9, i.e., nucleotides 545-28 position 763 (intron 1), nucleotides 29181–31238 (intron 2); Nucleotides 31419 to 32480 (intron 3), nucleotides 32520 to 4 Position 4798 (intron 4) and nucleotides 44936 to 46127 (intron 7).

[0092] Mouse CLRN1 protein isoform 1 (SEQ ID NO: 10) [ka]

[0093] Canine CLRN1 protein (SEQ ID NO: 11) [ka]

[0094] vector The compositions provided herein comprise at least two (e.g., two, three, four, five, or six) nucleic acid vectors, wherein each of the at least two different vectors is , comprising coding sequences encoding different portions of the CLRN1 protein, Each of the amino acids may contain at least 30 amino acids (e.g., from about 30 amino acids to about 202 amino acids, 30 amino acids to approximately 200 amino acids, approximately 30 amino acids to approximately 180 amino acids, approximately 30 amino acids ~ about 170 amino acids, ~ about 30 amino acids ~ about 160 amino acids, ~ about 30 amino acids ~ about 150 amino acids amino acids, about 30 amino acids to about 140 amino acids, about 30 amino acids to about 130 amino acids, about 3 0 amino acids to approximately 120 amino acids, approximately 30 amino acids to approximately 110 amino acids, approximately 30 amino acids or more Approximately 100 amino acids, approximately 30 to approximately 90 amino acids, approximately 30 to approximately 80 amino acids , about 30 to about 70 amino acids, about 30 to about 60 amino acids, about 30 amino acids ~ about 50 amino acids, ~ about 30 amino acids to about 40 amino acids, ~ about 60 amino acids to about 202 amino acids Acids, about 60 amino acids to about 200 amino acids, about 60 amino acids to about 180 amino acids, about 60 amino acids amino acids to about 170 amino acids, about 60 amino acids to about 160 amino acids, about 60 amino acids to about 1 50 amino acids, approximately 60 to approximately 140 amino acids, approximately 60 to approximately 130 amino acids , about 60 amino acids to about 120 amino acids, about 60 amino acids to about 110 amino acids, about 60 amino acids 100 amino acids, 60 amino acids to 90 amino acids, 60 amino acids to 80 amino acids amino acids, about 60 amino acids to about 70 amino acids, about 90 amino acids to about 202 amino acids, about 90 Amino acids up to about 200 amino acids, about 90 amino acids to about 180 amino acids, about 90 amino acids to about 170 amino acids, approximately 90 amino acids to approximately 160 amino acids, approximately 90 amino acids to approximately 150 amino acids Acids, about 90 amino acids to about 140 amino acids, about 90 amino acids to about 130 amino acids, about 90 amino acids amino acids to about 120 amino acids, about 90 amino acids to about 110 amino acids, about 90 amino acids to about 1 00 amino acids, about 100 amino acids to about 202 amino acids, about 100 amino acids to about 200 amino acids amino acids, about 100 amino acids to about 180 amino acids, about 100 amino acids to about 170 amino acids, about 100 amino acids to approximately 160 amino acids, approximately 100 amino acids to approximately 150 amino acids, approximately 100 amino acids amino acids ~ approximately 140 amino acids, approximately 100 amino acids ~ approximately 130 amino acids, approximately 100 amino acids ~ Approximately 120 amino acids, approximately 90 to approximately 110 amino acids, approximately 120 to approximately 202 amino acids amino acids, about 120 amino acids to about 200 amino acids, about 120 amino acids to about 180 amino acids, Approximately 120 amino acids to approximately 170 amino acids, approximately 120 amino acids to approximately 160 amino acids, approximately 120 Amino acids up to about 150 amino acids, about 120 amino acids to about 140 amino acids, about 120 amino acids ~ about 130 amino acids, ~ about 150 amino acids to about 202 amino acids, ~ about 150 amino acids to about 20 0 amino acids, about 150 amino acids to about 180 amino acids, about 150 amino acids to about 170 amino acids amino acids, about 150 to about 160 amino acids, about 170 to about 202 amino acids, about 1 70 amino acids to approximately 200 amino acids, approximately 170 amino acids to approximately 180 amino acids, approximately 190 amino acids The length of the nucleotide sequence is about 202 amino acids to about 202 amino acids, or about 190 amino acids to about 200 amino acids.

[0095] In some embodiments of these compositions, at least one of the coding sequences is CL It spans two consecutive exons of RN1 genomic DNA (e.g., exons 1 and 2, and exons 5 and 6), and a naturally occurring intron between the two consecutive exons. It includes nucleotide sequences lacking sequences.

[0096] In some embodiments, the amino acid sequence of any of the encoded portions is There is no overlap, even partially, between the amino acid sequences of different encoded parts. In some embodiments, the amino acid sequence of one or more of the encoded portions is In some embodiments, the amino acid sequence of a different one of the encoded portions overlaps with the amino acid sequence of the other encoded portion. In the case of the encoded portion, the amino acid sequence of each of the encoded portions is It partially overlaps with the amino acid sequence of the

[0097] In some embodiments, the overlapping amino acid sequences are from about 30 amino acid residues to about 202 amino acid residues. Length of the acid (e.g., or any of the subranges of this range described herein) is.

[0098] In some instances, the vector comprises two different vectors, each of which contains an intro The introns comprise different segments of the intron present in the CLRN1 genomic DNA. The nucleotide sequence of the ... introns), and the two different segments are at least 100 Nucleotides (e.g., about 100 nucleotides to about 10,000 nucleotides, about 100 Nucleotides to about 5,000 nucleotides, about 100 nucleotides to about 4,500 nucleotides nucleotides, from about 100 nucleotides to about 4,000 nucleotides, from about 100 nucleotides to about 3,500 nucleotides, about 100 nucleotides to about 3,000 nucleotides, about 100 Nucleotides to about 2,500 nucleotides, about 100 nucleotides to about 2,000 nucleotides nucleotides, from about 100 nucleotides to about 1,500 nucleotides, from about 100 nucleotides to about 1,000 nucleotides, approximately 100 nucleotides to approximately 800 nucleotides, approximately 100 nucleotides nucleotides to about 600 nucleotides, about 100 nucleotides to about 400 nucleotides, about 1 00 nucleotides to approximately 200 nucleotides, approximately 200 nucleotides to approximately 10,000 nucleotides nucleotides, from about 200 nucleotides to about 5,000 nucleotides, from about 200 nucleotides Approximately 4,500 nucleotides, approximately 200 nucleotides to approximately 4,000 nucleotides, approximately 20 0 nucleotides to approximately 3,500 nucleotides, approximately 200 nucleotides to approximately 3,000 nucleotides nucleotides, approximately 200 nucleotides to approximately 2,500 nucleotides, approximately 200 nucleotides Approximately 2,000 nucleotides, approximately 200 nucleotides to approximately 1,500 nucleotides, approximately 20 0 nucleotides to approximately 1,000 nucleotides, approximately 200 nucleotides to approximately 800 nucleotides nucleotides, about 200 nucleotides to about 600 nucleotides, about 200 nucleotides to about 400 Nucleotides, about 400 nucleotides to about 10,000 nucleotides, about 400 nucleotides nucleotides to about 5,000 nucleotides, about 400 nucleotides to about 4,500 nucleotides, About 400 nucleotides to about 4,000 nucleotides, about 400 nucleotides to about 3,50 0 nucleotides, about 400 nucleotides to about 3,000 nucleotides, about 400 nucleotides nucleotides to about 2,500 nucleotides, about 400 nucleotides to about 2,000 nucleotides, About 400 nucleotides to about 1,500 nucleotides, about 400 nucleotides to about 1,00 0 nucleotides, about 400 nucleotides to about 800 nucleotides, about 400 nucleotides ~ about 600 nucleotides, ~ about 600 nucleotides to about 10,000 nucleotides, ~ about 60 0 nucleotides to approximately 5,000 nucleotides, approximately 600 nucleotides to approximately 4,500 nucleotides leotide, approximately 600 nucleotides to approximately 4,000 nucleotides, approximately 600 nucleotides Approximately 3,500 nucleotides, approximately 600 nucleotides to approximately 3,000 nucleotides, approximately 60 0 nucleotides to approximately 2,500 nucleotides, approximately 600 nucleotides to approximately 2,000 nucleotides leotide, approximately 600 nucleotides to approximately 1,500 nucleotides, approximately 600 nucleotides Approximately 1,000 nucleotides, approximately 600 nucleotides to approximately 800 nucleotides, approximately 800 nucleotides Nucleotide to about 10,000 nucleotides, about 800 nucleotides to about 5,000 nucleotides Otide, about 800 nucleotides to about 4,500 nucleotides, about 800 nucleotides to about 4,000 nucleotides, about 800 nucleotides to about 3,500 nucleotides, about 800 Nucleotides to about 3,000 nucleotides, about 800 nucleotides to about 2,500 nucleotides Otide, about 800 nucleotides to about 2,000 nucleotides, about 800 nucleotides to about 1,500 nucleotides, about 800 nucleotides to about 1,000 nucleotides, about 1,0 00 nucleotides to about 10,000 nucleotides, about 1,000 nucleotides to about 5,0 00 nucleotides, about 1,000 nucleotides to about 4,500 nucleotides, about 1,00 0 nucleotides to approximately 4,000 nucleotides, approximately 1,000 nucleotides to approximately 3,500 Nucleotides, approximately 1,000 nucleotides to approximately 3,000 nucleotides, approximately 1,000 nucleotides Nucleotide to about 2,500 nucleotides, about 1,000 nucleotides to about 2,000 nucleotides nucleotides, about 1,000 nucleotides to about 1,500 nucleotides, about 1,500 nucleotides nucleotides to approximately 10,000 nucleotides, and approximately 1,500 nucleotides to approximately 5,000 nucleotides. nucleotides, about 1,500 nucleotides to about 4,500 nucleotides, about 1,500 nucleotides nucleotides to about 4,000 nucleotides, about 1,500 nucleotides to about 3,500 nucleotides about 1,500 nucleotides to about 3,000 nucleotides, about 1,500 nucleotides up to about 2,500 nucleotides, about 1,500 nucleotides to about 2,000 nucleotides, Approximately 2,000 nucleotides to approximately 10,000 nucleotides, approximately 2,000 nucleotides or more Approximately 5,000 nucleotides, approximately 2,000 nucleotides to approximately 4,500 nucleotides, approximately 2,000 nucleotides to approximately 4,000 nucleotides, approximately 2,000 nucleotides to approximately 3 ,500 nucleotides, about 2,000 nucleotides to about 3,000 nucleotides, about 2, 000 nucleotides to about 2,500 nucleotides, about 2,500 nucleotides to about 10, 000 nucleotides, about 2,500 nucleotides to about 5,000 nucleotides, about 2,5 00 nucleotides to about 4,500 nucleotides, about 2,500 nucleotides to about 4,00 0 nucleotides, about 2,500 nucleotides to about 3,500 nucleotides, about 2,500 Nucleotides to about 3,000 nucleotides, about 3,000 nucleotides to about 10,000 nucleotides Nucleotides, approximately 3,000 nucleotides to approximately 5,000 nucleotides, approximately 3,000 nucleotides Nucleotide to about 4,500 nucleotides, about 3,000 nucleotides to about 4,000 nucleotides nucleotides, about 3,000 nucleotides to about 3,500 nucleotides, about 3,500 nucleotides nucleotides to approximately 10,000 nucleotides, and approximately 3,500 nucleotides to approximately 5,000 nucleotides. nucleotides, approximately 3,500 nucleotides to approximately 4,500 nucleotides, approximately 3,500 nucleotides nucleotides to approximately 4,000 nucleotides, approximately 4,000 nucleotides to approximately 10,000 nucleotides nucleotides, about 4,000 nucleotides to about 5,000 nucleotides, about 4,000 nucleotides 4,500 to about 4,500 nucleotides, about 4,500 to about 10,000 nucleotides about 4,500 nucleotides to about 5,000 nucleotides, or about 5,000 nucleotides The sequences overlap by a length of approximately 10,000 nucleotides.

[0099] The overlapping nucleotide sequence in any two of the different vectors is CLR Part or all of one or more exons of the N1 gene (e.g., The exons may include any one or more of the exemplary exons in SEQ ID NO: 9.

[0100] In some embodiments, the number of different vectors in the composition is two, three, four, or In a composition where the number of different vectors in the composition is 2, two different vectors are used. The first vector contains a code encoding the N-terminal part of the CLRN1 protein. In some examples, the N-terminal portion of the CLRN1 gene may comprise a sequence of about 30 amino acids to It is approximately 202 amino acids in length (or any of the subranges within this range above). In some examples, the first vector comprises a promoter (e.g., a promoter described herein). or any promoter known in the art) and a Kozak sequence (e.g., Any of the exemplary Kozak sequences described herein or known in the art In some examples, the first vector further comprises one or both of the following: promoters that are sexual, constitutive, or tissue-specific promoters In some examples, the second of the two different vectors comprises the CLR. In some embodiments, the CLRN comprises a coding sequence encoding the C-terminal portion of the N1 protein. The C-terminal portion of a protein is 30 to about 202 amino acids (or any of the above ranges). In some examples, the second vector has a length of poly(2-amino-2-methyl-1,2-dioxane) or a subrange of poly(2-amino-2-methyl-1,2-dioxane). It further contains an adenylation signal sequence.

[0101] In some cases where the number of different vectors in the composition is two, one of the two vectors The N-terminal portion encoded by one of the wild-type CLRN1 proteins (e.g., SEQ ID NO: From amino acid position 1 of the amino acid sequence ... The amino acid at position 202, approximately the amino acid at position 200, approximately the amino acid at position 190, approximately the amino acid at position 210, approximately the amino acid at position 220, approximately the amino acid at position 230, approximately the amino acid at position 240, approximately the amino acid at position 250, approximately the amino acid at position 260, approximately the amino acid at position 270, approximately the amino acid at position 280, approximately the amino acid at position amino acid position 180, approximately amino acid position 170, approximately amino acid position 160, approximately amino acid position 150 amino acid position, approximately amino acid position 140, approximately amino acid position 130, approximately amino acid position 120, and The amino acid at position 110, approximately the amino acid at position 100, approximately the amino acid at position 90, approximately the amino acid at position at about amino acid position 80, at about amino acid position 70, at about amino acid position 60, at about amino acid position 50, or It may include a portion including about amino acid position 40.

[0102] In some instances where the number of different vectors in the composition is two, the precursor CLRN1 protein The N-terminal portion of the protein is a wild-type CLRN1 protein (e.g., SEQ ID NO: 1, 3, 5, or 7) amino acid 1 to amino acid 202, amino acid 1 to approximately amino acid 200, amino acid 1 to approximately amino acid 190, amino acid 1 to approximately amino acid 180, amino acid 1st to approximately 170th amino acid, 1st to approximately 160th amino acid, 1st amino acid ~ Approximately amino acid position 150, amino acid position 1 ~ Approximately amino acid position 140, amino acid position 1 ~ Amino acid position 130, amino acid position 1 to approximately amino acid position 120, amino acid position 1 to approximately Amino acid 110, amino acid 1 to approximately amino acid 100, amino acid 1 to approximately amino acid amino acid position 90, amino acid position 1 to approximately amino acid position 80, amino acid position 1 to approximately amino acid position 70 amino acid position, amino acid position 1 to approximately amino acid position 60, amino acid position 1 to approximately amino acid position 50, The amino acid sequence includes the portion from amino acid 1 to approximately amino acid 40, and the portion from amino acid 1 to approximately amino acid 30. It can be seen.

[0103] As used herein, the term "vector" refers to a vector that contains at least one exogenous nucleic acid. a composition comprising a polynucleotide capable of carrying the fragment, e.g., a plasmid vector -, transposons, cosmids, artificial chromosomes (e.g., human artificial chromosomes (HACs), yeast YAC, bacterial artificial chromosome (BAC), or P1-derived artificial chromosome (PAC) )), viral vectors (e.g., any adenoviral vector as described herein), vector (e.g., pSV or pCMV vector) or any retroviral vector ), and any Gateway® vector. Vectors include, for example, It may contain cis-acting elements sufficient for expression and may contain other elements for expression. The vector can be supplied by a host mammalian cell or in an in vitro expression system. The term "target" refers to any gene that has the ability to replicate when associated with appropriate regulatory elements. Genetic elements (e.g., plasmids, transposons, cosmids, artificial chromosomes, viruses) Thus, the term includes viral vectors (e.g., adeno-associated viruses, etc.). vectors, such as AAV vectors, adenoviral vectors, lentiviral vectors, or lentiviral vectors. This includes not only vectors (e.g., retroviral vectors) but also cloning and expression vectors.

[0104] Vectors include cosmids, plasmids (e.g., naked or contained in liposomes), and viruses (e.g., lentiviruses, retroviruses, All viruses known in the art, including viruses, adenoviruses, and adeno-associated viruses Those skilled in the art will appreciate that any of the nucleic acids described herein can be used in a variety of ways. One may select a suitable vector and mammalian cell for producing the vector.

[0105] In some embodiments, the vector is a plasmid (i.e., a vector that replicates autonomously inside a cell). In some embodiments, the vector is a cosmid. (e.g., the pWE and sCos series (Wahl et al. (1987) ), Evans et al. (1989)).

[0106] In some embodiments, the vector(s) are artificial chromosomes. Genetically engineered plasmids that can be used as vectors to carry various DNA inserts. In some embodiments, the artificial chromosome is a human artificial chromosome (HAC) (e.g., For example, Kouprina et al., Expert Opinion. Drug Deli v 11(4):517-535,2014, Basu et al., Pediatr .Clin.North Am.53:843-853,2006, Ren et al. .,Stem.Cell Rev.2(1):43-50,2006,Kazuki e t al.,Mol.Ther.19(9):1591-1601,2011, Kazu ki et al., Gen. Ther. 18:384-393, 2011, and Kat oh et al.,Biochem.Biophys.Res.Commun.321 :280-290,2004).

[0107] In some embodiments, the vector(s) are yeast artificial chromosomes (YACs) (e.g., For example, Murray et al., Nature 305:189-193, 1983, Ikeno et al. (1998) Nat.Biotech.16:431-439 In some embodiments, the vector(s) are bacterial artificially transformed. pBeloBAC11, pECBAC1, and pBAC In some embodiments, the vector(s) are P1-derived artificial chromosomes (PACs). ) Examples of artificial chromosomes are known in the art.

[0108] In some embodiments, the vector(s) are viral vectors (e.g., adeno-associated viruses, adenoviruses, lentiviruses, and retroviruses). Non-limiting examples of vectors are described herein. In some embodiments, the vector(s) ) is an adeno-associated viral vector (AAV) (see, e.g., Asokan et al. (See, e.g., J.Mol. Ther. 20:699-7080, 2012). AAV vectors or "rAAV" typically contain, at a minimum, a transgene or portion thereof. and control sequences, and optionally 5' and 3' AAV inverted terminal repeats (ITRs). Such recombinant AAV vectors are packaged into capsids and expressed in a selected It is delivered to target cells (e.g., cochlear hair cells).

[0109] The AAV sequences of the vector typically include cis-acting 5' and 3' ITR sequences (e.g., , BJ Carter, in “Handbook of Parvoviruses ”,ed.,P.Tijsser,CRC Press,pp.155 168,199 0). A typical AAV ITR sequence is approximately 145 nucleotides in length. In some embodiments, at least 75% (e.g., at least 80%, at least 85%, at least 90%, or at least 95%) of the cells expressing AAV vectors The ability to modify these ITR sequences is within the skill of one of ordinary skill in the art. (See, e.g., Sambrook et al., "Molecular Cloning .A Laboratory Manual”, 2d ed., Cold Spring Harbor Laboratory, New York, 1989, and K.Fis See Herr et al., J Virol. 70:520 532, 1996 In some embodiments, any of the coding sequences described herein includes A The AV vector is flanked by 5' and 3' AAV ITR sequences. AAV ITR sequences may be derived from any known AAV, including currently identified AAV types.

[0110] AAV vectors as described herein may contain the control elements described herein. any of (e.g., promoter, polyadenylation (poly(A)) signal sequence) , and one or more of an IRES).

[0111] In some embodiments, the AAV vector is an AAV1 vector, an AAV2 vector, an AA V3 vector, AAV4 vector, AAV5 vector, AAV6 vector, AAV7 vector Tar, AAV8 vector, AAV9 vector, AAV2.7m8 vector, AAV8BP 2 vector, and AAV293 vector. Additional exemplary AAV vectors are known in the art. n et al.,Mol.Ther.Nucleic Acids 8:184-19 7,2017, Li et al.,Mol.Ther.16(7):1252-126 0, Adachi et al.,Nat.Commun.5:3075,2014,I sgrig et al., Nat.Commun.10(1):427,2019, and and Gao et al., J. Virol. 78(12):6381-6388. I want to be.

[0112] In some embodiments, the AAV vectors provided herein are selected from the group consisting of SEQ ID NOs: 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 5 6, 57, 58, 59, or 60 at least 80% identical (e.g., at least 82% , at least 84%, at least 85%, at least 86%, at least 88%, less At least 90%, at least 92%, at least 94%, at least 95%, at least 96% %, at least 98%, at least 99%, or 100% identical) or In some embodiments, the vector(s) is / are an adenovirus. (e.g. Dmitriev et al. (1998) J. Virol. 72:97 06-9713, and Poulin et al., J. Virol 8:10074- 10086, 2010). In some embodiments, the vector(s) Retroviruses (e.g., Maier et al. (2010) Future (See Microbiol 5:1507-23).

[0113] In some embodiments, the vector(s) is a lentivirus (e.g., Mat rai et al. (2010) Mol Ther. 18:477-490, Bana Sik et al. (2010) Gene Ther. 17:150-7, and Wan See Isch et al. (2009) Mol. Ther. 17:1316-32 Lentiviral vectors have been described, inter alia, by Milone et al., Mol .Ther.17(8):1453-1464(2009) derived from at least a portion of the lentiviral genome, including modified lentiviral vectors. Non-limiting lentiviral vectors that may be used in the clinic include O LENTIVECTOR® Gene Delivery from xford BioMedica Other technologies include the LENTIMAX™ Vector System from Lentigen. A variety of lentiviral vectors are also available and will be known to those skilled in the art.

[0114] The vectors provided herein can be of different sizes. The selection of vectors for use in any of the compositions, kits, and methods described herein may be influenced by the vector This may depend on the size of the

[0115] In some embodiments, the vector(s) are plasmids, up to about 1 kb, Approximately 2kb, maximum approximately 3kb, maximum approximately 4kb, maximum approximately 5kb, maximum approximately 6kb, maximum approximately 7kb, Maximum of approximately 8kb, maximum of approximately 9kb, maximum of approximately 10kb, maximum of approximately 11kb, maximum of approximately 12kb, maximum It may comprise a total length of about 13 kb, up to about 14 kb, or up to about 15 kb. In the present specification, the vector(s) is a plasmid, and the vector(s) is / are about 1 kb to about 2 kb, about 1 kb to about 3 kb. kb, about 1kb to about 4kb, about 1kb to about 5kb, about 1kb to about 6kb, about 1kb to about 7 kb, about 1kb to about 8kb, about 1kb to about 9kb, about 1kb to about 10kb, about 1kb to about 11kb, about 1kb to about 12kb, about 1kb to about 13kb, about 1kb to about 14kb, and can have a total length ranging from about 1 kb to about 15 kb.

[0116] In some embodiments, the vector(s) contain a transposon (e.g., PiggyB ac™ transposon) and can contain more than 200 kb. - (Multiple possible) is about 1kb to about 10kb, about 1kb to about 20kb, about 1kb to about 30kb , about 1kb to about 40kb, about 1kb to about 50kb, about 1kb to about 60kb, about 1kb to about 70kb, about 1kb to about 80kb, about 1kb to about 90kb, about 10kb to about 20kb, about 10kb to approximately 30kb, approximately 10kb to approximately 40kb, approximately 10kb to approximately 50kb, approximately 10kb ~about 60kb, about 10kb to about 70kb, about 10kb to about 90kb, about 10kb to about 10 0kb, about 20kb to about 30kb, about 20kb to about 40kb, about 20kb to about 50kb, Approx. 20kb ~ approx. 60kb, approx. 20kb ~ approx. 70kb, approx. 20kb ~ approx. 80kb, approx. 20k b ~ approx. 90kb, approx. 20kb ~ approx. 100kb, approx. 30kb ~ approx. 40kb, approx. 30kb ~ approx. 50kb, about 30kb to about 60kb, about 30kb to about 70kb, about 30kb to about 80kb , about 30kb to about 90kb, about 30kb to about 100kb, about 40kb to about 50kb, about 4 0kb to approximately 60kb, approximately 40kb to approximately 70kb, approximately 40kb to approximately 80kb, approximately 40kb or more Approximately 90kb, approximately 40kb to approximately 100kb, approximately 50kb to approximately 60kb, approximately 50kb to approximately 70 kb, about 50kb to about 80kb, about 50kb to about 90kb, about 50kb to about 100kb, Approx. 60kb ~ approx. 70kb, approx. 60kb ~ approx. 80kb, approx. 60kb ~ approx. 90kb, approx. 60k b ~ approx. 100kb, approx. 70kb ~ approx. 80kb, approx. 70kb ~ approx. 90kb, approx. 70kb ~ approx. 100kb, about 80kb to about 90kb, about 80kb to about 100kb, about 90kb to about 10 0kb, about 1kb to about 100kb, about 100kb to about 200kb, about 100kb to about 30 Total length in the range of 0 kb, about 100 kb to about 400 kb, or about 100 kb to about 500 kb It is a transposon having the following structure:

[0117] In some embodiments, the vector is a cosmid and can have a total length of up to 55 kb. In some examples, the vector is a cosmid, and may be from about 1 kb to about 10 kb, from about 1 kb to about 20 kb. kb, about 1kb to about 30kb, about 1kb to about 40kb, about 1kb to about 50kb, about 1kb ~about 55kb, about 10kb to about 20kb, about 10kb to about 30kb, about 10kb to about 40 kb, about 10kb to about 50kb, about 10kb to about 55kb, about 15kb to about 55kb, about 15kb ~ approx. 50kb, approx. 15kb ~ approx. 40kb, approx. 15kb ~ approx. 30kb, approx. 15kb ~about 20kb, about 20kb to about 55kb, about 20kb to about 50kb, about 20kb to about 40 kb, about 20kb to about 30kb, about 25kb to about 55kb, about 25kb to about 50kb, about 25kb to approx. 40kb, approx. 25kb to approx. 30kb, approx. 30kb to approx. 55kb, approx. 30kb ~about 50kb, about 30kb to about 40kb, about 35kb to about 55kb, about 40kb to about 55 kb, about 40 kb to about 50 kb, or about 45 kb to about 55 kb Has.

[0118] In some embodiments, the vector(s) are artificial chromosomes, ranging from about 100 kb to about 2 In some embodiments, the artificial chromosome(s) may have a total number of nucleotides of 0.000 kb. ) is a human artificial chromosome (HAC), and is about 1 kb to about 10 kb, 1 kb to about 20 kb, Approx. 1kb ~ approx. 30kb, approx. 1kb ~ approx. 40kb, approx. 1kb ~ approx. 50kb, approx. 1kb ~ approx. 6 0, about 10kb to about 20kb, about 10kb to about 30kb, about 10kb to about 40kb, about 1 0kb to approximately 50kb, approximately 10kb to approximately 60kb, approximately 20kb to approximately 30kb, approximately 20kb or more Approximately 40kb, approximately 20kb to approximately 50kb, approximately 20kb to approximately 60kb, approximately 30kb to approximately 40kb b, about 30kb to about 50kb, about 30kb to about 60kb, about 40kb to about 50kb, about 4 having a total number of nucleotides ranging from 0 kb to about 60 kb, or from about 50 kb to about 60 kb obtain.

[0119] In some embodiments, the artificial chromosome(s) are yeast artificial chromosomes (YACs), and most In some embodiments, the artificial chromosome (or chromosomes) may have a total number of nucleotides of up to 1000 kb. (number possible) is about 100kb to about 1,000kb, about 100kb to about 900kb, about 100k b ~ approx. 800kb, approx. 100kb ~ approx. 700kb, approx. 100kb ~ approx. 600kb, approx. 10 0kb ~ approx. 500kb, approx. 100kb ~ approx. 400kb, approx. 100kb ~ approx. 300kb, approx. 100kb to approx. 200kb, approx. 200kb to approx. 1,000kb, approx. 200kb to approx. 900 kb, about 200kb to about 800kb, about 200kb to about 700kb, about 200kb to about 6 00kb, approx. 200kb ~ approx. 500kb, approx. 200kb ~ approx. 400kb, approx. 200kb ~ Approx. 300kb, approx. 300kb to approx. 1,000kb, approx. 300kb to approx. 900kb, approx. 30 0kb ~ approx. 800kb, approx. 300kb ~ approx. 700kb, approx. 300kb ~ approx. 600kb, approx. 300kb ~ approx. 500kb, approx. 300kb ~ approx. 400kb, approx. 400kb ~ approx. 1,000 kb, about 400kb to about 900kb, about 400kb to about 800kb, about 400kb to about 7 00kb, approx. 400kb ~ approx. 600kb, approx. 400kb ~ approx. 500kb, approx. 500kb ~ Approximately 1,000kb, approximately 500kb to approximately 900kb, approximately 500kb to approximately 800kb, approximately 50 0kb ~ approx. 700kb, approx. 500kb ~ approx. 600kb, approx. 600kb ~ approx. 1,000kb , about 600kb to about 900kb, about 600kb to about 800kb, about 600kb to about 700 kb, approx. 700kb ~ approx. 1,000kb, approx. 700kb ~ approx. 900kb, approx. 700kb ~ Approximately 800 kb, approximately 800 kb to approximately 1,000 kb, approximately 800 kb to approximately 900 kb, or YACs having a total number of nucleotides ranging from about 900 kb to about 1,000 kb.

[0120] In some embodiments, the artificial chromosome(s) are bacterial artificial chromosomes (BACs), and most In some embodiments, the artificial chromosome (multiple) may have a total number of nucleotides of up to 750 kb. (possible) is a BAC, about 100kb to about 750kb, about 100kb to about 700kb, about 100kb to approx. 600kb, approx. 100kb to approx. 500kb, approx. 100kb to approx. 400kb , about 100kb to about 300kb, about 100kb to about 200kb, about 150kb to about 750 kb, about 150kb to about 700kb, about 150kb to about 600kb, about 150kb to about 5 00kb, approx. 150kb ~ approx. 400kb, approx. 150kb ~ approx. 300kb, approx. 150kb ~ Approx. 200kb, approx. 200kb ~ approx. 750kb, approx. 200kb ~ approx. 700kb, approx. 200k b ~ approx. 600kb, approx. 200kb ~ approx. 500kb, approx. 200kb ~ approx. 400kb, approx. 20 0kb ~ approx. 300kb, approx. 250kb ~ approx. 750kb, approx. 250kb ~ approx. 700kb, approx. 250kb ~ approx. 600kb, approx. 250kb ~ approx. 500kb, approx. 250kb ~ approx. 400kb , about 250kb to about 300kb, about 300kb to about 750kb, about 300kb to about 700 kb, about 300kb to about 600kb, about 300kb to about 500kb, about 300kb to about 4 00kb, approx. 350kb ~ approx. 750kb, approx. 350kb ~ approx. 700kb, approx. 350kb ~ Approx. 600kb, approx. 350kb ~ approx. 500kb, approx. 350kb ~ approx. 400kb, approx. 400k b ~ approx. 750kb, approx. 400kb ~ approx. 700kb, approx. 450kb ~ approx. 600kb, approx. 45 0kb ~ approx. 500kb, approx. 500kb ~ approx. 750kb, approx. 500kb ~ approx. 700kb, approx. 500kb ~ approx. 600kb, approx. 550kb ~ approx. 750kb, approx. 550kb ~ approx. 700kb , about 550kb to about 600kb, about 600kb to about 750kb, about 600kb to about 700 kb, or the total number of nucleotides may range from about 650 kb to about 750 kb.

[0121] In some embodiments, the artificial chromosome(s) are P1-derived artificial chromosomes (PACs). In some embodiments, the P1-derived artificial Chromosome(s) of approximately 100 kb to approximately 300 kb, approximately 100 kb to approximately 200 kb, Alternatively, the total number of nucleotides may range from about 200 kb to about 300 kb.

[0122] In some embodiments, the vector(s) are viral vectors and are up to 10 kb In some embodiments, the viral vector(s) may have a total number of nucleotides of Available, approximately 1kb to approximately 2kb, 1kb to approximately 3kb, approximately 1kb to approximately 4kb, approximately 1kb to approximately 5kb b, about 1kb to about 6kb, about 1kb to about 7kb, about 1kb to about 8kb, about 1kb to about 9k b, about 1kb to about 10kb, about 2kb to about 3kb, about 2kb to about 4kb, about 2kb to about 5 kb, about 2kb to about 6kb, about 2kb to about 7kb, about 2kb to about 8kb, about 2kb to about 9 kb, about 2kb to about 10kb, about 3kb to about 4kb, about 3kb to about 5kb, about 3kb to about 6kb, about 3kb to about 7kb, about 3kb to about 8kb, about 3kb to about 9kb, about 3kb to about 10kb, approx. 4kb ~ approx. 5kb, approx. 4kb ~ approx. 6kb, approx. 4kb ~ approx. 7kb, approx. 4kb ~ Approximately 8kb, approximately 4kb to approximately 9kb, approximately 4kb to approximately 10kb, approximately 5kb to approximately 6kb, approximately 5kb ~about 7kb, about 5kb to about 8kb, about 5kb to about 9kb, about 5kb to about 10kb, about 6k b ~ approx. 7kb, approx. 6kb ~ approx. 8kb, approx. 6kb ~ approx. 9kb, approx. 6kb ~ approx. 10kb, approx. 7 kb ~ approx. 8kb, approx. 7kb ~ approx. 9kb, approx. 7kb ~ approx. 10kb, approx. 8kb ~ approx. 9kb, approx. It may have a total number of nucleotides ranging from 8 kb to about 10 kb, or from about 9 kb to about 10 kb. do.

[0123] In some embodiments, the vector(s) are lentiviral and contain up to 8 kb of nucleic acid. In some examples, the lentivirus(es) may have a total number of nucleotides of about 1 kb to about 1 kb. Approx. 2kb, approx. 1kb ~ approx. 3kb, approx. 1kb ~ approx. 4kb, approx. 1kb ~ approx. 5kb, approx. 1kb ~ Approx. 6kb, approx. 1kb ~ approx. 7kb, approx. 1kb ~ approx. 8kb, approx. 2kb ~ approx. 3kb, approx. 2kb ~ Approx. 4kb, approx. 2kb ~ approx. 5kb, approx. 2kb ~ approx. 6kb, approx. 2kb ~ approx. 7kb, approx. 2kb ~ Approx. 8kb, approx. 3kb ~ approx. 4kb, approx. 3kb ~ approx. 5kb, approx. 3kb ~ approx. 6kb, approx. 3kb ~ Approx. 7kb, approx. 3kb ~ approx. 8kb, approx. 4kb ~ approx. 5kb, approx. 4kb ~ approx. 6kb, approx. 4kb ~ Approx. 7kb, approx. 4kb ~ approx. 8kb, approx. 5kb ~ approx. 6kb, approx. 5kb ~ approx. 7kb, approx. 5kb ~ Nucleotides of about 8 kb, about 6 kb to about 8 kb, about 6 kb to about 7 kb, or about 7 kb to about 8 kb The total number of protease inhibitors may be 10 or more.

[0124] In some embodiments, the vector(s) is an adenovirus and contains up to 8 kb of nucleic acid. In some embodiments, the virus is an adenovirus or viruses, and the total number of nucleotides is 1 to 3. Approx. 1kb ~ approx. 2kb, approx. 1kb ~ approx. 3kb, approx. 1kb ~ approx. 4kb, approx. 1kb ~ approx. 5kb, Approximately 1kb to approximately 6kb, approximately 1kb to approximately 7kb, approximately 1kb to approximately 8kb, approximately 2kb to approximately 3kb, Approx. 2kb ~ approx. 4kb, approx. 2kb ~ approx. 5kb, approx. 2kb ~ approx. 6kb, approx. 2kb ~ approx. 7kb, Approx. 2kb ~ approx. 8kb, approx. 3kb ~ approx. 4kb, approx. 3kb ~ approx. 5kb, approx. 3kb ~ approx. 6kb, Approx. 3kb ~ approx. 7kb, approx. 3kb ~ approx. 8kb, approx. 4kb ~ approx. 5kb, approx. 4kb ~ approx. 6kb, Approximately 4kb to approximately 7kb, approximately 4kb to approximately 8kb, approximately 5kb to approximately 6kb, approximately 5kb to approximately 7kb, Approximately 5kb to approximately 8kb, approximately 6kb to approximately 7kb, approximately 6kb to approximately 8kb, or approximately 7kb to approximately 8kb It may have a total number of nucleotides in the kb range.

[0125] In some embodiments, the vector(s) are adeno-associated viruses (AAV vectors). and may contain a total number of nucleotides of up to 5 kb. The target(s) can be about 1kb to about 2kb, about 1kb to about 3kb, about 1kb to about 4kb, or about 1kb to approx. 5kb, approx. 2kb to approx. 3kb, approx. 2kb to approx. 4kb, approx. 2kb to approx. 5kb, approx. Nucleotides in the range of 3 kb to about 4 kb, about 3 kb to about 5 kb, or about 4 kb to about 5 kb The total number of nodes may be included.

[0126] In some embodiments, the vector(s) are Gateway® vectors. In some embodiments, each Gateway The ay® vector(s) may be about 1 kb to about 2 kb, about 1 kb to about 3 kb, or about 1kb to approx. 4kb, approx. 1kb to approx. 5kb, approx. 2kb to approx. 3kb, approx. 2kb to approx. 4kb, approx. 2kb to about 5kb, about 3kb to about 4kb, about 3kb to about 5kb, or about 4kb to about 5kb The total number of nucleotides in the range b is included.

[0127] In some embodiments of any of the compositions, kits, and methods provided herein Alternatively, the at least two different vectors may be substantially the same type of vector, In some embodiments, the at least two different vectors may have different The vectors may be of different types and may have substantially the same size or may have different sizes. That's fine.

[0128] In some embodiments, any of the at least two vectors comprises about 500 nucleotides. nucleotides to about 15,000 nucleotides, about 500 nucleotides to about 14,500 nucleotides Otide, about 500 nucleotides to about 14,000 nucleotides, about 500 nucleotides Approximately 13,500 nucleotides, approximately 500 nucleotides to approximately 13,000 nucleotides, approximately 500 nucleotides to about 12,500 nucleotides, about 500 nucleotides to about 12,0 00 nucleotides, about 500 nucleotides to about 11,500 nucleotides, about 500 nucleotides nucleotides to about 11,000 nucleotides, about 500 nucleotides to about 10,500 nucleotides Otide, about 500 nucleotides to about 10,000 nucleotides, about 500 nucleotides Approximately 9,500 nucleotides, approximately 500 nucleotides to approximately 9,000 nucleotides, approximately 50 0 nucleotides to approximately 8,500 nucleotides, approximately 500 nucleotides to approximately 8,000 nucleotides nucleotides, approximately 500 nucleotides to approximately 7,800 nucleotides, approximately 500 nucleotides to Approximately 7,600 nucleotides, approximately 500 nucleotides to approximately 7,400 nucleotides, approximately 50 0 nucleotides to approximately 7,200 nucleotides, approximately 500 nucleotides to approximately 7,000 nucleotides leotide, approximately 500 nucleotides to approximately 6,800 nucleotides, approximately 500 nucleotides to Approximately 6,600 nucleotides, approximately 500 nucleotides to approximately 6,400 nucleotides, approximately 50 0 nucleotides to approximately 6,200 nucleotides, approximately 500 nucleotides to approximately 6,000 nucleotides nucleotides, approximately 500 nucleotides to approximately 5,800 nucleotides, approximately 500 nucleotides to Approximately 5,600 nucleotides, approximately 500 nucleotides to approximately 5,400 nucleotides, approximately 50 0 nucleotides to approximately 5,200 nucleotides, approximately 500 nucleotides to approximately 5,000 nucleotides nucleotides, about 500 nucleotides to about 4,800 nucleotides, about 4,600 nucleotides about 500 nucleotides to about 4,400 nucleotides, about 500 nucleotides to about 4, 200 nucleotides, approximately 500 nucleotides to approximately 4,000 nucleotides, approximately 500 nucleotides nucleotides to approximately 3,800 nucleotides, approximately 500 nucleotides to approximately 3,600 nucleotides about 500 nucleotides to about 3,400 nucleotides, about 500 nucleotides to about 3, 200 nucleotides, approximately 500 nucleotides to approximately 3,000 nucleotides, approximately 500 nucleotides nucleotides to approximately 2,800 nucleotides, approximately 500 nucleotides to approximately 2,600 nucleotides about 500 nucleotides to about 2,400 nucleotides, about 500 nucleotides to about 2, 200 nucleotides, approximately 500 nucleotides to approximately 2,000 nucleotides, approximately 500 nucleotides nucleotides to approximately 1,800 nucleotides, approximately 500 nucleotides to approximately 1,600 nucleotides about 500 nucleotides to about 1,400 nucleotides, about 500 nucleotides to about 1, 200 nucleotides, approximately 500 nucleotides to approximately 1,000 nucleotides, approximately 500 nucleotides nucleotides up to about 800 nucleotides, about 800 nucleotides to about 15,000 nucleotides , about 800 nucleotides to about 14,500 nucleotides, about 800 nucleotides to about 14 ,000 nucleotides, about 800 nucleotides to about 13,500 nucleotides, about 800 Nucleotides to approximately 13,000 nucleotides, approximately 800 nucleotides to approximately 12,500 nucleotides Nucleotide, about 800 nucleotides to about 12,000 nucleotides, about 800 nucleotides 800 to approximately 11,500 nucleotides, and approximately 800 to approximately 11,000 nucleotides , about 800 nucleotides to about 10,500 nucleotides, about 800 nucleotides to about 10 ,000 nucleotides, about 800 nucleotides to about 9,500 nucleotides, about 800 nucleotides Nucleotide to about 9,000 nucleotides, about 800 nucleotides to about 8,500 nucleotides tide, about 800 nucleotides to about 8,000 nucleotides, about 800 nucleotides to about 7 ,800 nucleotides, about 800 nucleotides to about 7,600 nucleotides, about 800 nucleotides Nucleotide to approximately 7,400 nucleotides, approximately 800 nucleotides to approximately 7,200 nucleotides tide, about 800 nucleotides to about 7,000 nucleotides, about 800 nucleotides to about 6 ,800 nucleotides, about 800 nucleotides to about 6,600 nucleotides, about 800 nucleotides Nucleotide to approximately 6,400 nucleotides, approximately 800 nucleotides to approximately 6,200 nucleotides tide, about 800 nucleotides to about 6,000 nucleotides, about 800 nucleotides to about 5 ,800 nucleotides, about 800 nucleotides to about 5,600 nucleotides, about 800 nucleotides Nucleotide to about 5,400 nucleotides, about 800 nucleotides to about 5,200 nucleotides tide, about 800 nucleotides to about 5,000 nucleotides, about 800 nucleotides to about 4 ,800 nucleotides, about 800 nucleotides to about 4,600 nucleotides, about 800 nucleotides Nucleotide to about 4,400 nucleotides, about 800 nucleotides to about 4,200 nucleotides tide, about 800 nucleotides to about 4,000 nucleotides, about 800 nucleotides to about 3 ,800 nucleotides, about 800 nucleotides to about 3,600 nucleotides, about 800 nucleotides Nucleotide to about 3,400 nucleotides, about 800 nucleotides to about 3,200 nucleotides nucleotides, about 800 nucleotides to about 3,000 nucleotides, about 800 nucleotides to about 2 ,800 nucleotides, about 800 nucleotides to about 2,600 nucleotides, about 800 nucleotides Nucleotide to about 2,400 nucleotides, about 800 nucleotides to about 2,200 nucleotides nucleotides, about 800 nucleotides to about 2,000 nucleotides, about 800 nucleotides to about 1 ,800 nucleotides, about 800 nucleotides to about 1,600 nucleotides, about 800 nucleotides Nucleotide to about 1,400 nucleotides, about 800 nucleotides to about 1,200 nucleotides Tide, approximately 800 nucleotides to 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Claims

[Claim 1] The invention described in this specification.

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