EA045887B1 - TREATMENT METHODS FOR CLRN1-ASSOCIATED HEARING LOSS AND/OR VISION LOSS - Google Patents

Description

Cross reference to related applications

This invention claims priority to U.S. Provisional Patent Application No. 62/689,660, filed June 25, 2018; the entire contents of which are incorporated herein by reference.

Technical field

The present disclosure generally relates to the use of nucleic acids for the treatment of hearing loss, vision loss, or both in a human subject.

State of the art

Current treatments for hearing loss consist primarily of hearing amplification for mild to severe hearing loss and cochlear implantation for severe to profound hearing loss; however, there is a long-standing need for agents and methods for preventing or reversing syndromic deafness.

Hearing loss can be conductive (originating in the ear canal or middle ear), sensorineural (occurring in the inner ear or auditory nerve), or mixed. Most forms of syndromic deafness involve permanent hearing loss caused by damage to the structures of the inner ear (sensorineural deafness), although some forms may involve changes in the middle ear (conductive hearing loss). The vast majority of human cases of sensorineural hearing loss are caused by pathological changes in the hair cells of the organ of Corti in the cochlea (insufficient hair cell function). Hair cells may be atypical at birth or may become damaged during a person's life (for example, from noise trauma or infection).

The essence of the invention

The present invention relates to a composition containing at least two different nucleic acid vectors, wherein each of the at least two different vectors contains a coding sequence that encodes different parts of the CLRN1 protein, which can be used to create a sequence encoding the active CLRN1 protein (for example, full-length CLRN1 protein) in a mammalian cell, and thereby treat CLRN1-associated hearing loss and/or vision loss in a subject in need thereof. This invention also provides compositions comprising a single nucleic acid vector that contains a coding sequence for a first and/or second isoform of the CLRN1 protein.

Provided herein are compositions comprising at least two different nucleic acid vectors, wherein each of the at least two different vectors contains a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions is at least 30 amino acids in length. residues, wherein the amino acid sequence of each encoded portion may not necessarily partially overlap with the amino acid sequence of another encoded portion; no vector from at least two different vectors encodes the full-length CLRN1 protein; at least one of the coding sequences contains a nucleotide sequence spanning two consecutive exons of the CLRN1 genomic DNA and not having an intron sequence between the two consecutive exons; and when introduced into a mammalian cell, the at least two different vectors undergo homologous recombination with each other, thereby generating a recombined nucleic acid that encodes the full-length CLRN1 protein. In some embodiments, any of the compositions provided herein each of at least two different vectors contains a coding sequence that encodes a different portion of the first isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, one of at least two different nucleic acid vectors further comprises sequence that encodes the second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, at least two different vectors each comprise a coding sequence, which encodes another part of the second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 5. In some

- 1 045887 embodiments of any of the compositions presented herein, the second isoform of the CLRN1 protein comprises SEQ ID NO: 5. In some embodiments, any of the compositions presented herein, the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. In some embodiments, the implementation of any of the compositions presented herein consists of SEQ ID NO: 5. In any of the compositions provided herein, one of at least two different nucleic acid vectors further comprises a sequence that encodes a second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3.

In some embodiments, any of the compositions provided herein has at least one of at least two different vectors comprising a 5' untranslated region (UTR), a 3' UTR, or both. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 20 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 50 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the present in the compositions herein, the 5'-UTR contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the compositions presented herein in the 5'-UTR contains a sequence that is at least 80% identical SEQ ID NO: 12. In some embodiments, any of the 3'-UTR compositions described herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3' UTR compositions described herein The -UTR contains at least 20 contiguous nucleotides at any location in SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 50 contiguous nucleotides at any location in SEQ ID NO: 15. B In some embodiments, any of the 3'-UTR compositions provided herein contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains a sequence that at least 80% identical to SEQ ID NO: 15.

In some embodiments, any of the compositions provided herein, each of at least two different vectors, is a plasmid, transposon, cosmid, artificial chromosome, or viral vector. In some embodiments, any of the compositions provided herein, each of at least two different vectors is a human artificial chromosome (HAC), a yeast artificial chromosome (YAC), a bacterial artificial chromosome (BAC), or a bacteriophage P1 artificial chromosome (PAC). ). In some embodiments, any of the compositions provided herein, each of at least two different vectors is a viral vector selected from an adeno-associated virus (AAV) vector, an adenoviral vector, a lentiviral vector, or a retroviral vector. In some embodiments, any of the compositions provided herein, each of at least two different vectors, is an AAV-based vector.

In some embodiments of any of the compositions provided herein, the amino acid sequence of any encoded portion does not overlap with the amino acid sequence of another encoded portion. In some embodiments of any of the compositions provided herein, the amino acid sequence of any encoded portion does not partially overlap with the amino acid sequence of another encoded portion. In some embodiments of any of the compositions provided herein, the overlapping amino acid sequence has a length of from about 30 amino acid residues to about 202 amino acid residues. In some embodiments, any of the compositions provided herein, the vectors comprise two different vectors, each of which contains a different intron segment, wherein the intron contains the nucleotide sequence of an intron that is present in the CLRN1 genomic DNA, and wherein the two different intron segments overlap in a sequence length of at least 100 nucleotides. In some embodiments of any of the compositions provided herein, two different intronic segments overlap in a sequence ranging from 100 to about 800 nucleotides in length.

In some embodiments of any of the compositions provided herein, the complete nucleotide sequence of each of the at least two different vectors is from about 500 to about 10,000 nucleotides in length. In some embodiments, any of the compositions provided herein, the complete nucleotide sequence of each at least

- 2 045887 at least from two different vectors has a length of from 500 to 5000 nucleotides. In some embodiments of any of the compositions provided herein, the number of different vectors in the composition is two. In some embodiments, any of the compositions provided herein, the first of two different vectors contains a coding sequence that encodes the N-terminal portion of the CLRN1 protein. In some embodiments, any of the compositions provided herein has a length of the N-terminal portion of the CLRN1 protein ranging from 30 to 202 amino acids. In some embodiments, any of the compositions provided herein is 60 to 170 amino acids long at the N-terminal portion of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first vector further comprises a 5'UTR sequence. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 20 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 50 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the present in the compositions herein, the 5'-UTR contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the compositions presented herein in the 5'-UTR contains a sequence that is at least 80% identical SEQ ID NO: 12. In some embodiments, any of the compositions provided herein, the first vector further comprises one or both of a promoter and a Kozak sequence. In some embodiments, any of the compositions provided herein, the first vector contains a promoter that is an inducible promoter, a constitutive promoter, or a tissue-specific promoter. In some embodiments, any of the compositions provided herein, the second of two different vectors contains a coding sequence that encodes the C-terminal portion of the CLRN1 protein. In some embodiments, any of the compositions provided herein has a C-terminal portion of the CLRN1 protein ranging from 30 to 202 amino acids in length. In some embodiments, any of the compositions provided herein is 60 to 170 amino acids in length at the C-terminal portion of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second vector further comprises a polyadenylation signal sequence. In some embodiments, any of the compositions provided herein, the second vector further comprises a 3'UTR sequence. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 10 contiguous nucleotides anywhere in SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 20 contiguous nucleotides anywhere in SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 50 contiguous nucleotides anywhere in SEQ ID NO: 15. In some embodiments, any of the present in the compositions herein, the 3'-UTR contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the compositions presented herein in the 3'-UTR contains a sequence that is at least 80% identical SEQ ID NO: 15.

Also provided herein are compositions that contain a single nucleic acid vector, wherein the vector contains one or both of (i) 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 contain a nucleotide sequence spanning two consecutive exons of the CLRN1 genomic DNA and no intronic sequence between the two consecutive exons. In some embodiments, any of the compositions provided herein, one nucleic acid vector contains a first coding sequence and does not contain a second coding sequence. In some embodiments, any of the compositions provided herein, one nucleic acid vector contains a second coding sequence rather than a first coding sequence. In some embodiments, any of the compositions provided herein, a single nucleic acid vector contains both a first coding sequence and a second coding sequence. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments of any of the compositions provided herein, 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 isoform of the CLRN1 protein contains a sequence that is at least

- 3 045887

95% identical to SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein consists of SEQ ID NO: 5.

In some embodiments, any of the compositions provided herein, the single nucleic acid vector further comprises a 5' untranslated region (UTR), a 3' UTR, or both. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 20 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 50 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the present in the compositions herein, the 5'-UTR contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the compositions presented herein in the 5'-UTR contains a sequence that is at least 80% identical SEQ ID NO: 12. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3' compositions provided herein The -UTR contains at least 20 contiguous nucleotides at any location in SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 50 contiguous nucleotides at any location in SEQ ID NO: 15. B In some embodiments, any of the 3'-UTR compositions provided herein contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains a sequence that at least 80% identical to SEQ ID NO: 15.

In some embodiments, any of the compositions provided herein, the single nucleic acid vector is a plasmid, transposon, cosmid, artificial chromosome, or viral vector. In some embodiments of any of the compositions provided herein, the single nucleic acid vector is a human artificial chromosome (HAC), yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or P1-based artificial chromosome (PAC). In some embodiments, any of the compositions provided herein, the single nucleic acid vector is a viral vector selected from an adeno-associated virus (AAV) vector, an adenoviral vector, a lentiviral vector, or a retroviral vector. In some embodiments, any of the compositions provided herein, one nucleic acid vector is an AAV-based vector. In some embodiments, any of the compositions provided herein, the single nucleic acid vector further comprises one or both of a promoter and a Kozak sequence. In some embodiments, any of the compositions provided herein, the first vector contains a promoter that is an inducible promoter, a constitutive promoter, or a tissue-specific promoter. In some embodiments, any of the compositions provided herein, one nucleic acid vector further comprises a polyadenylation signal sequence. Some embodiments of any of the compositions provided herein further comprise a pharmaceutically acceptable excipient.

Also provided herein are kits that contain any of the compositions presented herein. Some embodiments of any of the kits provided herein further comprise a pre-filled syringe comprising or containing any of the compositions described herein.

Also provided herein are methods that include administering to the cochlea of a mammal a therapeutically effective amount of any of the compositions provided herein. In some embodiments of any of the methods presented herein, the mammal is a human. In some embodiments of any of the methods presented herein, the mammal has previously been identified to have a defective CLRN1 gene.

Also provided herein are methods of increasing the expression of full-length CLRN1 protein in a mammalian cell, which include introducing any of the compositions provided herein into a mammalian cell. In some embodiments of any of the methods presented herein, the mammalian cell is an inner cochlear hair cell or an outer cochlear hair cell. In some embodiments of any of the methods presented herein, the mammalian cell is a retinal cell. In some embodiments of any of the methods presented herein, the mammalian cell is a human cell. In some variants

- 4 045887 carrying out any of the methods presented herein, it was previously determined that the mammalian cell has a defective CLRN1 gene.

Also provided herein are methods of increasing the expression of full-length CLRN1 protein in the inner hair cell, outer hair cell, or both in the cochlea of a mammal, which comprises administering to the cochlea of the mammal a therapeutically effective amount of any of the compositions provided herein. Also provided herein are methods of increasing the expression of full-length CLRN1 protein in the eye of a mammal, which comprise intraocularly administering a therapeutically effective amount of any of the compositions provided herein to the eye of the mammal. In some embodiments of any of the methods presented herein, the mammal has previously been identified to have a defective CLRN1 gene. In some embodiments of any of the methods presented herein, the mammal is a human.

Also provided herein are methods of treating hearing loss in a subject who has been identified as having a defective CLRN1 gene, which comprises administering a therapeutically effective amount of any of the compositions provided herein to the cochlea of the subject. Also provided herein are methods of treating vision loss in a subject who has been identified as having a defective CLRN1 gene, which comprises administering a therapeutically effective amount of any of the compositions provided herein to the eye of the subject. In some embodiments of any of the methods presented herein, the subject has Usher syndrome type III. In some embodiments of any of the methods presented herein, the subject is a human. Some embodiments of any of the methods presented herein further include, prior to the administration step, determining that the subject has a defective CLRN1 gene.

Also provided herein are compositions that contain two different nucleic acid vectors, wherein the first nucleic acid vector of the two different nucleic acid vectors contains a promoter, a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located at the 3' end of the promoter, and a splice donor sequence located at the 3' end of the first coding sequence; and a second nucleic acid vector of two different nucleic acid vectors comprises a splice acceptor sequence, a second coding sequence that encodes a C-terminal portion of the CLRN1 protein located at the 3' end of the splice acceptor sequence, and a polyadenylation signal sequence at the 3' end of the second coding sequence sequences; wherein each of the encoded parts has a length of at least 30 amino acid residues, and the amino acid sequences of the two encoded parts do not overlap with each other; however, neither of the two different vectors encodes the full-length CLRN1 protein; and when introduced into a mammalian cell, splicing occurs between the splice donor sequence and the splice acceptor sequence, thereby generating a recombined nucleic acid that encodes the full-length CLRN1 protein. In some embodiments of any of the compositions provided herein, the first coding sequence encodes the N-terminal portion of the first isoform of the CLRN1 protein, and the second coding sequence encodes the C-terminal portion of the first isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first nucleic acid vector of two different nucleic acid vectors further comprises sequence that encodes the second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein consists of SEQ ID NO: 5.

In some embodiments, any of the compositions provided herein, the first coding sequence encodes the N-terminal portion of a second isoform of the CLRN1 protein, and the second coding sequence encodes the C-terminal portion of the second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein consists of

- 5 045887 from SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the first nucleic acid vector or the second nucleic acid vector further comprises a sequence that encodes a first isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3.

In some embodiments of any of the compositions provided herein, one or both of the first nucleic acid vector and the second nucleic acid vector comprise a 5' untranslated region (UTR), a 3' UTR, or both. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 20 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 50 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the present in the compositions herein, the 5'-UTR contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the compositions presented herein in the 5'-UTR contains a sequence that is at least 80% identical SEQ ID NO: 12. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3' compositions provided herein The -UTR contains at least 20 contiguous nucleotides at any location in SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 50 contiguous nucleotides at any location in SEQ ID NO: 15. B In some embodiments, any of the 3'-UTR compositions provided herein contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains a sequence that at least 80% identical to SEQ ID NO: 15.

In some embodiments of any of the compositions provided herein, the first nucleic acid vector and the second nucleic acid vector are each a plasmid, transposon, cosmid, artificial chromosome, or viral vector. In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is a human artificial chromosome (HAC), a yeast artificial chromosome (YAC), a bacterial artificial chromosome (BAC), or a P1-based artificial chromosome (ASD). In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is a viral vector selected from an adeno-associated virus (AAV) vector, an adenoviral vector, a lentiviral vector, or a retroviral vector. In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is an AAV-based vector. In some embodiments of any of the compositions provided herein, at least one of the coding sequences comprises a nucleotide sequence that spans two consecutive exons of the CLRN1 genomic DNA and has no intronic sequence between the two consecutive exons.

Also provided herein are compositions that contain two different nucleic acid vectors, wherein: the first nucleic acid vector of the two different nucleic acid vectors contains a promoter, a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located at the 3' end of the promoter , a splice donor sequence located at the 3' end of the first coding sequence, and a first detectable marker gene located at the 3' end of the splice donor sequence; and a second nucleic acid vector of two different nucleic acid vectors comprises a second detectable marker gene, a splice acceptor sequence located at the 3' end of the second detectable marker gene, a second coding sequence that encodes the C-terminal portion of the CLRN1 protein located at the 3' end of the sequence a splicing acceptor, and a polyadenylation signal sequence located at the 3' end of the second coding sequence; wherein each of the encoded parts has a length of at least 30 amino acid residues, and the amino acid sequences of the encoded parts do not overlap with each other; however, neither of the two different vectors encodes the full-length CLRN1 protein; and when introduced into a mammalian cell, splicing occurs between the splice donor sequence and the sequence

- 6 045887 splice acceptor, thereby forming a recombined nucleic acid that encodes the full-length CLRN1 protein. In some embodiments of any of the compositions provided herein, the first coding sequence encodes the N-terminal portion of the first isoform of the CLRN1 protein, and the second coding sequence encodes the C-terminal portion of the first isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first nucleic acid vector of two different nucleic acid vectors further comprises sequence that encodes the second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains SEQ ID NO: 5. In some embodiments of any of the compositions provided herein, the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. In some embodiments of any of the compositions provided herein, the first coding sequence encodes the N-terminal portion of the second isoform of the CLRN1 protein , and the second coding sequence encodes the C-terminal part of the second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the first nucleic acid vector or the second nucleic acid vector further comprises the sequence , which encodes the first isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3.

In some embodiments of any of the compositions provided herein, one or both of the first nucleic acid vector and the second nucleic acid vector comprise a 5' untranslated region (UTR), a 3' UTR, or both. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 20 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 50 contiguous nucleotides anywhere in SEQ ID NO: 12.

In some embodiments, any of the 5'-UTR compositions provided herein contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains a sequence that is at least 80% identical to SEQ ID NO: 12. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location in SEQ ID NO: 15. In some embodiments, any of of the compositions provided herein, the 3'-UTR contains at least 20 contiguous nucleotides at any location of SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 50 contiguous nucleotides at any location SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3' compositions provided herein The -UTR contains a sequence that is at least 80% identical to SEQ ID NO: 15.

In some embodiments of any of the compositions provided herein, the first nucleic acid vector and the second nucleic acid vector are each a plasmid, transposon, cosmid, artificial chromosome, or viral vector. In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is artificial

- 7 045887 human chromosome (HAC), yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC) or P1-based artificial chromosome (PAC). In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is a viral vector selected from an adeno-associated virus (AAV) vector, an adenoviral vector, a lentiviral vector, or a retroviral vector. In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is an AAV-based vector. In some embodiments, any of the compositions provided herein has at least one of the coding sequences comprising a nucleotide sequence that spans two consecutive exons of the CLRN1 genomic DNA and has no intronic sequence between the two consecutive exons. In some embodiments of any of the compositions provided herein, the first or second detectable marker gene is an alkaline phosphatase.

Also provided herein are compositions that contain two different nucleic acid vectors, wherein the first nucleic acid vector of the two different nucleic acid vectors contains a promoter, a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located 3' to the promoter, a donor sequence a splicing region located at the 3' end of the first coding sequence, and a recombinogenic region of phage F1 located 3' to the splicing donor sequence; and a second nucleic acid vector of two different nucleic acid vectors comprises a recombinogenic region of phage F1, a splice acceptor sequence located at the 3' end of the recombinogenic region of phage F1, a second coding sequence that encodes the C-terminal portion of the CLRN1 protein located at the 3' end end of the splice acceptor sequence, and a polyadenylation signal sequence located at the 3' end of the second coding sequence; wherein each of the two encoded parts has a length of at least 30 amino acid residues, and the amino acid sequences of the two encoded parts do not overlap with each other; however, neither of the two different vectors encodes the full-length CLRN1 protein; and when introduced into a mammalian cell, splicing occurs between the splice donor sequence and the splice acceptor sequence, thereby generating a recombined nucleic acid that encodes the full-length CLRN1 protein. In some embodiments of any of the compositions provided herein, the first coding sequence encodes the N-terminal portion of the first isoform of the CLRN1 protein, and the second coding sequence encodes the C-terminal portion of the first isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first nucleic acid vector of two different nucleic acid vectors further comprises sequence that encodes the second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein consists of SEQ ID NO: 5.

In some embodiments, any of the compositions provided herein, the first coding sequence encodes the N-terminal portion of a second isoform of the CLRN1 protein, and the second coding sequence encodes the C-terminal portion of the second isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein contains SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the second isoform of the CLRN1 protein consists of SEQ ID NO: 5. In some embodiments, any of the compositions provided herein, the first nucleic acid vector or the second nucleic acid vector further comprises the sequence , which encodes the first isoform of the CLRN1 protein. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains a sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, any of the compositions provided herein, the first isoform of the CLRN1 protein contains the SEQ ID NO: 3. In some embodiments, any of the above

- 8 045887 compositions set forth herein, the first isoform of the CLRN1 protein consists of SEQ ID NO: 3.

In some embodiments of any of the compositions provided herein, one or both of the first nucleic acid vector and the second nucleic acid vector comprise a 5' untranslated region (UTR), a 3' UTR, or both. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 20 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the 5'-UTR compositions provided herein contains at least 50 contiguous nucleotides anywhere in SEQ ID NO: 12. In some embodiments, any of the present in the compositions herein, the 5'-UTR contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 12. In some embodiments, any of the compositions presented herein in the 5'-UTR contains a sequence that is at least 80% identical SEQ ID NO: 12. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 10 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3' compositions provided herein The -UTR contains at least 20 contiguous nucleotides at any location in SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains at least 50 contiguous nucleotides at any location in SEQ ID NO: 15. B In some embodiments, any of the 3'-UTR compositions provided herein contains at least 80 contiguous nucleotides at any location within SEQ ID NO: 15. In some embodiments, any of the 3'-UTR compositions provided herein contains a sequence that at least 80% identical to SEQ ID NO: 15.

In some embodiments of any of the compositions provided herein, the first nucleic acid vector and the second nucleic acid vector are each a plasmid, transposon, cosmid, artificial chromosome, or viral vector. In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is a human artificial chromosome (HAC), a yeast artificial chromosome (YAC), a bacterial artificial chromosome (BAC), or a P1-based artificial chromosome (ASD). In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is a viral vector selected from an adeno-associated virus (AAV) vector, an adenoviral vector, a lentiviral vector, or a retroviral vector. In some embodiments, any of the compositions provided herein, each of the first nucleic acid vector and the second nucleic acid vector is an AAV-based vector. In some embodiments of any of the compositions provided herein, at least one of the coding sequences comprises a nucleotide sequence that spans two consecutive exons of the CLRN1 genomic DNA and has no intronic sequence between the two consecutive exons.

Also provided herein are kits that contain any of the compositions presented herein. Some embodiments of any of the kits provided herein further include a pre-filled syringe containing the composition.

Also provided herein are methods that include administering to the cochlea of a mammal a therapeutically effective amount of any of the compositions provided herein. In some embodiments of any of the methods presented herein, the mammal is a human. In some embodiments of any of the methods presented herein, the mammal has previously been identified to have a defective CLRN1 gene.

Also provided herein are methods of increasing the expression of full-length CLRN1 protein in a mammalian cell, which include introducing any of the compositions provided herein into a mammalian cell. In some embodiments of any of the methods presented herein, the mammalian cell is an inner cochlear hair cell or an outer cochlear hair cell. In some embodiments of any of the methods presented herein, the mammalian cell is a retinal cell. In some embodiments of any of the methods presented herein, the mammalian cell is a human cell. In some embodiments of any of the methods presented herein, it has been previously determined that the mammalian cell has a defective CLRN1 gene.

This document also provides methods for increasing the expression of full-length CLRN1 protein in the inner hair cell, outer hair cell, or both cells in the cochlea

- 9 045887 mammal, which include administering to the cochlea of the mammal a therapeutically effective amount of any of the compositions described herein. Also provided herein are methods of increasing the expression of full-length CLRN1 protein in the eye of a mammal, which comprise intraocularly administering a therapeutically effective amount of any of the compositions provided herein to the eye of the mammal. In some embodiments of any of the methods presented herein, the mammal has previously been identified to have a defective CLRN1 gene. In some embodiments of any of the methods presented herein, the mammal is a human.

Also provided herein are methods of treating hearing loss in a subject who has been identified as having a defective CLRN1 gene, which comprises administering a therapeutically effective amount of any of the compositions provided herein to the cochlea of the subject. Also provided herein are methods of treating vision loss in a subject who has been identified as having a defective CLRN1 gene, which comprises administering a therapeutically effective amount of any of the compositions provided herein to the eye of the subject. In some embodiments of any of the methods presented herein, the subject has Usher syndrome type III. In some embodiments of any of the methods presented herein, the subject is a human. Some embodiments of any of the methods presented herein further include, prior to the administration step, determining that the subject has a defective CLRN1 gene.

The singular form is used to denote one or more than one (i.e. at least one) grammatical object. For example, an element includes one element and more than one element.

The term mutation in the CLRN1 gene refers to a modification of a type CLRN1 gene that results in the production of a CLRN1 protein having one or more of: a deletion of one or more amino acids, one or more amino acid substitutions, and one or more amino acid insertions relative to the type CLRN1 protein, and /or leads to a decrease in the level of expression of the encoded CLRN1 protein in a mammalian cell compared to the level of expression of the encoded CLRN1 protein in a mammalian cell that does not have the mutation. In some embodiments, the mutation may result in the production of a CLRN1 protein having a deletion of 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, as is known in the art, covers any mutation in a coding sequence that results in a frameshift of the coding sequence. In some embodiments, a frameshift may result in the formation of a nonfunctional protein. In some embodiments, the point mutation may be a nonsense mutation (ie, result in a premature stop codon in an exon of a gene). A nonsense mutation can result in a truncated protein (compared to the corresponding wild-type protein), which may or may not be functional. In some embodiments, the mutation may result in a loss (or decreased level) of expression of CLRN1 mRNA or CLRN1 protein, or both mRNA and protein. In some embodiments, the mutation may result in the formation of an altered CLRN1 having a loss or reduction of one or more biological activities compared to the wild-type CLRN1 protein.

In some embodiments, the mutation is an insertion of one or more nucleotides into the CLRN1 gene. In some embodiments, the mutation is in the regulatory sequence of the CLRN1 gene, i.e. part of a gene that is not a coding sequence. In some embodiments, a mutation in the regulatory sequence may be in a promoter or enhancer region and prevent or reduce proper transcription of the CLRN1 gene. The term conservative mutation refers to a mutation that does not change the amino acid encoded at the mutation site (due to the innateness of the codons).

Modifications can be introduced into the nucleotide sequence by standard methods known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which an amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been identified in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains (e.g., aspartic acid and glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, 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 isoleucine) and aromatic side chains (e.g. tyrosine, phenylalanine , tryptophan and histidine).

Unless otherwise stated, the nucleotide sequence encoding the amino acid sequence

- 10 045887 value includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence.

The term endogenous refers to any material originating from an organism, cell or tissue.

The term exogenous refers to any material introduced from or originating from an organism, cell or tissue that is not produced or derived from the same organism, cell or tissue into which it is introduced.

The term isolated means altered or removed from its natural state. For example, a nucleic acid or peptide naturally present in a living being is not isolated, but the same nucleic acid or peptide, partially or completely separated from coexisting materials in its natural state, will be isolated. The isolated nucleic acid or protein may exist in substantially purified form or may exist in a foreign environment, such as, for example, a host cell.

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

The term expression refers to the transcription and/or translation of a specific nucleotide sequence encoding a protein.

The term transient expression refers to the expression of a non-integrated coding sequence over a short period of time (eg, hours or days). A coding sequence that is transiently expressed in a cell (eg, a mammalian cell) is lost during multiple cycles of cell division.

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

A treatment is therapeutically effective when it results in a reduction in one or more of the number, severity, and frequency of one or more symptoms of a condition (eg, hearing loss or vision loss) in a subject (eg, a human). In some embodiments, a therapeutically effective amount of the composition may result in an increase in the expression level of active CLRN1 protein (e.g., full-length wild-type CLRN1 protein or a variant of CLRN1 protein having the desired activity) (e.g., compared to the expression level before treatment with the composition). In some embodiments, a therapeutically effective amount of the composition may result in an increase in the level of expression of active CLRN1 protein (eg, wild type, full-length CLRN1 protein, or active variant) in a target cell (eg, an inner hair cell of the cochlea). In some embodiments, a therapeutically effective amount of the composition may result in an increase in the expression level of active CLRN1 protein (e.g., full-length wild-type or active variant CLRN1 protein) and/or an increase in one or more CLRN1 protein activity in the target cell (e.g., compared to a reference level , such as the level(s) in a subject before treatment, the level(s) in a subject having a mutation in the CLRN1 gene, or the level(s) in a subject or population of subjects with hearing loss and/or vision loss).

The term nucleic acid or polynucleotide refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) or a combination thereof in single- or double-stranded form. Unless specifically limited, the term covers nucleic acids containing known analogs of natural nucleotides that have binding properties similar to those of the reference nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly includes complementary sequences as well as explicitly stated sequences. In some embodiments, any of the nucleic acids described herein, the nucleic acid is DNA. In some embodiments, any of the nucleic acids described herein, the nucleic acid is RNA.

The term active CLRN1 protein means a protein encoded by DNA in which the replacement of both wild-type alleles encoding the full-length CLRN1 protein in auditory hair cells or eye cells in a mammal that is otherwise a wild-type mammal, and its expression in auditory hair cells or cells the eyes of that mammal results in that mammal having a level of hearing or vision approaching the normal level of hearing or vision of a similar mammal that is entirely wild-type. Neog

- 11 045887 limited examples of active CLRN1 proteins are full-length CLRN1 proteins (eg, any of the full-length CLRN1 proteins described herein).

For example, an active CLRN1 protein may comprise the sequence of a full-length wild-type CLRN1 protein (e.g., a human full-length wild-type CLRN1 protein), including 1 to about 100 amino acid substitutions, 1 to about 95 amino acid substitutions, 1 to about

90 amino acids replacements, from 1 before about 85 amino acid substitutions, from 1 replacement before 80 amino acids replacements, from 1 up to about 75 amino acid substitutions, from 1 to 70 amino acids replacements, from 1 up to about 65 amino acid substitutions, from 1 to 60 amino acids replacements, from 1 up to about 55 amino acid substitutions, from 1 to 50 amino acids replacements, from 1 up to about 45 amino acid substitutions, from 1 to 40 amino acids replacements, from 1 up to about 35 amino acid substitutions, from 1 to thirty amino acids replacements, from 1 up to about 25 amino acid substitutions, from 1 to 20 amino acids replacements, from 1 up to about 15 amino acid substitutions, from 1 to 10 amino acids replacements from 1 up to about 9 amino acid substitutions, from 1 to 8 amino acids replacements, from 1 up to about 7 amino acid substitutions, from 1 to 6 amino acids replacements, from 1 up to about 5 amino acid substitutions, from 1 to 4 amino acids replacements, from 1 before about 3 amino acid substitutions, from about 2 to 100 amino acids replacements, from about 2 to about 95 amino acid substitutions, from about 2 to

amino acid substitutions, from about 2 to about 85 amino acid substitutions, from about 2 to about 80 amino acid substitutions, from about 2 to about 75 amino acid substitutions, from about 2 to about 70 amino acid substitutions, from about 2 to about 65 amino acid substitutions, from about 2 to 60 amino acid substitutions, from about 2 to about 55 amino acid substitutions, from about 2 to about 50 amino acid substitutions, from about 2 to about 45 amino acid substitutions, from about 2 to about 40 amino acid substitutions, from about 2 to about 35 amino acid substitutions, from about 2 up to 30 amino acid substitutions, from about 2 to about 25 amino acid substitutions, from about 2 to about 20 amino acid substitutions, from about 2 to about 15 amino acid substitutions, from about 2 to about 10 amino acid substitutions, from about 2 to about 9 amino acid substitutions, from about 2 to 8 amino acid substitutions, from about 2 to about 7 amino acid substitutions, from about 2 to about 6 amino acid substitutions, from about 2 to about 5 amino acid substitutions, from about 2 to 4 amino acid substitutions, from about 3 to about 100 amino acid substitutions, from about 3 to about 95 amino acid substitutions, from about 3 to about 90 amino acid substitutions, from about 3 to about 85 amino acid substitutions, from about 3 to about 80 amino acid substitutions, from about 3 to about 75 amino acid substitutions, from about 3 to about 70 amino acid substitutions, about 3 to about 65 amino acid substitutions, about 3 to about 60 amino acid substitutions, about 3 to about 55 amino acid substitutions, about 3 to about 50 amino acid substitutions, about 3 to about 45 amino acid substitutions, about 3 to about 40 amino acid substitutions , from about 3 to about 35 amino acid substitutions, from about 3 to about 30 amino acid substitutions, from about 3 to about 25 amino acid substitutions, from about 3 to about 20 amino acid substitutions, from about 3 to about 15 amino acid substitutions, from about 3 to about 10 amino acid substitutions substitutions, from about 3 to about 9 amino acid substitutions, from about 3 to about 8 amino acid substitutions, from about 3 to 7 amino acid substitutions, from about 3 to about 6 amino acid substitutions, from about 3 to 5 amino acid substitutions, from about 4 to about 100 amino acid substitutions, from about 4 to about 95 amino acid substitutions, from about 4 to about 90 amino acid substitutions, from about 4 to about 85 amino acid substitutions, from about 4 to about 80 amino acid substitutions, from about 4 to about 75 amino acid substitutions, from about 4 to about 70 amino acid substitutions, from about 4 to about 65 amino acid substitutions, from about 4 to about 60 amino acid substitutions, from about 4 to about 55 amino acid substitutions, from about 4 to about 50 amino acid substitutions, from about 4 to 45 amino acid substitutions, from about 4 to about 40 amino acid substitutions, from about 4 to about 35 amino acid substitutions, from about 4 to about 30 amino acid substitutions, from about 4 to 25 amino acid substitutions, from about 4 to about 20 amino acid substitutions, from about 4 to 15 amino acid substitutions, from about 4 to about 10 amino acid substitutions, from about 4 to 9 amino acid substitutions, from about 4 to about 8 amino acid substitutions, from about 4 to 7 amino acid substitutions, from about 4 to about 6 amino acid substitutions, from about 5 to 100 amino acid substitutions, from about 5 to about 95 amino acid substitutions, from about 5 to about 90 amino acid substitutions, from about 5 to about 85 amino acid substitutions, from about 5 to about 80 amino acid substitutions, from about 5 to about 75 amino acid substitutions, from about 5 to about 70 amino acid substitutions, from about 5 to about 65 amino acid substitutions, about 5 to about 60 amino acid substitutions, about 5 to about 55 amino acid substitutions, about 5 to about 50 amino acid substitutions, about 5 to about 45 amino acid substitutions, about 5 to about 40 amino acid substitutions, from about 5 to about 35 amino acid substitutions, from about 5 to about 30 amino acid substitutions, from about 5 to about 25 amino acid substitutions, from about 5 to about 20 amino acid substitutions, from about 5 to about 15 amino acid substitutions, from about 5 to about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about

- 12 045887 amino acid substitutions, from about 5 to about 9 amino acid substitutions, from about 5 to about 8 amino acid substitutions, from about 5 to about 7 amino acid substitutions, from about 6 to 100 amino acid substitutions, from about 6 to about 95 amino acid substitutions, from about 6 to about 90 amino acid substitutions, about 6 to about 85 amino acid substitutions, about 6 to about 80 amino acid substitutions, about 6 to about 75 amino acid substitutions, about 6 to about 70 amino acid substitutions, about 6 to about 65 amino acid substitutions, about 6 to about 60 amino acid substitutions, about 6 to about 55 amino acid substitutions, about 6 to about 50 amino acid substitutions, about 6 to about 45 amino acid substitutions, about 6 to about 40 amino acid substitutions, about 6 to about 35 amino acid substitutions , from about 6 to about 30 amino acid substitutions, from about 6 to about 25 amino acid substitutions, from about 6 to about 20 amino acid substitutions, from about 6 to about 15 amino acid substitutions, from about 6 to about 10 amino acid substitutions, from about 6 to about 9 amino acid substitutions substitutions, from about 6 to about 8 amino acid substitutions, from about 7 to about 100 amino acid substitutions, from about 7 to about 95 amino acid substitutions, from about 7 to about 90 amino acid substitutions, from about 7 to about 85 amino acid substitutions, from about 7 to about 80 amino acid substitutions, from about 7 to about 75 amino acid substitutions, from about 7 to about 70 amino acid substitutions, from about 7 to about 65 amino acid substitutions, from about 7 to about 60 amino acid substitutions, from about 7 to about 55 amino acid substitutions, from about 7 to about 50 amino acid substitutions, from about 7 to about 45 amino acid substitutions, from about 7 to about 40 amino acid substitutions, from about 7 to about 35 amino acid substitutions, from about 7 to about 30 amino acid substitutions, from about 7 to 25 amino acid substitutions, from about 7 to about 20 amino acid substitutions, from about 7 to about 15 amino acid substitutions, from about 7 to about 10 amino acid substitutions, from about 7 to 9 amino acid substitutions, from about 8 to about 100 amino acid substitutions, from about 8 to 95 amino acid substitutions, from about 8 to about 90 amino acid substitutions, from about 8 to about 85 amino acid substitutions, from about 8 to about 80 amino acid substitutions, from about 8 to about 75 amino acid substitutions, from about 8 to about 70 amino acid substitutions, from about 8 to about 65 amino acid substitutions, from about 8 to about 60 amino acid substitutions, from about 8 to about 55 amino acid substitutions, from about 8 to about 50 amino acid substitutions, from about 8 to about 45 amino acid substitutions, from about 8 to about 40 amino acid substitutions, from about 8 to 35 amino acid substitutions, from about 8 to about 30 amino acid substitutions, about 8 to about 25 amino acid substitutions, about 8 to about 20 amino acid substitutions, about 8 to about 15 amino acid substitutions, about 8 to about 10 amino acid substitutions, about 10 to about 100 amino acid substitutions, from about 10 to about 95 amino acid substitutions, from about 10 to about 90 amino acid substitutions, from about 10 to about 85 amino acid substitutions, from about 10 to about 80 amino acid substitutions, from about 10 to about 75 amino acid substitutions, from about 10 to about 70 amino acid substitutions , from about 10 to about 65 amino acid substitutions, from about 10 to about 60 amino acid substitutions, from about 10 to about 55 amino acid substitutions, from about 10 to about 50 amino acid substitutions, from about 10 to about 45 amino acid substitutions, from about 10 to about 40 amino acid substitutions substitutions, from about 10 to about 35 amino acid substitutions, from about 10 to about 30 amino acid substitutions, from about 10 to about 25 amino acid substitutions, from about 10 to about 20 amino acid substitutions, from about 10 to about 15 amino acid substitutions, from about 15 to 100 amino acid substitutions, from about 15 to about 95 amino acid substitutions, from about 15 to about 90 amino acid substitutions, from about 15 to about 85 amino acid substitutions, from about 15 to about 80 amino acid substitutions, from about 15 to about 75 amino acid substitutions, from about 15 to 70 amino acid substitutions, from about 15 to about 65 amino acid substitutions, from about 15 to about 60 amino acid substitutions, from about 15 to about 55 amino acid substitutions, from about 15 to about 50 amino acid substitutions, from about 15 to about 45 amino acid substitutions, from about 15 up to 40 amino acid substitutions, from about 15 to about 3 5 amino acid substitutions, from about 15 to 30 amino acid substitutions, from about 15 to about 25 amino acid substitutions, from about 15 to 20 amino acid substitutions, from about 20 to about 100 amino acid substitutions, from about 20 to about 95 amino acid substitutions, from about 20 to about 90 amino acid substitutions, from about 20 to about 85 amino acid substitutions, from about 20 to about 80 amino acid substitutions, from about 20 to about 75 amino acid substitutions, from about 20 to about 70 amino acid substitutions, from about 20 to about 65 amino acid substitutions, from about 20 to about 60 amino acid substitutions, from about 20 to about 55 amino acid substitutions, from about 20 to about 50 amino acid substitutions, from about 20 to about 45 amino acid substitutions, from about 20 to about 40 amino acid substitutions , from about 20 to about 35 amino acid substitutions, from about 20 to about 30 amino acid substitutions, from about 20 to about 25 amino acid substitutions, from about 25 to about 100 amino acid substitutions, from about 25 to about 95 amino acid substitutions, from about 25 to about 90 amino acid substitutions substitutions, from about 25 to about 85 amino acid substitutions, from about 25 to about 80 amino acid substitutions, from about 25 to about 75 amino acid substitutions, from about 25 to about 70 amino acid substitutions, from about 25 to about 65 amino acid substitutions, from about 25 to about 60 amino acid substitutions, from about 25 to about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about about

- 13 045887 amino acid substitutions, from about 25 to about 50 amino acid substitutions, from about 25 to about 30 amino acid substitutions, from about 25 to about 40 amino acid substitutions, from about 25 to about 30 amino acid substitutions, from about 30 to about

100 amino acid substitutions, from about 30 to about 95 amino acid substitutions, from about 30 to about amino acid substitutions, from about 30 to about 85 amino acid substitutions, from about 30 to about 95 amino acid substitutions, from about 30 to about 75 amino acid substitutions, from about 30 to about amino acid substitutions, from about 30 to about 65 amino acid substitutions, from about 30 to about amino acid substitutions, from about 30 to about 55 amino acid substitutions, from about 30 to about amino acid substitutions, from about 30 to about 45 amino acid substitutions, from about 30 to about amino acid substitutions, from about 30 to about 35 amino acid substitutions, from about 35 to about

100 amino acid substitutions, from about 35 to about 95 amino acid substitutions, from about 35 to about 75 amino acid substitutions, from about 35 to about 85 amino acid substitutions, from about 35 to about 75 amino acid substitutions, from about 35 to about amino acid substitutions, from about 35 to about 65 amino acid substitutions, from about 35 to about amino acid substitutions, from about 35 to about 55 amino acid substitutions, from about 35 to about amino acid substitutions, from about 35 to about 45 amino acid substitutions, from about 35 to about amino acid substitutions, from about 40 to about 100 amino acid substitutions, from about 40 to about amino acid substitutions, from about 40 to about 90 amino acid substitutions, from about 40 to about 80 amino acid substitutions, from about 40 to about 80 amino acid substitutions, from about 40 to about 60 amino acid substitutions, about 40 to about 70 amino acid substitutions, about 40 to about 50 amino acid substitutions, about 40 to about 60 amino acid substitutions, about 40 to about 50 amino acid substitutions, about 40 to about 50 amino acid substitutions, about 40 to about 40 amino acid substitutions, about 45 to about 100 amino acid substitutions, about 45 to about 90 amino acid substitutions, about 45 to about 90 amino acid substitutions, about 45 to about 80 amino acid substitutions , from about 45 to about 60 amino acid substitutions, from about 45 to about 70 amino acid substitutions, from about 45 to about 5 amino acid substitutions, from about 45 to about 60 amino acid substitutions, from about 45 to about 50 amino acid substitutions replacements, from about 50 to about

100 amino acid substitutions, about 50 to about 95 amino acid substitutions, about 50 to about 90 amino acid substitutions, about 50 to about 85 amino acid substitutions, about 50 to about 75 amino acid substitutions, about 50 to about 75 amino acid substitutions, about 50 to about amino acid substitutions, from about 50 to about 65 amino acid substitutions, from about 50 to about amino acid substitutions, from about 50 to about 55 amino acid substitutions, from about 60 to about

100 amino acid substitutions, from about 60 to about 95 amino acid substitutions, from about 60 to about 90 amino acid substitutions, from about 60 to about 85 amino acid substitutions, from about 60 to about 75 amino acid substitutions, from about 60 to about amino acid substitutions, from about 60 to about 65 amino acid substitutions, from about 70 to about

100 amino acid substitutions, about 70 to about 95 amino acid substitutions, about 70 to about 90 amino acid substitutions, about 70 to about 85 amino acid substitutions, about 70 to about 75 amino acid substitutions, about 70 to about 75 amino acid substitutions, about 80 to about

100 amino acid substitutions, about 80 to about 95 amino acid substitutions, about 80 to about 90 amino acid substitutions, about 80 to about 85 amino acid substitutions, about 90 to about 100 amino acid substitutions, about 90 to about 95 amino acid substitutions, or about 95 to about 100 amino acids.

One skilled in the art will appreciate that amino acids that are not conserved between wild-type CLRN1 proteins from different species can be mutated without loss of activity, while those amino acids that are conserved between wild-type CLRN1 proteins from different species cannot must mutate because they are more likely (than amino acids that are not conserved across species) to be involved in activity.

An active CLRN1 protein may comprise, for example, the sequence of a full-length wild-type CLRN1 protein (e.g., a human full-length wild-type CLRN1 protein) in which about 1 to about 100 amino acids, about 1 to about 95 amino acids, or about 1 to about 90 amino acids have been removed. amino acids, from about 1 to about 85 amino acids, from about 1 to about 80 amino acids, from about 1 to about 75 amino acids, from about 1 to about 70 amino acids, from about 1 to about 65 amino acids, from about 1 to about 60 amino acids, from about 1 to about 55 amino acids, from about 1 to about 50 amino acids, from about 1 to about 45 amino acids, from about 1 to about 40 amino acids, from about 1 to about 35 amino acids, from about 1 to about 30 amino acids, from about 1 to about 25 amino acids, about 1 to about 20 amino acids, about 1 to about 15 amino acids, about 1 to about 10 amino acids, about 1 to about 9 amino acids, about 1 to about 8 amino acids, about 1 to about 10 amino acids about 7 amino acids, about 1 to about 6 amino acids, about 1 to about 5 amino acids, about 1 to about 4 amino acids, about 1 to about 3 amino acids, about 2 to about 100 amino acids, about 2 to about 95 amino acids amino acids, from about 2 to about 90 amino acids, from about 2 to about 85 amino acids, from about 2 to about 85 amino acids

- 14 045887 about 80 amino acids, from about 2 to about 75 amino acids, from about 2 to about 70 amino acids, from about 2 to about 65 amino acids, from about 2 to about 60 amino acids, from about 2 to about 55 amino acids, from about 2 to about 50 amino acids, from about 2 to about 45 amino acids, from about 2 to about 40 amino acids, from about 2 to about 35 amino acids, from about 2 to about 30 amino acids, from about 2 to about 25 amino acids, from about 2 to about 20 amino acids, about 2 to about 15 amino acids, about 2 to 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 , from about 2 to about 5 amino acids, from about 2 to about 4 amino acids, from about 3 to about 100 amino acids, from about 3 to about 95 amino acids, from about 3 to about 90 amino acids, from about 3 to about 85 amino acids, from about 3 to about 80 amino acids, about 3 to about 75 amino acids, about 3 to about 70 amino acids, about 3 to about 65 amino acids, about 3 to about 60 amino acids, about 3 to about 55 amino acids, about 3 to about 50 amino acids, from about 3 to about 45 amino acids, from about 3 to about 40 amino acids, from about 3 to about 35 amino acids, from about 3 to about 30 amino acids, from about 3 to about 25 amino acids, from about 3 to about 30 amino acids 20 amino acids, about 3 to about 15 amino acids, about 3 to about 10 amino acids, about 3 to about 9 amino acids, about 3 to about 8 amino acids, about 3 to about 7 amino acids, about 3 to about 6 amino acids , from about 3 to about 5 amino acids, from about 4 to about 100 amino acids, from about 4 to about 95 amino acids, from about 4 to about 90 amino acids, from about 4 to about 85 amino acids, from about 4 to about 80 amino acids, from about 4 to about 75 amino acids, about 4 to about 70 amino acids, about 4 to about 65 amino acids, about 4 to about 60 amino acids, about 4 to about 55 amino acids, about 4 to about 50 amino acids, about 4 to about 45 amino acids, from about 4 to about 40 amino acids, from about 4 to about 35 amino acids, from about 4 to about 30 amino acids, from about 4 to about 25 amino acids, from about 4 to about 20 amino acids, from about 4 to about 15 amino acids, about 4 to about 10 amino acids, about 4 to about 9 amino acids, about 4 to about 8 amino acids, about 4 to about 7 amino acids, about 4 to about 6 amino acids, about 5 to about 100 amino acids , from about 5 to about 95 amino acids, from about 5 to about 90 amino acids, from about 5 to about 85 amino acids, from about 5 to about 80 amino acids, from about 5 to about 75 amino acids, from about 5 to about 70 amino acids, from about 5 to about 65 amino acids, about 5 to about 60 amino acids, about 5 to about 55 amino acids, about 5 to about 50 amino acids, about 5 to about 45 amino acids, about 5 to about 40 amino acids, about 5 to about 35 amino acids, from about 5 to about 30 amino acids, from about 5 to about 25 amino acids, from about 5 to about 20 amino acids, from about 5 to about 15 amino acids, from about 5 to about 10 amino acids, from about 5 to about 9 amino acids, about 5 to about 8 amino acids, about 5 to about 7 amino acids, about 6 to about 100 amino acids, about 6 to about 95 amino acids, about 6 to about 90 amino acids, about 6 to about 85 amino acids , from about 6 to about 80 amino acids, from about 6 to about 75 amino acids, from about 6 to about 70 amino acids, from about 6 to about 65 amino acids, from about 6 to about 60 amino acids, from about 6 to about 55 amino acids, from about 6 to about 50 amino acids, about 6 to about 45 amino acids, about 6 to about 40 amino acids, about 6 to about 35 amino acids, about 6 to about 30 amino acids, about 6 to about 25 amino acids, about 6 to about 20 amino acids, from about 6 to about 15 amino acids, from about 6 to about 10 amino acids, from about 6 to about 9 amino acids, from about 6 to about 8 amino acids, from about 7 to about 100 amino acids, from about 7 to about 95 amino acids, about 7 to about 90 amino acids, about 7 to about 85 amino acids, about 7 to about 80 amino acids, about 7 to about 75 amino acids, about 7 to about 70 amino acids, about 7 to about 65 amino acids , from about 7 to about 60 amino acids, from about 7 to about 55 amino acids, from about 7 to about 50 amino acids, from about 7 to about 45 amino acids, from about 7 to about 40 amino acids, from about 7 to about 35 amino acids, from about 7 to about 30 amino acids, about 7 to about 25 amino acids, about 7 to about 20 amino acids, about 7 to about 15 amino acids, about 7 to about 10 amino acids, about 7 to about 9 amino acids, about 8 to about 100 amino acids, from about 8 to about 95 amino acids, from about 8 to about 90 amino acids, from about 8 to about 85 amino acids, from about 8 to about 80 amino acids, from about 8 to about 75 amino acids, from about 8 to about 70 amino acids, about 8 to about 65 amino acids, about 8 to about 60 amino acids, about 8 to about 55 amino acids, about 8 to about 50 amino acids, about 8 to about 45 amino acids, about 8 to about 40 amino acids , from about 8 to about 35 amino acids, from about 8 to about 30 amino acids, from about 8 to about 25 amino acids, from about 8 to about 20 amino acids, from about 8 to about 15 amino acids, from about 8 to about 10 amino acids, from about 10 to about 100 amino acids, about 10 to about 95 amino acids, about 10 to about 90 amino acids, about 10 to about 85 amino acids, about 10 to about 80 amino acids, about 10 to about 75 amino acids, about 10 to about 70 amino acids, from about 10 to about 65 amino acids, from about 10 to about 60 amino acids, from about 10 to about 55 amino acids, from about 10 to about 50 amino acids, from about 10 to about 45 amino acids, from 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 15 to about 100 amino acids , from about 15 to about 95 amino acids, from about 15 to about 90 amino acids,

- 15 045887 from about 15 to about 85 amino acids, from about 15 to about 80 amino acids, from about 15 to about 75 amino acids, from about 15 to about 70 amino acids, from about 15 to about 65 amino acids, from about 15 to about 60 amino acids , from about 15 to about 55 amino acids, from about 15 to about 50 amino acids, from about 15 to about 45 amino acids, from about 15 to about 40 amino acids, from about 15 to about 35 amino acids, from about 15 to about 30 amino acids, from about 15 to about 25 amino acids, about 15 to about 20 amino acids, about 20 to about 100 amino acids, about 20 to about 95 amino acids, about 20 to about 90 amino acids, about 20 to about 85 amino acids, about 20 to about 80 amino acids, from about 20 to about 75 amino acids, from about 20 to about 70 amino acids, from about 20 to about 65 amino acids, from about 20 to about 60 amino acids, from about 20 to about 55 amino acids, from about 20 to about 50 amino acids, about 20 to about 45 amino acids, about 20 to about 40 amino acids, about 20 to about 35 amino acids, about 20 to about 30 amino acids, about 20 to about 25 amino acids, about 25 to about 100 amino acids , from about 25 to about 95 amino acids, from about 25 to about 90 amino acids, from about 25 to about 85 amino acids, from about 25 to about 80 amino acids, from about 25 to about 75 amino acids, from about 25 to about 70 amino acids, from about 25 to about 65 amino acids, about 25 to about 60 amino acids, about 25 to about 55 amino acids, about 25 to about 50 amino acids, about 25 to about 45 amino acids, about 25 to about 40 amino acids, about 25 to about 35 amino acids, from about 25 to about 30 amino acids, from about 30 to about 100 amino acids, from about 30 to about 95 amino acids, from about 30 to about 90 amino acids, from about 30 to about 85 amino acids, from about 30 to about 80 amino acids, about 30 to about 75 amino acids, about 30 to about 70 amino acids, about 30 to about 65 amino acids, about 30 to about 60 amino acids, about 30 to about 55 amino acids, about 30 to about 50 amino acids , from about 30 to about 45 amino acids, from about 30 to about 40 amino acids, from about 30 to about 35 amino acids, from about 35 to about 50 amino acids, from about 35 to about 45 amino acids, from about 35 to about 40 amino acids, from about 40 to about 100 amino acids, about 40 to about 95 amino acids, about 40 to about 90 amino acids, about 40 to about 85 amino acids, about 40 to about 80 amino acids, about 40 to about 75 amino acids, about 40 to about 70 amino acids, from about 40 to about 65 amino acids, from about 40 to about 60 amino acids, from about 40 to about 55 amino acids, from about 40 to about 50 amino acids, from about 40 to about 45 amino acids, from about 45 to about 50 amino acids, about 50 to about 100 amino acids, about 50 to about 95 amino acids, about 50 to about 90 amino acids, about 50 to about 85 amino acids, about 50 to about 80 amino acids, about 50 to about 75 amino acids , from about 50 to about 70 amino acids, from about 50 to about 65 amino acids, from about 50 to about 60 amino acids, from about 50 to about 55 amino acids.

In some embodiments, where two or more amino acids are deleted from the wild-type full-length CLRN1 protein sequence, at least two of the two or more deleted amino acids may be contiguous in the wild-type full-length protein sequence. In other examples, where two or more amino acids are deleted from the wild-type full-length CLRN1 protein sequence, some or all of the two or more deleted amino acids are not contiguous in the wild-type full-length protein sequence. One skilled in the art will appreciate that amino acids that are not conserved between full-length wild-type CLRN1 proteins from different species can be removed without loss of activity, while amino acids that are conserved between full-length wild-type CLRN1 proteins from different species should not be removed because they are more likely (than amino acids that are not conserved across species) to be involved in the activity.

In some examples, an active CLRN1 protein may, for example, a full-length CLRN1 protein from 1 to about 95 amino acids, from 1 to about 80 amino acids, from 1 to about 65 amino acids, from 1 to about 50 amino acids, from 1 to about 35 amino acids, from 1 to about 20 amino acids, from 1 to about 9 amino acids, from 1 to about 6 amino acids, wild type, which has from 1 to about 90 amino acids, from 1 to about 75 amino acids, from 1 to about 60 amino acids, from 1 to about 45 amino acids, 1 to about 30 amino acids, 1 to about 15 amino acids, 1 to about 8 amino acids, 1 to about 5 amino acids, contain a sequence of up to about 100 amino acids, 1 to about 85 amino acids, 1 to about 70 amino acids amino acids, from 1 to about 55 amino acids, from 1 to about 40 amino acids, from 1 to about 25 amino acids, from 1 to about 10 amino acids, from 1 to about 7 amino acids, from 1 to about 4 amino acids, from from from from from from from from from

1 to about 3 amino acids, about 2 to about 100 amino acids, about 2 to about 95 amino acids, near 2 before near 90 amino acids, from near 2 before near 85 amino acids, near 2 before near 80 amino acids, from near 2 before near 75 amino acids, near 2 before near 70 amino acids, from near 2 before near 65 amino acids, near 2 before near 60 amino acids, from near 2 before near 55 amino acids, near 2 before near 50 amino acids, from near 2 before near 45 amino acids, near 2 before near 40 amino acids, from near 2 before near 35 amino acids, near 2 before near thirty amino acids, from near 2 before near 25 amino acids, near 2 before near 20 amino acids, from near 2 before near 15 amino acids,

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from near 2 before near 10 amino acids, from near 2 before near 9 amino acids, from near 2 before near 8 amino acids, from near 2 before near 7 amino acids, from near 2 before near 6 amino acids, from near 2 before near 5 amino acids, from near 2 before near 4 amino acids, from near 3 before near 100 amino acids, from near 3 before near 95 amino acids, from near 3 before near 90 amino acids, from near 3 before near 85 amino acids, from near 3 before near 80 amino acids, from near 3 before near 75 amino acids, from near 3 before near 70 amino acids, from near 3 before near 65 amino acids, from near 3 before near 60 amino acids, from near 3 before near 55 amino acids, from near 3 before near 50 amino acids, from near 3 before near 45 amino acids, from near 3 before near 40 amino acids, from near 3 before near 35 amino acids, from near 3 before near thirty amino acids, from near 3 before near 25 amino acids, from near 3 before near 20 amino acids, from near 3 before near 15 amino acids, from near 3 before near 10 amino acids, from near 3 before near 9 amino acids, from near 3 before near 8 amino acids, from near 3 before near 7 amino acids, from near 3 before near 6 amino acids, from near 3 before near 5 amino acids, from near 4 before near 100 amino acids, from near 4 before near 95 amino acids, from near 4 before near 90 amino acids, from near 4 before near 85 amino acids, from near 4 before near 80 amino acids, from near 4 before near 75 amino acids, from near 4 before near 70 amino acids, from near 4 before near 65 amino acids, from near 4 before near 60 amino acids, from near 4 before near 55 amino acids, from near 4 before near 50 amino acids, from near 4 before near 45 amino acids, from near 4 before near 40 amino acids, from near 4 before near 35 amino acids, from near 4 before near thirty amino acids, from near 4 before near 25 amino acids, from near 4 before near 20 amino acids, from near 4 before near 15 amino acids, from near 4 before near 10 amino acids, from near 4 before near 9 amino acids, from near 4 before near 8 amino acids, from near 4 before near 7 amino acids, from near 4 before near 6 amino acids, from near 5 before near 100 amino acids, from near 5 before near 95 amino acids, from near 5 before near 90 amino acids, from near 5 before near 85 amino acids, from near 5 before near 80 amino acids, from near 5 before near 75 amino acids, from near 5 before near 70 amino acids, from near 5 before near 65 amino acids, from near 5 before near 60 amino acids, from near 5 before near 55 amino acids, from near 5 before near 50 amino acids, from near 5 before near 45 amino acids, from near 5 before near 40 amino acids, from near 5 before near 35 amino acids, from near 5 before near thirty amino acids, from near 5 before near 25 amino acids, from near 5 before near 20 amino acids, from near 5 before near 15 amino acids, from near 5 before near 10 amino acids, from near 5 before near 9 amino acids, from near 5 before near 8 amino acids, from near 5 before near 7 amino acids, from near 6 before near 100 amino acids, from near 6 before near 95 amino acids, from near 6 before near 90 amino acids, from near 6 before near 85 amino acids, from near 6 before near 80 amino acids, from near 6 before near 75 amino acids, from near 6 before near 70 amino acids, from near 6 before near 65 amino acids, from near 6 before near 60 amino acids, from near 6 before near 55 amino acids, from near 6 before near 50 amino acids, from near 6 before near 45 amino acids, from near 6 before near 40 amino acids, from near 6 before near 35 amino acids, from near 6 before near thirty amino acids, from near 6 before near 25 amino acids, from near 6 before near 20 amino acids, from near 6 before near 15 amino acids, from near 6 before near 10 amino acids, from near 6 before near 9 amino acids, from near 6 before near 8 amino acids, from near 7 before near 100 amino acids, from near 7 before near 95 amino acids, from near 7 before near 90 amino acids, from near 7 before near 85 amino acids, from near 7 before near 80 amino acids, from near 7 before near 75 amino acids, from near 7 before near 70 amino acids, from near 7 before near 65 amino acids, from near 7 before near 60 amino acids, from near 7 before near 55 amino acids, from near 7 before near 50 amino acids, from near 7 before near 45 amino acids, from near 7 before near 40 amino acids, from near 7 before near 35 amino acids, from near 7 before near thirty amino acids, from near 7 before near 25 amino acids, from near 7 before near 20 amino acids, from near 7 before near 15 amino acids, from near 7 before near 10 amino acids, from near 7 before near 9 amino acids, from near 8 before near 100 amino acids, from near 8 before near 95 amino acids, from near 8 before near 90 amino acids, from near 8 before near 85 amino acids, from near 8 before near 80 amino acids, from near 8 before near 75 amino acids, from near 8 before near 70 amino acids,

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from near 8 before near 65 amino acids, from near 8 before near 60 amino acids, from near 8 before near 55 amino acids, from near 8 before near 50 amino acids, from near 8 before near 45 amino acids, from near 8 before near 40 amino acids, from near 8 before near 35 amino acids, from near 8 before near thirty amino acids, from near 8 before near 25 amino acids, from near 8 before near 20 amino acids, from near 8 before near 15 amino acids, from near 8 before near 10 amino acids, from near 10 before near 100 amino acids, from near 10 before near 95 amino acids, from near 10 before near 90 amino acids, from near 10 before near 85 amino acids, from near 10 before near 80 amino acids, from near 10 before near 75 amino acids, from near 10 before near 70 amino acids, from near 10 before near 65 amino acids, from near 10 before near 60 amino acids, from near 10 before near 55 amino acids, from near 10 before near 50 amino acids, from near 10 before near 45 amino acids, from near 10 before near 40 amino acids, from near 10 before near 35 amino acids, from near 10 before near thirty amino acids, from near 10 before near 25 amino acids, from near 10 before near 20 amino acids, from near 10 before near 15 amino acids, from near 20 before near 100 amino acids, from near 20 before near 95 amino acids, from near 20 before near 90 amino acids, from near 20 before near 85 amino acids, from near 20 before near 80 amino acids, from near 20 before near 75 amino acids, from near 20 before near 70 amino acids, from near 20 before near 65 amino acids, from near 20 before near 60 amino acids, from near 20 before near 55 amino acids, from near 20 before near 50 amino acids, from near 20 before near 45 amino acids, from near 20 before near 40 amino acids, from near 20 before near 35 amino acids, from near 20 before near thirty amino acids, from near 20 before near 25 amino acids, from near thirty before near 100 amino acids, from near thirty before near 95 amino acids, from near thirty before near 90 amino acids, from near thirty before near 85 amino acids, from near thirty before near 80 amino acids, from near thirty before near 75 amino acids, from near thirty before near 70 amino acids, from near thirty before near 65 amino acids, from near thirty before near 60 amino acids, from near thirty before near 55 amino acids, from near thirty before near 50 amino acids, from near thirty before near 45 amino acids, from near thirty before near 40 amino acids, from near thirty before near 35 amino acids, from near 40 before near 100 amino acids, from near 40 before near 95 amino acids, from near 40 before near 90 amino acids, from near 40 before near 85 amino acids, from near 40 before near 80 amino acids, from near 40 before near 75 amino acids, from near 40 before near 70 amino acids, from near 40 before near 65 amino acids, from near 40 before near 60 amino acids, from near 40 before near 55 amino acids, from near 40 before near 50 amino acids, from near 40 before near 45 amino acids, from near 50 before near 100 amino acids, from near 50 before near 95 amino acids, from near 50 before near 90 amino acids, from near 50 before near 85 amino acids, from near 50 before near 80 amino acids, from near 50 before near 75 amino acids, from near 50 before near 70 amino acids, from near 50 before near 65 amino acids, from near 50 before near 60 amino acids, from near 50 before near 55 amino acids, from near 60 before near 100 amino acids, from near 60 before near 95 amino acids, from near 60 before near 90 amino acids, from near 60 before near 85 amino acids, from near 60 before near 80 amino acids, from near 60 before near 75 amino acids, from near 60 before near 70 amino acids, from near 60 before near 65 amino acids, from near 70 before near 100 amino acids, from near 70 before near 95 amino acids, from near 70 before near 90 amino acids, from near 70 before near 85 amino acids, from near 70 before near 80 amino acids, from near 70 before near 75 amino acids, from near 80 before near 100 amino acids, from near 80 before near 95 amino acids, from near 80 before near 90 amino acids, from near 80 before near 85 amino acids, from near 90 before near 100 amino acids, from about 90 before about 95 amino acids or

from about 95 to about 100 amino acids deleted from its N-terminus, and/or from 1 to 100 amino acids (or any of the subranges of this range described herein) deleted from its C-terminus.

In some embodiments, the active CLRN1 protein may, for example, comprise a full-length wild-type CLRN1 protein sequence inserted with 1 to 50 amino acids, 1 to 45 amino acids, 1 to 40 amino acids, 1 to 35 amino acids, 1 to 30 amino acids, from 1 to 25 amino acids, from 1 to 20 amino acids, from 1 to 15 amino acids, from 1 to 10 amino acids, from 1 to 9 amino acids, from 1 to 8 amino acids, from 1 to 7 amino acids, from 1 to 6 amino acids, from 1 to 5 amino acids, from 1 to 4 amino acids, from 1 to 3 amino acids, from about 2 to 50 amino acids, from about 2 to 45 amino acids, from about 2 to 40 amino acids, from about 2 to 35 amino acids, from about 2 to 30 amino acids, about 2 to 25 amino acids, about 2 to 20 amino acids, about 2 to 15 amino acids, about 2 to 10 amino acids, about 2 to 9 amino acids,

- 18 045887 from about 2 to 8 amino acids, from about 2 to 7 amino acids, from about 2 to 6 amino acids, from about 2 to 5 amino acids, from about 2 to 4 amino acids, from about 3 to about 50 amino acids, from about 3 to 45 amino acids, about 3 to 40 amino acids, about 3 to 35 amino acids, about 3 to 30 amino acids, about 3 to 25 amino acids, about 3 to 20 amino acids, about 3 to 15 amino acids, about 3 to 10 amino acids, about 3 to 9 amino acids, about 3 to 8 amino acids, about 3 to 7 amino acids, about 3 to 6 amino acids, about 3 to 5 amino acids, about 4 to 50 amino acids, about 4 to 45 amino acids , from about 4 to 40 amino acids, from about 4 to 35 amino acids, from about 4 to 30 amino acids, from about 4 to 25 amino acids, from about 4 to 20 amino acids, from about 4 to 15 amino acids, from about 4 to 10 amino acids, from about 4 to 9 amino acids, from about 4 to 8 amino acids, from about 4 to 7 amino acids, from about 4 to 6 amino acids, from about 5 to 50 amino acids, from about 5 to 45 amino acids, from about 5 to 40 amino acids, from about 5 to 35 amino acids, about 5 to 30 amino acids, about 5 to 25 amino acids, about 5 to 20 amino acids, about 5 to 15 amino acids, about 5 to 10 amino acids, about 5 to 9 amino acids, about 5 to 8 amino acids, about 5 to 7 amino acids, about 6 to 50 amino acids, about 6 to 45 amino acids, about 6 to 40 amino acids, about 6 to 35 amino acids, about 6 to 30 amino acids, about 6 up to 25 amino acids, from about 6 to 20 amino acids, from about 6 to 15 amino acids, from about 6 to 10 amino acids, from about 6 to 9 amino acids, from about 6 to 8 amino acids, from about 7 to 50 amino acids, from about 7 to 45 amino acids, about 7 to 40 amino acids, about 7 to 35 amino acids, about 7 to 30 amino acids, about 7 to 25 amino acids, about 7 to 20 amino acids, about 7 to 15 amino acids, about 7 to 10 amino acids, about 7 to 9 amino acids, about 8 to 50 amino acids, about 8 to 45 amino acids, about 8 to 40 amino acids, about 8 to 35 amino acids, about 8 to 30 amino acids, about 8 to 25 amino acids , from about 8 to 20 amino acids, from about 8 to 15 amino acids, from about 8 to 10 amino acids, from about 10 to 50 amino acids, from about 10 to 45 amino acids, from about 10 to 40 amino acids, from about 10 to 35 amino acids, from about 10 to 30 amino acids, from about 10 to 25 amino acids, from about 10 to 20 amino acids, from about 10 to 15 amino acids, from about 15 to 50 amino acids, from about 15 to 45 amino acids, from about 15 to 40 amino acids, from about 15 to 35 amino acids, about 15 to 30 amino acids, about 15 to 25 amino acids, about 15 to 20 amino acids, about 20 to 50 amino acids, about 20 to 45 amino acids, about 20 to 40 amino acids, about 20 to 35 amino acids, about 20 to 30 amino acids, about 20 to 25 amino acids, about 25 to 50 amino acids, about 25 to 45 amino acids, about 25 to 40 amino acids, about 25 to 35 amino acids, about 25 up to 30 amino acids, from about 30 to 50 amino acids, from about 30 to 45 amino acids, from about 30 to 40 amino acids, from about 30 to 35 amino acids, from about 35 to 50 amino acids, from about 35 to 45 amino acids, from about 35 to 40 amino acids, about 40 to 50 amino acids, about 40 to 45 amino acids, or about 45 to about 50 amino acids.

In some examples, 1 to 50 amino acids (or any subrange thereof) can be inserted as a contiguous sequence into the sequence of the full-length wild-type protein. In some examples, 1 to 50 amino acids (or any subrange thereof) are inserted at multiple non-contiguous locations within the sequence of the full-length wild-type protein. As can be understood from the prior art, from 1 to 50 amino acids can be inserted into a portion of the wild-type full-length protein sequence that is not highly conserved across species.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as would normally be understood by one of ordinary skill in the art to which this invention relates. This document describes methods and materials for use in this invention; other suitable methods and materials known in the art may also be used. Materials, methods and examples are for illustrative purposes only and are not restrictive. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, this description, including definitions, will control.

Other features and advantages of the present invention will become apparent from the following detailed description and figures, as well as from the claims.

Brief description of graphic materials

In fig. 1 is an exemplary schematic representation of the genetic map of the CLRN-1 vector (SEQ ID NO: 40; 3397 base pairs (bp)), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), T2A sequence (SEQ ID NO: 31 ), CLRN1 isoform 2 (SEQ ID NO: 6), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. Figure 2 shows a typical schematic representation of a genetic map of a vector

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CLRN-2GFP(SEQ ID NO: 41; 4177 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), T2A sequence (SEQ ID NO: 31 ), CLRN1 isoform 2 (SEQ ID NO: 6), T2A sequence (SEQ ID NO: 31), eGFP (SEQ ID NO: 32), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 3 is an exemplary schematic representation of the genetic map of the CLRN-3 vector (SEQ ID NO: 42; 4607 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), 5UTR-291, CLRN1 isoform 1 (SEQ ID nO: 1), 3'-UTR -1357 (SEQ ID NO: 36), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 4 is an exemplary schematic representation of the genetic map of the CLRN-4 vector (SEQ ID NO: 43; 4796 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), T2A sequence (SEQ ID NO: 31 ), CLRN1 isoform 2 (SEQ ID NO: 6), 3UTR-1406 (SEQ ID NO: 37), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 5 is an exemplary schematic representation of the genetic map of the pITR-CBA-5'UTR-tGFP-3'UTR (5026 bp) vector, which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), 5UTR-291, tGFP (SEQ ID NO: 19), 3UTR-1595, poly( A) bGH signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 6 is an exemplary schematic representation of the genetic map of the CLRN-6eGFP vector (SEQ ID NO: 44; 4756 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), eGFP (SEQ ID NO: 32), 3UTR-1406 (SEQ ID NO: 37) , bGH poly(A) signal (SEQ ID NO: 20) and ITRAAV2.

In fig. 7 is an exemplary schematic representation of the genetic map of the pITR-CBA-3'UTR-600A (3982 bp) vector, which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 4), T2A sequence (SEQ ID NO: 31 ), CLRN1 isoform 2 (SEQ ID NO: 6), 3UTR-600 (SEQ ID NO: 27), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 8 is an exemplary schematic representation of the genetic map of the CLRN-8 vector (SEQ ID NO: 46; 3982 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), T2A sequence (SEQ ID NO: 31 ), CLRN1 isoform 2 (SEQ ID NO: 6), 3UTR-600B (SEQ ID NO: 28), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 9 is an exemplary schematic representation of the genetic map of the CLRN-9 vector (SEQ ID NO: 47; 3982 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), T2A sequence (SEQ ID NO: 31 ), CLRN1 isoform 2 (SEQ ID NO: 6), 3UTR-600C (SEQ ID NO: 29), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 10 is an exemplary schematic representation of the genetic map of the CLRN-0 vector (SEQ ID NO: 39; 4732 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), 3'UTR 1773 (SEQ ID NO : 15), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 11 is an exemplary schematic representation of the genetic map of the CLRN-7eGFP vector (SEQ ID NO: 45; 3580 bp), which can be used in any of the present methods described herein. The vector contains the AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), eGFP sequence (SEQ ID NO: 32), bGH poly(A) signal. (SEQ ID NO: 20) and ITR AAV2.

In fig. 12 is a typical schematic representation of the CLRN-10 genetic map (SEQ ID NO: 48; 3511 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 4), HA sequence (SEQ ID NO: 34 ), FP sequence (SEQ ID NO: 30), T2A sequence (SEQ ID NO: 31), CLRN1 isoform 2 (SEQ ID NO: 5), 3xFLAG tag sequence (SEQ ID NO: 35), bGH poly(A) signal (SEQ ID NO: 20) and ITR AAV2.

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In fig. 13 is an exemplary schematic representation of the genetic map of the CLRN-10myc vector (SEQ ID NO: 49; 3574 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), myc sequence (SEQ ID NO: 33 ), FP sequence (SEQ ID NO: 30), T2A sequence (SEQ ID NO: 31), 3xFLAG tag sequence (SEQ ID NO: 35), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR .

In fig. 14 is an exemplary schematic representation of the genetic map of the CLRN-10NF vector (SEQ ID NO: 50; 3499 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), T2A sequence (SEQ ID NO: 31 ), HA sequence (SEQ ID NO: 34), CLRN-1 isoform 2 (SEQ ID NO: 5), 3xFLAG tag sequence (SEQ ID NO: 35), bGH poly(A) signal (SEQ ID NO: 20) and ITR AAV2.

In fig. 15 is an exemplary schematic representation of the genetic map of the CLRN-11 vector (SEQ ID NO: 51; 4908 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), HA sequence (SeQ ID NO: 34 ), FP sequence (SEQ ID NO: 30), T2A sequence (SEQ ID NO: 31), CLRN-1 isoform 2 (SEQ ID NO: 5), 3xFLAG tag sequence (SEQ ID NO: 35), 3UTR-1406 ( SEQ ID NO: 37), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 16 is an exemplary schematic representation of the genetic map of the CLRN-11myc vector (SEQ ID NO: 52; 4971 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), myc sequence (SEQ ID NO: 33 ), FP sequence (SEQ ID NO: 30), T2A sequence (SEQ ID NO: 31), CLRN1 isoform 2 (SEQ ID NO: 5), 3xFLAG tag sequence (SEQ ID NO: 35), 3UTR-1406 (SEQ ID NO: 37), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 17 is an exemplary schematic representation of the genetic map of the CLRN-11NF vector (SEQ ID NO: 53; 4896 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 1 (SEQ ID NO: 1), HA sequence (SEQ ID NO: 34 ), T2A sequence (SEQ ID NO: 31), CLRN1 isoform 2 (SEQ ID NO: 5), 3xFLAG sequence (SEQ ID NO: 33), 3UTR-1406 (SEQ ID NO: 37), bGH poly(A) signal (SEQ ID NO: 20) and ITR AAV2.

In fig. 18 is an exemplary schematic representation of the genetic map of the CLRN-12 vector (SEQ ID NO: 54; 4640 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), 5UTR-291 sequence (SEQ ID NO: 12), CLRN1 isoform 1 (SEQ ID NO : 1), HA sequence (SEQ ID NO: 34), 3UTR-1357 (SEQ ID NO: 36), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 19 is a typical schematic representation of the genetic map of the CLRN-13 vector (SEQ ID NO: 55; 4291 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 4 (SEQ ID NO: 7), 3xFLAG tag sequence (SEQ ID NO: 35), T2A sequence (SEQ ID NO: 31), CLRN1 isoform 1 (SEQ ID NO: 1), HA sequence (SEQ ID NO: 34), 3UTR-600 (SEQ ID NO: 27), poly(A)- bGH signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 20 is an exemplary schematic representation of the genetic map of the CLRN-14 vector (SEQ ID NO: 56; 4192 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 4 (SEQ ID NO: 7), T2A sequence (SEQ ID NO: 31 ), CLRN1 isoform 1 (SEQ ID NO: 1), 3UTR-600 (SEQ ID NO: 27), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 21 is an exemplary schematic representation of the genetic map of the CLRN-15 vector (SEQ ID NO: 57; 3505 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 4 (SEQ ID NO: 7), 3xFLAG tag sequence (SEQ ID NO: 35), 3'UTR-600 (SEQ ID NO: 27), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. Figure 22 shows a typical schematic representation of the genetic map of the CLRN-16 vector

- 21 045887 (SEQ ID NO: 58; 3439 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, chimeric intron (SEQ ID NO: 16), CLRN1 isoform 4 (SEQ ID NO: 7), 3UTR-600 (SEQ ID NO: 27), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 23 is an exemplary schematic representation of the genetic map of the CLRN-17 vector (SEQ ID NO: 59; 130 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, sh chimeric intron (SEQ ID NO: 26), 5UTR-291 (SEQ ID NO: 12), CLRN1 isoform 1 (SEQ ID NO: 1), HA sequence (SEQ ID NO: 34), 3UTR-1773 (SEQ ID NO: 15), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 24 is an exemplary schematic representation of the genetic map of the CLRN-18 vector (SEQ ID NO: 60; 4277 bp), which can be used in any of the present methods described herein. Vector contains AAV2 ITR, CMV enhancer (SEQ ID NO: 17), chicken β-actin promoter, sh chimeric intron (SEQ ID NO: 26), CLRN1 isoform 1 (SEQ ID NO: 1), 3UTR-1773 (SEQ ID NO: 15), bGH poly(A) signal (SEQ ID NO: 20) and AAV2 ITR.

In fig. 25 shows an immunoblot image of CLRN1 protein levels from transfected HEK293FT cells 48 hours post-transfection using anti-HA and anti-FLAG antibodies. Track 1 - PageRuler Plus Prestained; lane 2 - CLRN-10 (denaturation at 37°C);

lane 3 - CLRN-11 (denaturation at 37°C); lane 4 - CLRN-12 (denaturation at 37°C); lane 5 - negative control; lane 6 - CLRN-10 (denaturation at 56°C);

lane 7 - CLRN-11 (denaturation at 56°C); lane 8 - CLRN-12 (denaturation at 56°C); Lane 9 - negative control. The CLRN-1 isoform protein is a glycosylated protein and often migrates in smeared bands.

In fig. 26 shows an immunoblot image of CLRN1 protein levels from transfected HEK293FT cells 48 hours after transfection using an anti-FLAG antibody. Track 1 - PageRuler Plus Prestained; lane 2 -CLRN-10; track 3 - CLRN-11; track 4 - CLRN-12; lane 5 - CLRN-13; track 6 - CLRN-15; Lane 7 - negative control.

In fig. 27 shows an immunoblot image of CLRN1 protein levels from transfected HEK293FT cells 48 hours post-transfection using an anti-FLAG antibody. Track 1 - PageRuler Plus Prestained; lane 2 -CLRN-10; track 3 - CLRN-10NF;

lane 4 - CLRN-10myc; track 5 - CLRN-PNF; lane 6 - CLRN-11myc;

Lane 7 - negative control. All samples were stored at room temperature.

In fig. 28 shows an immunoblot image of CLRN1 protein levels from transfected HEK293FT cells 48 hours after transfection using an anti-myc antibody. Track 1 PageRuler Plus Prestained; lane 2 -CLRN-10; track 3 - CLRN-10NF; lane 4 - CLRN-10myc; track 5 - CLRN-PNF; lane 6 - CLRN-11myc; Lane 7 - negative control.

In fig. 29 shows an immunoblot image of CLRN1 protein levels obtained from transfected HEK293FT cells 48 hours post-transfection using anti-HA and anti-FLAG antibodies. Track 1 - PageRuler Plus Prestained; track 2 - CLRN-13; track 3 - CLRN-10; track 4 - CLRN-10NF; lane 5 - CLRN-10myc; lane 6 - CLRN-11NF; lane 7 - CLRN-11myc; lane 8 - negative control.

In fig. 30 shows an immunoblot using rabbit polyclonal anti-CLRN antibody (EKIANYKEGTYVYKTQSEKY; SEQ ID NO: 38) for CLRN1 isoform 1 protein levels obtained from HEK239FT cells transfected with the plasmids described herein at 48 hours post-transfection. Track 1 - PageRuler Plus Prestained; track 2 - CLRN-10; lane 3 - CLRN-1; track 4 - CLRN-2; track 5 - CLRN-3; track 6 - CLRN-4; Lane 7 CLRN-8; track 8 - CLRN-9; track 9 - CLRN-10; track 10 - CLRN-11; track 11 - CLRN-12; track 12 - CLRN-13; Drozhka 13 - CLRN-14; track 14 - CLRN-15; track 15 - CLRN-16; lane 16 - negative control; Lane 17 - negative control.

In fig. 31 shows an immunoblot image of CLRN1 protein levels obtained from transfected HEK293FT cells 48 hours post-transfection using rabbit polyclonal anti-CLRN antibodies. Track 1 - PageRuler Plus Prestained; lane 2 - Anc80-CLRN-0; lane 3 - Anc80-CLRN-0 + APGase F; Lane 4: Anc80-CLRN-3; lane 5 - Anc80-CLRN-3 + APGase F; lane 6 - Anc80-CLRN-6eGFP; lane 7 - Anc80-CLRN-6eGFP+PNGase F; Lane 8 - Anc80CLRN-13; lane 9 - Anc80-CLRN-13 + APGase F; track 10 - without vector; Lane 11 - without vector + PNGase F. The CLRN-1 isoform protein is a glycosylated protein and often migrates in the form of smeared bands (lanes 2, 4 and 8). After treatment with APGase F, the smeared bands disappeared and shifted to separate bands (lanes 3, 5, and 8).

In fig. Figure 32 shows a set of immunofluorescence images of HEK293FT cells transduced with AAVanc80-CLRN6eGFP obtained 24 hours and 48 hours after transfection at MOI 8.41E+04 and MOI 2.53E+05, respectively.

- 22 045887

In fig. 33 is a histogram showing the relative expression of CLRN1 and GFP in HEK293FT cells transduced with AAVanc80-CLRN-6eGFP (at MOI 1.05E+05 and MOI 3.15E+05), AAVanc80-CLRN-0 (at MOI 8.23E+04 and MOI 2.47E+05), AAVAnc80-CLRN-3 (at MOI 8.41E+04 and MOI 2.53E+04) and AAVanc80-CLRN-13 (at MOI 8.33E+04 and MOI 2.50E+05), respectively.

In fig. Figure 34 is a histogram showing the relative expression of CLRN1 and GFP in P2 cochlear explants from WT mice infected for 16 hours with AAVanc80-CLRN-6eGFP (at MOI 2.0E+05), AAVanc80-CLRN-0 (at MOI 2.5E+ 05 and MOI 7.6E+0.5), AAVanc80-CLRN-3 (at MOI 2.0E+05 and 6.03E+05) and AAVAnc80-CLRN-13 (at MOI 2.0E+05 and MOI 6.0E+05), respectively.

In fig. Figure 35 shows a set of fluorescent images through P2 cochlear explants from WT mice infected for 72 hours with 1.3E10 VG (viral genomes) AAVanc80-CLRN-0/snail, 9.9E9 VG AAVanc80-CLRN-3/snail, and 1.0E10 VG AAVanc80-CLRN -13/cochlea showing Myo7a and DAPI staining.

In fig. 36 shows a set of fluorescent images of P2 cochlear explants from WT mice infected for 72 hours with 1E09 rv AAVAnc80.CAG.eGFP.3UTR/cochlea showing eGFP, Myo7a and DAPI staining.

Detailed description of the invention

Deficiencies or mutations in clarin 1, a protein encoded by the CLRN1 gene, cause hearing and vision loss. For example, mutations in CLRN1 lead to Usher syndrome type III and retinitis pigmentosa.

Provided herein are compositions that contain at least two different nucleic acid vectors, wherein: each of the at least two different vectors contains a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions contains at least 30 amino acids residues in length, wherein the amino acid sequence of each encoded portion may not necessarily partially overlap with the amino acid sequence of another encoded portion; no vector from at least two different vectors encodes the full-length CLRN1 protein; at least one of the coding sequences contains a nucleotide sequence spanning two consecutive exons of the CLRN1 genomic DNA and not having an intron sequence between the two consecutive exons; and when introduced into a mammalian cell, the at least two different vectors undergo homologous recombination with each other, thereby generating a recombined nucleic acid that encodes the full-length CLRN1 protein.

As used herein, compositions that contain a single nucleic acid vector, wherein the vector contains one or both of (i) 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 contain a nucleotide sequence spanning two consecutive exons of the CLRN1 genomic DNA, and do not have an intronic sequence between two consecutive exons.

Provided herein are compositions that contain two different nucleic acid vectors, wherein: the first nucleic acid vector of the two different nucleic acid vectors contains a promoter, a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located at the 3' end of the promoter , and a splice donor sequence located at the 3' end of the first coding sequence; and a second nucleic acid vector of two different nucleic acid vectors comprises a splice acceptor sequence, a second coding sequence that encodes a C-terminal portion of the CLRN1 protein located at the 3' end of the splice acceptor sequence, and a polyadenylation signal sequence at the 3' end of the second coding sequence sequences; wherein each of the encoded parts has a length of at least 30 amino acid residues, and the amino acid sequences of the two encoded parts do not overlap with each other; however, neither of the two different vectors encodes the full-length CLRN1 protein; and when introduced into a mammalian cell, splicing occurs between the splice donor sequence and the splice acceptor sequence, thereby generating a recombined nucleic acid that encodes the full-length CLRN1 protein.

Provided herein are compositions that contain two different nucleic acid vectors, wherein: the first nucleic acid vector of the two different nucleic acid vectors contains a promoter, a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located at the 3' end of the promoter , a splice donor sequence located at the 3' end of the first coding sequence, and a first detectable marker gene located at the 3' end of the splice donor sequence; and a second nucleic acid vector of two different nucleic acid vectors comprises a second detectable marker gene, a splice acceptor sequence located at the 3' end of the second detectable marker gene, a second coding sequence that encodes the C-terminal portion of the CLRN1 protein located at the 3' end end of the splice acceptor sequence, and a polyadenylation signal sequence located at the 3' end of the second coding sequence; wherein

- 23 045887 each of the encoded parts has a length of at least 30 amino acid residues, and the amino acid sequences of the encoded parts do not overlap with each other; however, neither of the two different vectors encodes the full-length CLRN1 protein; and when introduced into a mammalian cell, splicing occurs between the splice donor sequence and the splice acceptor sequence, thereby generating a recombined nucleic acid that encodes the full-length CLRN1 protein.

Also provided herein are compositions that contain two different nucleic acid vectors, wherein: the first nucleic acid vector of the two different nucleic acid vectors contains a promoter, a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located 3' to the promoter, a splice donor sequence located at the 3' end of the first coding sequence, and a recombinogenic region of phage F1 located 3' to the splice donor sequence; and a second nucleic acid vector of two different nucleic acid vectors comprises a recombinogenic region of phage F1, a splice acceptor sequence located at the 3' end of the recombinogenic region of phage F1, a second coding sequence that encodes the C-terminal portion of the CLRN1 protein located at the 3' end end of the splice acceptor sequence, and a polyadenylation signal sequence located at the 3' end of the second coding sequence; wherein each of the two encoded parts has a length of at least 30 amino acid residues, and the amino acid sequences of the two encoded parts do not overlap with each other; however, neither of the two different vectors encodes the full-length CLRN1 protein; and when introduced into a mammalian cell, splicing occurs between the splice donor sequence and the splice acceptor sequence, thereby generating a recombined nucleic acid that encodes the full-length CLRN1 protein.

Provided herein are methods that include administering to the cochlea of a mammal a therapeutically effective amount of any of the compositions described herein.

Provided herein are methods for increasing the expression of full-length CLRN1 protein in a mammalian cell, which include introducing any of the compositions described herein into a mammalian cell.

Provided herein are methods of increasing the expression of full-length CLRN1 protein in an inner hair cell, an outer hair cell, or both cells in the cochlea of a mammal, which comprises administering to the cochlea of a mammal a therapeutically effective amount of any of the compositions described herein.

Provided herein are methods of increasing the expression of full-length CLRN1 protein in the eye of a mammal, which comprise intraocular administration into the eye of the mammal of a therapeutically effective amount of any of the compositions described herein.

Provided herein are methods of treating hearing loss in a subject who has been identified as having a defective CLRN1 gene, which comprises administering a therapeutically effective amount of any of the compositions described herein to the cochlea of the subject.

Also provided herein are methods of treating vision loss in a subject who has been identified as having a defective CLRN1 gene, which comprises administering a therapeutically effective amount of any of the compositions described herein to the eye of the subject.

Additional non-limiting aspects of the compositions, kits and methods are described herein and may be used in any combination without limitation.

CLRN1.

The CLRN1 gene encodes clarin 1 (CLRN1), a protein that is expressed in the hair cells of the inner ear (eg, inner ear hair cells, outer ear hair cells) and the retina.

The human CLRN1 gene is located on chromosome 3q25.1. It contains 7 exons spanning ~47 kilobase pairs (kb) (Vastinsalo et al. (2011), Eur. J. Hum. Genet. 19(1):30-35; NCBI accession number NG 009168.1 ).

Various mutations in the CLRN1 genes have been associated with Usher syndrome type III (eg, Usher syndrome type IIIA (MIM #606397) (see, e.g., Fields et al. (2002), Am. J. Hum. Genet. 71:607- 617 and Joensuu et al. (2001), Am. J. Hum. Genet. 69:673-684) and retinitis pigmentosa (see, for example, Khan et al. (2011), Ophthalmology, 118:1444-1448). Mutations , which cause Usher syndrome type III, are predominantly found in exon 3 of CLRN1. Usher syndrome type III with deafness can be modeled by generating CLRN1-deficient mice (see, for example, Geng et al. (2017), Sci. Rep. 7(1 :13480) Exemplary CLRN1 mutations associated with Usher syndrome type III include T528G, M12OK, M44K, N48K, and C40G.

Exemplary CLRN1 mutations associated with retinitis pigmentosa include L154W and P31L (see, eg, Khan et al. (2011), Ophthalmology, 118:1444-1448).

Additional exemplary mutations in the CLRN1 gene that have been found in subjects with hearing loss and methods for sequencing the nucleic acid encoding CLRN1 are described, e.g.

- 24 045887 measures, in Fields et al. (2002), Am. J.Hum. Genet. 71:607-617, Joensuu et al. (2001), Am. J.Hum. Genet. 69:673684, Adato et al. (2002), Europ. J.Hum. Genet. 10: 339-350, Aller et al. (2004), Clin. Genet. 66:525-529. Methods for detecting mutations in a gene are well known in the art. Non-limiting examples of such methods include real-time polymerase chain reaction (RT-PCR), PCR, sequencing, Southern blotting and Northern blotting.

An exemplary human wild-type CLRN1 protein is or includes the sequences SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, and SEQ ID NO: 7. Non-limiting examples of nucleotide sequences encoding a wild-type CLRN1 protein are or include SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 and SEQ ID NO: 8.

In some embodiments, any of the compositions described herein, the CLRN1 protein contains a sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identical to SEQ ID NO: 1.

In some embodiments, any of the compositions described herein, the CLRN1 protein contains a sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identical to SEQ ID NO: 3.

In some embodiments, any of the compositions described herein, the CLRN1 protein contains a sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identical to SEQ ID NO: 5.

In some embodiments, any of the compositions described herein, the CLRN1 protein contains a sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identical to SEQ ID NO: 7.

Wild-type human CLRN1 protein isoform D (SEQ ID NO: 1):

MPSQQKKIIFCMAGVFSFACALGVVTALGTPLWIKATVLCKTGALLVNASGQEL DKFMGEMQYGLFHGEGVRQCGLGARPFRFSFFPDLLKAIPVSIHVNVILFSAILIVLTMV GTAFFMYNAFGKPFETLHGPLGLYLLSFISVALWLPATRHQAQGSCGCLVMILFASEVKI HHLSEKIANYKEGTYVYKTQSE KYTTSFWVIFFCFFVHFLNGLLIRLAGFQFPFAKSKDA ETTNVAADLMY wild-type human CLRN1 isoform D cDNA (SEQ ID NO: 2):

atgccaagc caacagaaga aaatcatttt ttgcatggcc ggagtgttca gttttgcatg tgccctcgga gttgtgacag ccttggggac accgttgtgg atcaaagcca ctgtcctctg caaaacggga gctctgctcg tcaatgcctc agggcaggag ctggacaagt ttatgggtga aatgca gtac gggcttttcc acggagaggg tgtgaggcag tgtgggttgg gagcaaggcc ctttcggttc tcattttttc tcattttttc cagatttgct caaagcaatc ccagtgagca tccacgtcaa tgtcattctc ttctctgcca tccttattgt gttaaccatg gtggggacag ccttcttcat gtacaatgct tt tggaaaac cttttgaaac tctgcatggt cccctagggc tgtacctttt gagcttcatt tcagttgccc tttggctgcc agctaccagg caccaggctc aaggctcctg tggctgtctt gtcatgatat tgtttgcctc tgaagtgaaa atccatcacc tctcagaaaa aattgcaaat tataaagaag ggacttatgt ctacaaaacg caaagtgaaa aatataccac ctcattctgg gtcattttct tttgcttttt tgttcatttt ctgaatgggc tcctaatacg acttgctgga tttcagttcc ct tttgcaaa atctaaagac gcagaaacaa ctaatgtagc tgcagatcta atgtactga

Wild-type human CLRN1 protein isoform A (SEQ ID NO: 3):

MPSQQKKIIFCMAGVFSFACALGVVTALGTPLWIKATVLCKTGALLVNASGQEL DKFMGEMQYGLFHGEGVRQCGLGARPFRFSFFPDLLKAIPVSIHVNVILFSAILIVLTMV GTAFFMYNAFGKPFETLHGPLGLYLLLSFISGSCGCLVMILFASEVKIHHLSEKIANYKEGT YVYKTQSEKYTTSFWVIFFCFF VHFLNGLLIRLAGFQFPFAKS KDAETTNVAADLMY

- 25045887 wild-type human CLRN1 isoform A cDNA (SEQ ID NO: 4):

atgccaagc caacagaaga aaatcatttt ttgcatggcc ggagtgttca gttttgcatg tgccctcgga gttgtgacag ccttggggac accgttgtgg atcaaagcca ctgtcctctg caaaacggga gctctgctcg tcaatgcctc agggcaggag ctggacaagt ttatgggtga aatgca gtac gggcttttcc acggagaggg tgtgaggcag tgtgggttgg gagcaaggcc ctttcggttc tcattttttc tcattttttc cagatttgct caaagcaatc ccagtgagca tccacgtcaa tgtcattctc ttctctgcca tccttattgt gttaaccatg gtggggacag ccttcttcat gtacaatgct tt tggaaaac cttttgaaac tctgcatggt cccctagggc tgtacctttt gagcttcatt tcaggctcct gtggctgtct tgtcatgata ttgtttgcct ctgaagtgaa aatccatcac ctctcagaaa aaattgcaaa ttataaagaa gggacttatg tctacaaaac gcaaagtgaa aaatatacca cctcattctg ggtcattttc ttttgctttt ttgttcattt tctgaatggg ctcctaatac gacttgctgg atttcagttc ccttttgcaa aatctaaaga cgcagaaaca actaatgtag ctg cagatct aatgtactga

Wild-type human CLRN1 protein isoform C (SEQ ID NO: 5):

MQALQQQPVFPDLLKAIPVSIHVNVILFSAILIVLTMVGTAFFMYNAFGKPFETLH GPLGLYLLLSFISGSCGCLVMILFASEVKIHHLSEKIANYKEGTYVY

KTQSEKYTTSFWLTKGHS wild-type human CLRN1 isoform C cDNA (SEQ ID NO: 6):

atgcaggc cctgcagcag caaccagttt ttccagattt gctcaaagca atcccagtga gcatccacgt caatgtcatt ctcttctctg ccatccttat tgtgttaacc atggtgggga cagccttctt catgtacaat gcttttggaa aaccttttga aactctgcat ggtcccctag ggctgtacct tttgag cttc atttcaggct cctgtggctg tcttgtcatg atattgtttg cctctgaagt gaaaatccat cacctctcag aaaaaattgc aaattataaa gaagggactt atgtctacaa aacgcaaagt gaaaaatata ccacctcatt ctggctgact aaaggccaca gctga

Wild-type human CLRN1 protein isoform E (SEQ ID NO: 7):

MPSQQKKIIFCMAGVFSFACALGVVTALGTPLWIKATVLCKTGALLVNASGQEL DKFMGEMQYGLFHGEGVRQCGLGARPFRFSCYFLDPFMGLPTGVPHLLSLPCSTSCRRE HTSERVQEPAGCFSAVRSKLHAGPAAATSFSRFAQSNPSEHPRQCHS LLCHPYCVNHGGDSLLHVQCFWKTF human isoform E cDNA Wild type CLRN1 (SEQ ID NO: 8):

atgccaagc caacagaaga aaatcatttt ttgcatggcc ggagtgttca gttttgcatg tgccctcgga gttgtgacag ccttggggac accgttgtgg atcaaagcca ctgtcctctg caaaacggga gctctgctcg tcaatgcctc agggcaggag ctggacaagt ttatgggtga aatgca gtac gggcttttcc acggagaggg tgtgaggcag tgtgggttgg gagcaaggcc ctttcggttc tcatgctatt ttcttgaccc cttcatgga ctcccaacag gggtacccca tttactcagc ctgccctgct caacctcttg caggagggag cacacgagtg aacgagtgca ggaaccagct ggctgcttta gtgctgtgag gagtaaactc catgcaggcc ctgcagcagc aaccagtttt tccagatttg ctcaaagcaa tcccagtgag catccacgtc aatgtcattc tcttctctgc catccttatt gtgttaacca tggtggggac agccttcttc atgtacaatg cttttggaaa accttttga

Genomic sequence of wild type human CLRN1 (SEQ ID NO: 9):

aggagatact tgaaggcagt ttgaaagact tgttttacag attcttagtc caaagatttc 61 caattaggga gaagaagcag cagaaaagga gaaaagccaa gtatgagtga tgatgaggcc 121 ttcatctact gacatttaac ctggcgagaa ccgtcgatgg

- 26 045887 tgaagttgcc ttttcagctg 181 ggagctgtcc gttcagcttc cgtaataaat gcagtcaaag aggcagtccc ttcccattgc 241 tcacaaaggt cttgtttttg aacctcgccc tcacagaagc cgtttctcat catgccaagc 301 caac agaaga aaatcatttt ttgcatggcc ggagtgttca gttttgcatg tgccctcgga 361 gttgtgacag ccttggggac accgttgtgg atcaaagcca ctgtcctctg caaaacggga 421 gctctgctcg tcaatgcctc agggcaggag ctggacaagt ttatgggtga aatgca gtac 481 gggcttttcc acggagaggg tgtgaggcag tgtgggttgg gagcaaggcc ctttcggttc 541 tcatgtaagt agcaattgca tttgagttat ttaatgcttt aggcagactc ttcccagtgt 601 tgcgaggaat tatatttgag aattttgccg tgtttactgc aggacttttt aaatcggtgt 661 gaaccatatg aaaaacctat gactctgagc aatttcttct tcctagtttt tattatttta 721 tactt gcttt ttattataat atagagttaa ttcattgtta cataattaag gtttttggaa 781 atattggcaa ttaagatgct taagtattaa tatttatgta aaaaattatg gagtcttttt 841 aaaaaagtaa acttggggaa ataggaaagc tgtaaagaat gatctttatg ctttttgtt c 901 tttataaaaa gaaccaaggt catgggctcc gtatttaacc aggttgccac ctttctcatg 961 attttgtttc ctgctcccca ctccctccca ttattcctgc taagaccttt cctgctgcta 1021 aatattcagt tttcattttt aactaatttg gaatcatttg gctatagaaa tttaaaatga 1081 tctgctgtgc taactgggaa agaaatggat gcctatttag tatagaacat tttaaactga 1141 ttgacctgca aatcatgtag agaatatgag agagattttc ttgttgtgat ttttgtgaaa 1201 tggaagtgta atccacagta tttataacct gtttatctta agaagagaat ttttaaaaat 1261 taccatgtga ataggcaact cattaaatga aaattaatag gaagtcattt gttatatctc 1321 ttacaaca ca cattcagaag ttattattat ttcagaaggg ctggtttgga acaaccttat 1381 gaagacacag tcagtaaatt actgcataaa tcactcttca ggaaaggagg ttaccaactg 1441 aagcatttaa aatgaattat tattttgccc aggttttttt tttctttcta gtataggtag 1501 aaggctaaat taattgaatt tattattaac atatgcagtg cctaattaaa tttcagtgct 1561 ggtctattta tatttctgca acattcctta tat cttctta gcagtcattg gacaccaacc 1621 ttcagctcac ataggttact aagtgatatg aattttcata gggctccaga aaatttccaa 1681 gaattggttg ttagcttttt aattgatgaa gtggatacca gttcttttca ctgaatggct 1741 tttattcatt aaggtaatgg ggctgtt aga gttgcttagt tttcctgggg aaggggaagg 1801 aagaaaacaa agcagaatgt catgtgatat gcaactgtat taaaaaaccg aaaaggaaaa 1861 aagttgagag agatgattta accgtgagtc accggcagcc aaagcgtgag taaagcttct 1921 cacagatgaa tttagacaaa agcggagaag gtactggtga attttctgga gcctttacat 1981 tttctacagt gaaatggaga taaactttac t catgccata ggacatgttt caaaacaata 2041 ataagatgtt ttctgaacac ttactacata ctaagcactt tatatgcttt gtctcattta 2101 atccttacac agccacattc ttctggggtt tagcgaatga tttttgtggt tgtgtcctat 2161 gcttgtcctg tctaaggatg aagttgttct aattgggtgc ccctcctttt gctttctgtg 2221 aggacttgca gaactggtgg ggtttaaaca gtaccctcac ttatctcaca gaatttcatt 2281 agctcccaga tacccctgac attctccccc tagcctagtg aagaaaatct tccatttact 2341 tgttcattct gcagtgacag ctccatcaat atacaataga ctatacatat taagtgtact 2401 gtatatacta tacatgttaa aaatctcatt cattttggtg aggcccagct aagaatactt 2461 acagtagagc tttttttttt ttcctaagca taaaagtatc tttttcaatg cagcatgaga 2521 cagagttggg aaaaccaaaa taaatagatc caatggactc cccaaagagg ataatattca 2581 tttaaataaa cacccctctc agtgttaaaa ctttctaatc aa catgcctt tgggacacat 2641 tgcaccctca aagtttacac tcccattgca acgcagcttt gtggttcacg ttttttccat 2701 tcagaatgtc attaccctgt caatgatgtt tcatcaacgt ttgcttggat gagaatcctc 2761 tgatattctt cctgatagaa atgtataagc cctgttcata taaatgaata aaagatctaa 2821 ccttactttc tcagtagtgg cttccttgga gcaaaaagca gggacctcca gagagct cag 2881 gtggatgact cttttctgtt tcttccagag ctcaacttac aattagtgca caattcattt 2941 cccagaatgt cttctttctt attgtgcctt tagaaagtta ttaagcaaac atttgaattc 3001 acagaatctt accagtgtaa gaggaatgga aaaggtaact tatcaaggta acaatcactt 3061 cgtggccagt tttttcggct cactgcaact acccctcctg ggttcaagcg attctcctgc 3121 ctcagcctcc caagtagctg ggactacagg cgtgcaccac catgcccagc taattttttt 3181 tttgtatttt tagtaaagac agggtttcac catgtgggcc aggctggtct catggcaagt 3241 tttctttgtg ttgtcatgtt attatcaatt aataggaatt tatatttcag ttctgttagg 330 1 tggataaaca ctattttgca tacctaaatg tttcatttat atcagcactg gccaataaaa 3361 atatactata agcaggccgg gtgcagtggc tcacgcctgt aatcccaact

- 27 045887 tttgggaggc 3421 caacactttg ggaggacaca gggtcaggag atcgagacca tcctggctaa cctggtgaaa 3481 tcccgtctct actaaaata caaaaaatta gccgggcgtg gcgggggcgc ctgtagtccc 3541 agctacttgg gaggctga gg caggagaatg gcacgaaccc gggaggtgga gcttgcagtg 3601 agccgagatc tcgccactgc actccagcct tggtgacaga gcaagactct gtctcaaaaa 3661 aaaaaaaaaa aaaaaaaaaa aaaaaatata tatatatata tatatattac aagccacaag 3721 ccacat atgt acttttaaat gtcctagtag ccatattaga aaacaaaagt aaaaaggaat 3781 agatgaaatt aattttaatg atttttttaa acccaagata tccaaaatat tatcatttta 3841 acatataatt aaaaatttat tgagatgttt tacattgttt ttttttttct tgacgctgtc 3901 ttggaaatct agagtgtatt ttacatttac attacatcta attcagtcta gccacatttc 3961 acatgctcat ttttttg tgt gtggttttat ggagcagaga gtttaatagg caagaaagaa 4021 aagagaaggc agaagaaaat ggctcccctg tacagagacg cgggggtggg gcgctccaaa 4081 gccaaaagag gaggtcccta agtatggtag acaccagcca ggaatatatg cagtgtctgg 4141 aggaggggat g tctgatttg catagggtca catgctcatt tttatggcta ctgtattggt 4201 cagtacagat ttagatgggg atttgctctg aacaagttgg tgattgatgg tgttcatatt 4261 ttaattgaat ttttcctggg ttctgctgta cacttgtatg tgtgttagtt tcatgtgcaa 4321 tgcttgtgtc acttttaaaa cccagatata tggcataaca tgagaatgaa aaatggacca 4381 gaaaaatagt ttggcaatgt a gtcatgttt gttcctatta aatgttccct attgaccact 4441 ctatctcttt taattataac aagaatctgc cctgccagca tgcccagtta cgctgggaaa 4501 acttctgcct catttactct ggctgattct catccactta tgggtcagtg gttcattttc 4561 tagaggtcac cagcat tcat acctagcata caatttcatt cattataatg aaggaatgtt 4621 ttcccttcaa agagacacaa ctagtgggct taatttttct tgatatgtca cctgtaaaat 4681 tttaatgatg atgtttaaac tctaaatgta gccatcaaga caaaaactgc aaattttgag 4741 cctcagtgtg tgtgggtggg tttctgtttc ggtaatttga aacattgcag aatatcatca 4801 aaatatgata cccaagaatc atatggtatc aatcat tcct agatatactg atctattcat 4861 tgccaagata gttcaatgag ctggcaaaaa catatggaat tattttctta aaatgtgaaa 4921 aataaaattt aaccaatcat gtatcacagc ttgcaacttt agtcatactt tgaaaagcat 4981 tttaatttgg acctcatgat tgaaaattta taa aaagctg aacagaaatt agttcacttc 5041 atattttaga aaagcagagt ttctttacta aatgaggcat ttgacccaaa ttggagagaa 5101 aatgttgaaa ctacttctgt gagcaagcag gtggcttctc aaacacatgt tgggatgaaa 5161 tggttgggcc tcagggtctc agtgcctgtc actgagagtt ggcactctct atctccatgg 5221 tctcctccaa gtgtgactct tgtctcttgc tgacctgacc tgccccaagt gactcactgg 5281 tcatgaccct gcacaccttg cgtctctcct atcaccctgc cgatggcaga gctacaaagg 5341 tctttgatgt agctctgtct gatatcctgt gtttccccct atggtctgtg tggaagcagg 5401 tatgggggtg tgtaaagggg aagcctat ga agttcatctg caaagactac ctggttaggg 5461 gaggagagga agaagctata tgcaccattt caccagcaag catgggctct tctgcctttt 5521 agcttagggg tcctgttgtc tagtctcact cacctattaa aacagtccag caaatagagg 5581 ttttgtttac ctcccattaa aaaaaaagca attaatggaa tagaagataa taatgtatga 5641 gaagcactat tgtgaaagaa aaaccttcaa cttctctcag ccaaataatt gcttcc tcct 5701 ctgtccttcc cagaccttga tgtttgctct attatttcaa aacaactata ttataaatat 5761 ttgagaatgt gtatttccct gcaaggagat cttaatcccc aagaaggcag gagctgtgta 5821 ttattcatcc cagtgctcct tcaaaccagg gcctcagaca gtgcatggcc caaagaggta 5881 cttaataaac gtttggtaaa ctgacactat tgaaattaag caacctggat ttgaggtggg 5941 tctctgccac tcacaagaga ttacgctttg agaaaattcc atcacttcat tgattttcag 6001 ttcttgcatc tgtatatggg agacgatact aggtgatttc tgacatctct caccgtttaa 6061 atgctctgtg atctatacaa cgaggggctc gctgttctag acaagttcct tccagcttta 6121 ca gttgcata acccttctaa tcttagtcac atgatgactc cactgacaga tttttggcca 6181 ccatcattag acatgctgag ttacgtgtgc ctttgctctg atcctcaaaa ctcatgattt 6241 ttaaagtttt ctgaaatatc taccatttat caggatccag atggatttca tgaccaaagt 6 301 ggatgtttct tttctctccc attacaatct tttacttttt gtgtgggaaa ttgcatgtta 6361 aagaaaggga aattgaagaa tgggatgctt tggaattctg gcaagatgga ttagtgggtt 6421 ccagaaagta ggggcagcca caaataccga aataaatgag atcgtattat tgagaaagca 6481 caaatggaag aaggtcaaaa gcaagaagaa gctgacatcc tgcttcctcc aatttttgct 6541 ttctctgttt tt ccaagaaa ctcctcttcc

- 28 045887 aagccttgct gaaaaactcc actttcctaa 6601 atctaacttc ttaaactgat aatggcaaga agttaggaat gaccaatatg tttaacactc 6661 caagagtatt tgttttgttt tgttttgaga ctgggtctca ctctgtcgtc cagcctggag 67 21 tgcagtggtg tgatcacagc tcactgcagc cttgacctct cctgcccaag gaatcctccc 6781 acctcagcct cctgagtaga agggaccaca ggcatgtgcc actacacctg gctaactttt 6841 aaaaaatttt tttgtagaga tggggttgcc caggcaggtc tcaaactgct g ggctcaagc 6901 aatcctcctg cattggcctc ccaaagtgct ggaattatgg gcataagcca ctacgcctga 6961 cctctccaag ggcattcttt acccagaaga ggaacttggc agaacttatc ctccaattgg 7021 tgaggaatat ggagaaaatg actttaagca aaggaacttc tggttctgcc tacctaatcc 7081 agaaaaagaa gttttatttc tcccttcccc tagtaactat cttcccatat tcacataaaa 7141 aagtacagaa t caacattgt tcaagaatta taattttact tgtaagcaca tgtgcacacg 7201 cacacccata taccttcctt ccctttaaat catcccacac cctaatagta gtaaaatcat 7261 tgacccgagc atacctggga gaggaagagg agtctgacag gggcaggttc taagtggcac 7321 tcctggaact taaccctggt gtatatgaac tttacctatt gaaggatgac tcctcaactg 7381 ttctcacaat ttgctgctct gctttctttt ctaatttctg aaggtgactc atcttcccca 7441 aggactttca gacttctcag aagaaaaaaa tattgggtgg gtctctgcca ctggcaaaag 7501 attagacttt gagaatcata aaagtatatc agtatatact cattaatatt gaattactat 7561 aattaatatt atgatattga tata atgata gaatgatatt gataaaagca atattcaata 7621 atgaatatta tttcagctgc ccacttattg ggtgcctcat aggtgccagg cattttgtat 7681 gtattatcta caacccttac atgggacata ttatgatgct gtttctcttg aagaaatatg 7741 gaaactggaa acagagaggt caccaca att ttccaaagtc acatagctaa taggtagcag 7801 acttgggatt caaattcata tgcatatggt aaatcatgct cttcctctgc tacattttgc 7861 ccccttagaa tatgaaaaag ggatacaaag agatgaagaa aatatgtaag attatccttc 7921 aatttcacta tcttttttaa agtttttttt attatacttt aaattctgaa atacatgtgc 7981 agaacatgca ggtttgttac ataggtatac acgtgccatg atggtttgtt gcacccatca 8041 acctgtcatc tacattaggt atttttccta atgctatccc tcccctagtc ccccacccac 8101 cgacaagccc cggtgtgtga tattcccctc cctgtgtcca tgtgttctca ttgttcaact 8161 cccacttatg agtgagaaca tgcggtgttt ggttttctgt tcctgcgtca gtttgctgag 8221 aatgatggtt tccagcttca ttcatgttcc tgcaaaaggc atgaactcat tttatggctg 8281 cataccattc tatggtatac atgtgccaca ttttcttaat ctagtctatc attgatgggc 8341 atttggctta gttccaagtc cttgctattg tgaacagtgc tgcaataaac atatgtgggc 8401 atatgtcttt atagtagaat gatttataat cctttg ggta tagacccagt aatgggattg 8461 ctgggtcaaa tggcatttct ggttctaggt ccttcaggaa ttgccacact gtcttccaca 8521 atagctgaac tagtttacac tcccaccaac agtgtaaaag cgttcctatt tctccacatc 8581 ctctccaaca tctgttgctt cctgacttt t taatgattgc cattctaatt ggagtgagat 8641 ggtatctcag tgtggttttg attagcattt ctttaatgac aagtgatgat gagctttttt 8701 tcatgtttgt tggccgtata aatgtcttct tttgagaagt gtccgttcat atcctttgcc 8761 cactttttaa cggggttttt tcttgtaaat ttgtttaact tccttgtaga ttctggatat 8821 tagtcctttg tcagatgggt agatt gcaaa aattttcttc cattctgcag gttgcccgtt 8881 cactctgata atagtttctt ttgctgcgca gaagtttttt tagtttaatt agatcccatt 8941 tgtcaatttt ggcttttgtt gccattgctt ttggtgttta gtcatgaagt ctttgcccac 9001 gcctatgtcc tgaatggtaa tgcctaggtt ttcttctagg atttttatgg ttttaggtct 9061 tatgtttaaa tctttaatcc atcttgagtt aatttttgta taaggtataa ggaaggggtc 9121 cagtttagtt ttctgcatat ggctagccag ttttcccaac accatttatt aaatagggaa 9181 tcctttcccc gttgcttgtt tttgtcaggt ttgtcaaaga gcagatggtt gtagatgtgt 9241 ggcattattt ctgaggcctc tgttctgttt cattggtct c tgtatctgtt ttgatacaag 9301 taccatgctg ttttggttac tgtagacttg tagtataatt tgaagtcagg tagcgtaata 9361 cctccagttt tgttcttttt gcttaggatt gtcttgacta ttcaggctct tttttggttc 9421 catatgaaat ttaaagtagt tttttc taat tctgtgaaga aagtcaatgg tagcttgatg 9481 ggaaaagcat tgaatctata agttactttg ggcagtatgg ccattttcat gatattaatt 9541 cttcctatcc gtgagcatgg aatgtttttc catttgtttg tgtcctttct tatttccttg 9601 agcagtagtt tgtagttctc cttgaagagg tccatcacat cccttgtaag ttgtattcct 9661 aggtattttg ttctctttgt agcaattgtg aatggaagtt c actcataag tttgctctct 9721 gtttgtctgt tattggtgta taggaatgct tgtgattttt gcacattgat tttgtatcct 9781 gagactttgc cgaagttgct tatcagctta

- 29 045887 aggagattt gggctgagac gacagggttt 9841 tctaaatata caatcatctc atctgcaaac agagacaatt tgacttcctc tcttcctatt 9901 tgaatacgct ttatttcttt ctcttgcctg tttgccctgg ccagaacttc caatactgtg 9961 ttgaata gga gtgttcacca cctattttaa gaatagtatt gaagcctcac aaaagctggt 10021 tctcatgtaa ccatctgaga atatttggcc ttatgacttg aattcattca ttgccttttt 10081 atttcacatt ttagtgatcc tgatgtctaa atcttaatct ttgatccttg caaggtaaaa 10141 tagccaagtc aagcctgttt aataatattg gttgaggaag tcacatgctt atgatcaatc 10201 tttgggttat gtaattatat taccttaatg ttggcagttt aggtgtaagg cagagatatc 10261 tgatcacatg tgtggttagc taatttaaga tcactgccaa ctaaaatctt catggtatga 10321 tcttcaaagt tagctacttt gaccacagca atgatttcac cacagcaatt aacaaaatgg 10381 cagact cttt cctgaggtgg catgaacagt tttaaaacaa agtcaaggac caaaagaaaa 10441 gcaggcacat ggcatttgat tcatttcaaa aactagtatt gtattaagag ccaaggggat 10501 agaattgtag catcaattaa aatcttgttt gaaaaaaaat aaaaacaaac gtccatttt t 10561 atctctcaaa tatattaggg ttttcataaa gttataggtg tatttttaaa aaaacaaaac 10621 tcatatacat tagactgaaa aatttgcctg tcatctcatc atgcagctaa atgcaattgt 10681 ctatggcgag atacactctt attagaggta tgatagcact aactaatagc aaactttgta 10741 cctggtagtc taatttatgc agggttcata tttcgctccc tctcagcatg ctgtaactgt 10801 ggcaaag cca ttctcaggag ttattacccc aacataatca tacccctgtg gattaggagc 10861 agttaaatgg gtcctgttat cagagacaca tatgtgccac agccgctgtc atccctaagc 10921 caccgtgggt gattaagact cactgatggg actacctctg aataggcttg agtgaggtgg 10981 atacacttca gctgagagaa attcaggtaa ggggctgaga aaatcagatt ttgaatggtt 11041 ttatcatacc atcaggtctc cttttaagtg ctggggtcat ggatttcatt caacctgacc 11101 acatagcctt tggaagcttg gctcaatacc tgagtgtgag attatgggtg atattaaagg 11161 agatgaatgc attgagctga tgtcagagaa tgtcttttac tggattttca taatgactgg 11221 ctgcagatgg gctga gggga aagtcagatc aagagcattt ctgtaagaag aaagaaatct 11281 tccctcttat tctctttcaa gaaaatgaat agctgagcac caagaggcca aatacttttt 11341 taaaaaacac atccttttat gtagagaagg acaggttgag acgaaaaaca ggacctctga 11401 a actgtcttt atagctttaa tctaggaaga aattgcggca ccattgctga catcattatc 11461 agaggctgcc ttagttctga gagcttcaca gatggccttt tctgcatttt acatctggcc 11521 agatgaaggc aaaaaggttg atgaaaccaa aactattaga tcagtggtcc ataactctgg 11581 ctgcacttta gaatcatctg gggagtcctt aaaactactg atcctgaggc tccatcccag 11641 accaattgaa tcaggatctc tggggtggg acctgagcat tggaatgctt taaaagttcc 11701 tcagggactc taatgtgcag ccaaggctga gaatgactga ggtggatggt ggccaagaca 11761 ggtgaggcca agagttagaa gcccttactg ttagggaagg cagaagccac aaggaggagg 11821 ggaggggaa ggagcagt at ttagcatttc ttccacacag ttggggggtt ttctgatcaa 11881 aattaggctg ggatctttcg cttccatttt catgaaggtc ttatgctttg tccacagcca 11941 cctggcctca gggcaatgag caatctgatt gatgaatttt cagtaagaaa ctgagcacac 12001 ttggctctca gccccagtgg cttcccctgt ttccaaatct gcccaccagt tacaggagcc 12061 tgctcaccaa ctggttgggt taaagaagtc ggctctgt cc ttggcaggga ggccttcagc 12121 tgtctggccc tgtctgtgac tgcgtgggtg aagctgccta atttggggaa cttgatggaa 12181 gatctaagct atgttctcta acagttttat cagaaataaa gttaactttt gacctccatc 12241 tgcctgtctc ctgtggaagg gctctgctcc ttccaaagag actctcaggg gttctcctta 12301 gaggtgtgtt atcagtccaa agatcatttt agaccagcca ttacagagga tgtccaagaa 12361 attgcacaag ggaaatagaa gtaagaatga gagcaatata tcagatagta aggaaagtat 12421 gtgactggtt tcaaataagt aattaaccat aaatccaaag ttcctgcatt agttatagca 12481 atagtcatcc acctggtcag gaaaaaaaaa gtaaaagact gagctgcaag at agaaagtt 12541 tgcctgaatt ccacgtactt caaggactac tatggaggat tccttggtcc caatgcagag 12601 acatgtactc tgaccaccca tgggccaaat ccctcttacc caccctcagt gattcctcct 12661 gggacctcac tacattgagt tcttacattc cccactcttt tcgggggaa a tataaccctt 12721 ctgctcttct catgatgtta aaaatattta gacaattact taaaatttac aacaatcttc 12781 cacataaatg atctcactta tgtttcttgt gagctctgtg atttatttct attatcatct 12841 atgctgatag ttaaggaaac tgagatatcg agaccaacat gcatagtaaa tggcaaaacc 12901 agatgaattt taaactttcc

- 30 045887 taactccaaa agccacatcc tgcccaaccc gccatgctgc 12961 cgctcagtta atgcctggct gtttgtctcc ccattggccc ctctacccat tgtgctttga 13021 tggcacactg tattccaact gcctgagact cctggttaat gccattacgt acagacttag 1308 1 gttgaattta ctaggatttt taagatttgt aggataagag atatgactgt tagactggaa 13141 tcagcaatag ataaaaggtt aacaaagttt cagaataaaa tataatagaa aaccccagca 13201 gatagaagta aaatgaatgg taagacaact gaaatgaaag ccatacattt agaaatatca 1326 1 aataaaacac agattaatgg cagacaataa aggaacatac ttagcagtta gtaaaaacac 13321 tttttacctt attcttatta ccctccagta accttttttt tttttttttt tgagacaaag 13381 tctcgctgtg tcgtccaggc tggagggtag tgatgtgatc tcggctcact gcaacttctg 13441 cctcttgggc tgaagagatt ctcctgcccc agcctcctga g tagctggga ctataggggc 13501 ccatcactgc acctggctaa tttttgtatt tttagtagag acggggtttc accatgttgg 13561 ccaggctggt cttgaactcc tggcctcagg tgatccaccc gcctcagcct cccaaagtgc 13621 tgagattaca agcgtgagcc accaagcccg gctgtaacct attgaaaata acattacttg 13681 acatgtgaga caaattattt gtaagttaaa gagtttatgt gccttcaatg ctcccaccct 13741 tccctcccct aaaaagatta ttgagtgccc atgatgtgcc taagccttct ggtagactct 13801 gagaatgtga agagagttag aggatacttg ttcaacaacc cagaatctag cagaagtgtt 13861 ttgaaatgac cagccacttg ggagagctat gctagcatat cattcaggat gggctgggtc 13921 atgttttaat aacaagtaag tttgaacttt ataggtttga aacaaaaaag atgtgtttct 13981 tgctcacagt tcatattttt tggagattgg ctggagcttc attccaggat actgccacca 14041 tctggaatgt tgacagttac cgtaacagag aaagagttgt ggaggctgtc ac actggcaa 14101 ttaaattcgc tgacctggaa ctgacacatg ccacctccac ttatatttta ttggccaagg 14161 cttgttacac agccacatct aacttcagag aggtcaagat gagcaaatcc taccacgagc 14221 tatagatgga tgagtagcac tcattattat cacaattatt ttatttgtta taaaaactcc 14281 aagaaggaga ggtactctat gtgaggaata ggcataggaa aatcagaggg aagttcttaa 14341 agatgagcta gatttc acta gatggcattg aagaaacatt ccaagtaaat gaacagcata 14401 agcaaatgca tgaagaactt attgtggtcc tagtacagac gatgcgtgag agtgtggagg 14461 agggaaaagg taagactgga gaggaaggca ggaaccagaa caggacagac tgtgttcact 14521 gtcaggca gt taagtctatc ttgtaggcaa catgaagcct tttaaggaag gcaagcagct 14581 atgtgacagg acagaagatg gattggaaga aaatcaaaag agaagtgggg accagtcata 14641 aggctcctcc aatatttggg gatccaaacc aaagcactgg cagagaaata gaaaggaagg 14701 gaaatatttc caaaatattc aaaacagaaa ccaagagaac ttgatgacag aagatgaacc 14761 caggtttcta ctgaatggac ag ttgttaca ttctctgaga taaggaatac agaaggaaaa 14821 agttgagagg gaatatgaaa ttatttttaa tcatgtttaa tttgatcact tgtggaacat 14881 caaccagaga tgtccatcag ttacaccaat ttgtaggttt tgagagaggc ctgaggtaga 14941 ggcaga gaag tgggaatcag cagattagcg gcagtagttg gaaccataac tgaagatgag 15001 atttcccagg gaggggagtt gaacaggaag gtagacaaag gctgagtgca gtggctcata 15061 cctgtaatcc cagcactttg ggaggctgca gtgggtagat cacaaacaag atcaggagtt 15121 caagaccagc ctggccaaca tggtgaaacc ccgtctctac taaaaaaaca caaaaattag 15181 ccgggcgtgg tggcacacac ttg taatccc agcctcagga ggctgaggca ggagaattgc 15241 ttgaacccgg gaggcagagg ttgcagtgag ccaagatcgt gccattgcac tccagcctgg 15301 gcgacagagc gagactccgt ccccaccgac cccctaaaaa agaaagtaga caaagatgtg 15361 tcctagaa aa cactaatatg aatgggtaga gaggggagac ttgtcaagga gatcgagggg 15421 agagtcagtg aggtgaaacc ttagaggata gaccttcacc aaggaagtaa cagtcaacag 15481 gcctaaatgc cacagagatg tcaaatgaga gacactggaa atggttcttt gaatattaca 15541 gccagaacat cacaggagac catttccaaa gcagtcttga tgaagtggtg gggaagggag 15601 gtccctgaag gagctaagga gggactggga gatcatgacc cagagata ag tgttgcaggt 15661 ataaaaggga aagactgaga tcaggaaata gccacaggat ccctaaggcc aggcttcggg 15721 tggggtggtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tataaaatgg gaagaccttg 15781 agtataattc tgtactaaga agatagagca gtagagagga aaaggctgaa gacagatggg 15841 agggtaaata gtgaattaga aaggtctgtg caaagatgag aaaggatgag tctgaaagca 15901 cagggaag ggccagcctt ggacaggaga aaacatttct ttcactaaga

- 31 045887 ataaagggaa 15961 ggttggggtat acaccacaaa gaaggtgtag atgggtggca atggagttct gtcaagttga 16021 gggcattcca tgatagcctc acctttctct gtgaaatgag agagtttagt ttacaagata 16081 tttctgagca cttcat aagc caggttcata gactgaaaga agtggaggtg gagtgtgata 16141 ggtccttaag aataggggaa gtttggaata tctgacaagg gacagagagg aaaaaactag 16201 aaaaggcttt gcagaatgtg ggcccacaga tcagaggcta aggggtcccc atttgtgcag 1626 1 gagagtaagg gcagggaggc aaggctcaca gcccaaaata tagagcccct caccaaatga 16321 ctgcaggagg gcagctttcc tatgagagca tccctatcac tgttttcact ccgagtcatt 16381 aacttacgac ttactcagct ctgtttcgta atagcagact cgagtaatga gggtatgaca 16441 gcctctctct gcatgccaag gtatgcagcg tggatttcct ttttcgcttt ctctctcctg 16501 tggcttaggt gccttctgtt ctgctaccag gatagagaac ccagtgacta gtttcttcta 16561 gctctctttt tctgactagg tatcttgtca gaaatttctg cttaccagac ttcatggaga 16621 gggaatcaag ctttgaatca gggttgaaaa agtagagctt aatatatata ttacaaaatg 1 6681 ccactcacgt tcttgaggtt accttgtatc tataccacaa ctagcattct tttagaaagc 16741 accattaccg aagtaatccc tttcctggga attcacccaa aaaggttatt cccacttatc 16801 ccccatctcc aaaataaaaa agaaaaatgt gtgtgcttag agatgttcct ggaagcatga 16861 gctgtaatac tgaaccaata gaagacgaac taacagattg cagggcatcc gtttggcaaa 16921 aaacttatgc agttatctaa at gatagtta tgaagacaat atgtataaca cattatattc 16981 tgagtgaaaa gaacagaagg tgatttcaaa actgcattgg gataatagta atataggaaa 17041 tagtgagatg aacaaagatt tcaaaggaac aaaaataaag aaaaattttg ctttttatat 17101 tggtaggcgt atgg gtgaaa ttccaatttt aattttaatt tcatagttat aaaattgttc 17161 ataaaaaaag gtcccccata gacagttggg ctttgggaca aactaacaga aacagagtag 17221 gaagaaaatt catcttcctt caatcccctt tctctgctta aaacaaaaca aaaaagagct 17281 ttgtcatgtt caggtgtgca acgaattctt tttccaaatc tggaacttta catctgctat 17341 taaacaggag tcagtttcca tgtaacatgt tgaca atccc ccaagtgtgt tggaataatt 17401 ttttttaatg aggagatttg aaattccatt tcaattgcca acctgcctct ttcaacttct 17461 aaaaacaaag taaaacaaaa caaaaacaca ctgggtccta tcaccccctc ttgctactac 17521 tattttatct ccattgcc ct gaattctttc caaacttctt tccacccagc tttgatttgt 17581 tttcagtcgg gtttattgag gcataattta cgtacagtaa aattcatcct tcttagattt 17641 agaggtctat gcattttgac taatgcatat tggcttataa tgactaccac aacaaagata 17701 tagaacacac ccatcactcc cgggttctcc ctgtcccttt tttggtccat ctcctctcct 17761 acccccaacc ccttggcaac cactgatctg ttttctgtcc ttatcatttt gctttttcca 17821 ggatgttgta tataaggaat catgcagcat gcagcctctc gagtctgact tcttccagtt 17881 agcacagtta tttaagatct atccgagtta ttgtgagtag cagcatcttt tttattgctg 17941 actagtattt catcacatgg atgggccaca acttgtttat ct gttcacct gtcaatggat 18001 actaagttgt ttccagtttt tggcaaatat gaataaagta aacatttgca tacagatttt 18061 tgtgtggaca catgttttca attctcttag gtaaatactg agcaatggga ttgctgggtt 18121 atatgttaag tctatgttca gttttctaag ttctgaaaca attggatatc tatatgcaaa 18181 aatacaaaat taaccttgac tcaaacttgt accatacaca aaaaataacc tgaaagagat 18241 cacaggtgta aatgtaaacc tagaactaaa aacttcaagg agagaaacat agcagaaaat 18301 atttgtgacc ttgcattagg caaagacttc ttagatttga catttgaaac atgatacata 18361 aaaaatcttg ataaattgga gttcataaaa ataagaacta ct cttcaaaa gacactgata 18421 agagaatgaa aatacaagcc acagacagag aaaatatttg tgaatttctt atctgataaa 18481 gggtttgtat ccagcatgca taaagacttt tcaaaactca ataataaaca atccaataag 18541 aaatgcacaa aagatacaaa cacatcatcg aaaatgacct atgaaaggca aataagccca 18601 caaaaaaatt ctcaacatca ttagacactt gggaaatgca aattaaaaca acactgagat 18661 aaactac ata tctattaaat ggctaccact ttaaaaacct gtcaagtgcc agccagaatg 18721 tggaacaagt aggactctct tacattgcta gtgggaaggt gaatggtaca gccactttgg 18781 aaaacactcc gcagcttctt atagttacac ataggacctg ggggtagagg atggattgac 18841 tg taaagggg caaaacttcc tggtaggggt ggggaaagtt tttagaaggg tgaaattgtt 18901 ctatatcttg attattgtgg tggttacaca actgtctgca tttgtcaaaa ctcacagaac 18961 tgtacactaa aaaggtatat ttttatgctc tgctaatttt actttaatct taaaaatagg 19021 aaggaaaaaa taaaatcaat gccactgtgc

- 32 045887 gactttgggc aagttacttc acttctctgt 19081 gccttggtct tttgaaatct atacattaag gataaaataa taccttcctc atactgttag 19141 aattaaatgt gctaatttat gttttatata tataaagtac ttggccgggt gtggtgactc 192 01 acacctgtaa tcccagcact gtgggaggcc gaggtgggca gatcacttga ggacaggagt 19261 tcaagactag cctggtcaac atggtgaaac cctgtctcta ctaaaaatac aaaaattagc 19321 tgggcttggt ggtgcgtgct tgtaatccca gctacttgag tggctgaggt gg gaggatca 19381 cttgaactcc agaggtggag gctgcagtgg gctccaccca ctgcctgggt gacagagcta 19441 gactccatct cgaagaaaaa ataagtactt gaaacatagc aaatgtttta taattattgg 19501 cttttttttc ttattgttat tacttgcatt attgctgttt gaagaagttt ggtgataatg 19561 gagagaaaag ggcaattagg ggtctgggat ggtttaagta tgaggagacc gagaca catt 19621 gactcagagt gaagaaatca aagataagag aatgaaagaa agggaggta attctgaacg 19681 cacagacaaa gttatgttac taacgtggca tcggctgtgt gttgtaataa ataactccct 19741 ttcacttgtc aatagctaat caaatacttt ctggagacca gaagt gactt gctggatcaa 19801 tgacaactcc tccacagatc aaaatgttca aatccttttt ctgtgttgta atcctaaatc 19861 taaaagaaca gagagaccaa gcaaatctac ctcccaacat cattaaagtg acaactctca 19921 gtatttattt gaatggtctg ctctcagctt caaccaagga aaagtcaaat tagtgttggt 19981 cagaaaacag aagggtgtta cgagagttct ggctggtcat tacagacttg gggatttttg 20041 attaaaaga a gaagaagaag aagaaacctg ataaagtgta aatatagcaa gcagggatta 20101 gtgtcctgct gggtcatgtt ctcacaacag tgagaatttc agagatttca taagaattaa 20161 actgctccac atgacaattt attttacctt ctggcttttc caggaggcaa atcagtgcaa 20221 cttctttctg cctttgtttc aatttggtaa caaccctcaa ttttaggaca ggctaaacct 20281 agccacccta tcagagatga tgaagtagcc atctttttaa caggtgggga gatgaatgga 20341 atcagggttt gtttgtttgt ttgtttaata actgctagta aaaaccaagt caatagctga 20401 ctgagtgtaa gggaggctcc agaaggcagg ttattgtagt atagatgtga ctcgacttat 20461 gatgatgtta cttcccgata aacccgtcat aagttgaaat atcgttaaat tgaaaatgct 20521 tttaatacac cgaatctacc gaacatcata gcttagctca gcctacgtta aatgtgctca 20581 ggacgcacat tgcctacagc tgagccaaat cacctggcaa cacaggacac tgtagagtat 20641 c ggttgctgg cccttgtgat gctgtgactg actgggagct gcgcttagtg cctctaccca 20701 gcattgagag tttcttatcg cttattacta gcctgggaaa agaccaaaat tcaaaactca 20761 aagtgcggtt tctaccgaat gcttataact ttcagaccat catgatgttg aaaaatcgaa 20821 ccatcgtagg ttgggatcca tcctataaga cgagctacac tgccggaagt gtaagactgc 20881 tatgctgccg gaagatgggg catagtggac a actgcaagt cctgacaaca ggaggtcagc 20941 atctgcgacc tttaacatcc acattgacac taccacagtc ttccaaacag agctgatgat 21001 atagtttgga tgtcgtccct gcccaaatct catgtcgaat cgtaatcccc agtgttggag 21061 gtggggcctg gtgggagg tg attgggtcat gggggcagag ttcttatgaa tggtttagca 21121 cggtcccccc ttggtactgt atagtgagtg agttctcatg cgatctggtt gtttaaaagt 21181 gtgtggcacc tcccctctct ctctttctcc tactctggcc atgtgaagtg ttggctcccg 21241 ctttgccttc caccatgatt gttaaattcc cagaggtctc cctagaagct aatgctgcca 21301 cgtacagcct ggagaactgt gagccaatta aacctcat ct ctttttaaat tacccagtct 21361 caggccgggc gcggtgactg acacctgtaa tctcagcact ttgggaggct caggcaggaa 21421 gatgatttga ggtcaggagt tcgagaccag cctggccaac atggtgaaac cccatctcta 21481 ctgaaaatat aaaaattagc caggcatggt ggcgggtgcc tgtaatccca gctacttggg 21541 aggctgaggc aggagaatcg cttgaacctg ggagtcagag gttgcagaga gccaaaatgg 21601 agccactgta ctccagcctg ggcaatggag tgagaccctg tctcaaaaaa tatatatata 21661 ttacccagac tcaggtattt ctttacctga gactatgaga gaatggacta atatagctga 21721 agaattttat tttattttta aaaaactttt acgtttgggg gtacctg taa aagtctgtta 21781 cataggtaaa ctcctgtcat gaggatttgt tgtacagatt ctttcctgct cctccccctc 21841 ctcccaccct ccatcctcaa gaagatccca gtgtctgttg tttccttctt tgtgttcgta 21901 agttctcatc atgtagctcc cac gtataag tgagaacatg cagtatttgg ttttctgtcc 21961 ctgtgttagt ttgctaagga tgatagcctc caactccatc tatcttcctg caaaagacat 22021 gatctcattc atttttattg ctgcatagta ttccatggtg tatatgtacc acattttctt 22081 tatccagtct gtcattgatg ggcatttagg ttgattctgt gtcttcagaa ttgtgaatag 22141

- 33 045887 tgctgcaacg aacattcgtg tgcttgtgtc tttatagtag aatgatttct attcttctgg 22201 tagtaatggg attgctgggt caaatggtcg ttctgctttt agctctttgc agaatcacca 22261 tactgctttc cacagtggtt gaactaattt ac actcccac taacagtgta taagtgttcc 22321 cttttctctg caaccttgcc agcctctgtt atcttttgac tttttaataa aaaccattct 22381 aattagtgtg atggtatttc attgttgttt tgatttgcat ttctctaatg atcagtgatg 22441 ttgagct ttt tttcatgttc gttggctgca ggtacatctt cttttgaaaa gtgtctgctc 22501 atgtcctttg cccacttttt aatggggttg tttttctctt gtaaatttaa gttcctcata 22561 gatgctgggt attagacctt tgtcagatgt atagcttgca aatattttct cccattctgt 22621 aggttgtctg cttactcttt tgattgtttc ttttaccatg cagaagctcc taagtttaat 22681 tagatcccat ttgtcaattt ttgcttttg t tgcaattgct tttggtgtct ttgtcatgaa 22741 atctttgcca ggtcctatgt ccagaatgat attgcctagg ttgtcttcta gggttttttat 22801 agttttgggt tttacattta aatctttaat ccatcttgag ttgatttttg tgtttggtgt 2286 1 aaggaagggg tccagtttca atattctgca tatggctagc cagttatccc agcattattt 22921 attgagtaag gagtatctcc tccgttgctt gtttttccca ggtttgttga agatcagatg 22981 gttgtaggtg tgtggcctta ttttggggct ctctatcctg ttcatttggt ctatgtgcct 23041 gtttttgtac cagtaccatt ctgttttggt tactgtagcc ctatagcata tttcaaagtt 23101 gggtaacatg atgcctccag ctttattctt tt tgcttaga attaccttgg ccatttgggc 23161 tctttttggt accatatgaa gtttaaaata gttttttttc tagttatgtg aagaatgtcg 23221 ttggtaattt gataggaata acatgtaatg atattgattc ttcctatcca tgagcatggg 23281 atgtttttcc attt gtttgt gtcttctctg atttcttcaa gcagtgtttt gtaactcata 23341 ttgtagagat tattcacctc cttgcttagc tgtattccta ggtattgtat tctttctgta 23401 gtaattgtga atgggattgc ttttctgatt tggccctcag cttggtattg ttggtgtata 23461 ggaatgctag tgattttttg tatcctgaga ctttgctgaa gttatttatc agctgaagga 23521 gcttttgggc tgagactagg gggtttttta gatatagaat catgttct ct gcaaacagat 23581 ttagtttgac ttcctctctt cctacttgga tgccctttat ttctttctct tgcctgattt 23641 ccctggccag gacttccagt accatgttga ataggcgtgg tgagagaggg cattcttgtc 23701 ttgtgccagt tttcagggag aatgcttcca ccttttgccc attcagtacg atgtttgtgg 23761 tggtttgtca tatatggcta ttattatttt gaggtgtgtt cctttaatac ctagtttatt 23821 gacagttttt aacatgaagc agtgtttaat tttattaaaa gtcttttctg cctctgttga 23881 gatagtcatg tggcttttgt ctttagttct gtttatgtga tgaatcacat ttgttgattt 23941 ccttatgttg gaccaacctt gcatcccagg gatgaagcct acttgattgt gg tggtttag 24001 ctttttgata tactactgga ttcagtttgc aagtattttg ttgaggattt ttgcattgat 24061 gttcatcacg gatatcggcc tgaagtttct ttttttgttg tgtctctgtc aggttttggt 24121 atcagaatga tgctggcctc ct agaatgag ttggggagga gttcctcctc ctcaattttt 24181 ttggaatagg ttctgtagga atggtaccag ctcttcttta tacatctggt agagtttggc 24241 tgtgaagcca tcaggtcctg ggatttttta gttggtaggg tatttattac tgattcccta 24301 aatagaccga taatgatttt agaagtggag tcggtttttt cctggtccag tcttgggaag 24361 gtgtatgtat caccaattt atttagctct tctaggtttt ctagtttgtg tgcatatggg 24421 tg ttcatagt agtttctgat ggttgttttt atttccgtgg gatcagtggt aacattctct 24481 tcatcatttc tttttttttt tttttttttt ttttttgaga cggagtctcg ctctgtcgcc 24541 caggctggag tgcagtggcg cgatctcggc tc actgcaag ctccgcctcc cgggttcacg 24601 ccattctcct gcctcagcct cccgagtagc tgggactaca ggcgcccgct accacgtccg 24661 gctaattttt tgtattttta gtagagacgg ggtttcaccg tgttagccag gatggtctcg 24721 atctcctgac ctcgtgatcc gcccgcctcg gcctcccaaa gtgctgggat tacaggcgtg 24781 agccaccgcg cccggcccat ttctaattgt gtttatttga atcctctctc ttctcttctt 24841 tat taggcta gctagtggcc tatctatctt attaattttt tcaaaaaacc agctcctgga 24901 tttcttgatc ttttgaatgg tttttcatgt atcaatcctt cagttcagct ctgattttgg 24961 ttatttcttg tcttgtgcta gctttggggt tgacttgttc ttgct tctct aattctttca 25021 gttctgatgt tagtttgtta gtttgagatc taactttttg atgtggacat ttagtgctat 25081 aaatttaact cttaacactg ccttagctgt gtcccagaga gtctggtatg ttgtatcttt 25141 gttctcatta gtttgaaaaa acttcttgat ttctgtctta atttaattat ttatccaaag 25201 tcattcagga acatgttgtt taatttccat gtaattgcat ggttttgagc gattttctta 25261 gtcttgactt ctatttt tat tgtaccgtgg tctgagggtg tttgatatga ctttggttct 25321 tttgcatttg ctgaggattg ttttatgtcc aattatgtgg ttgattttag agtatgtgcc 25381 atgtggtgat gagaagaatg tatattctgt

- 34 045887 tggttttggg tacagagttc tgtagaggtc 25441 tattagatcc atttggtcca atgttgagtt cagatcctga atatctttgc taatttcctg 25501 cctccatgat ctaatactgt cagtaaagca ctgaagtctc ctactactat tgtgtgggag 2 5561 tctatgtctc tttataggtc tctaagaact tgctttatga atctgggtgc ttctgtgttg 25621 gatgcatata tatttaggat agttagatct tcttgttgaa ttgaaccctt taccattatg 25681 taacgccctt ctttgtcttt ttttttcttt gttggttt ga agtcttcttt gtctgaaatt 25741 aggattgcaa cccctgcttt tttctgtttt ctgtttgctt ggtagatttt cctccatccc 25801 tttattttgg acctatgggt gtccttacat attttatctt tatctatcca tccagccatc 25861 cagccatcca ttcatccgta tcatttttaa ccaataagga cttttaaaag cgcaaccaca 25921 acaccattaa cataaccaat aaaatctata acaatgataa aatatcatct aatactcagt 25981 ccatgtcca a ttttccctcg ctatctcaaa atcgtcttct tagaaatggt ctgttcaaat 26041 gagatcacat ggacagagga aggcgaacct cacactgtgg ggactgttgt ggggtggggg 26101 gaggggggag ggatagcatt gggagatata cctaatgcta gatgacaagt tagtgggtgc 2 6161 agcgcaccag catggcacat gtatatgtat gtaactaacc tgcacaatgt gcacatgtac 26221 cctaaaactt aaagtataat aataaaaaat aaaaataaaa aaataaaaag tgaaaaaaga 26281 aaaaaaaaaa aaaaagaaat ggtctgttca aatcacaaac cagattcaga aacaatagcc 26341 atacattaca ttttattaat atgtctctta aatttctttt aatctattac agtctttgga 26 401 atttttatgt cttcgtttat ccttccaatt attaaaaaaa aagtattttt gtattcattg 26461 aatagacaat gcttgcagaa aagtaaaaaa aaaaaaattt agtacaaaaa ggtacatagt 26521 gagctgttcc ttagtctccc ttcccagaag caatgttacc acttttgtac aaatagtctc 26581 tgcctagaca cacatgccag tccctaaggt ggctgtaaca aggtggttaa gagtgagaac 26641 atgaattcaa attcctatta tgccactcac taagtataaa tcttggtcat ggtacatgcc 26701 tctgtgcctc agtttttaat aatggtacct acctcatagg gctgttgaga gaattaaatc 26761 agataagtgc ttaaataact attaatattt attattattc acattccctt ttggcttttt 26821 tcccaaatag cagagt ggtg cacatatgtc ttcatttatt tggcttgttt tttcacctca 26881 catcacattt tgatgaataa ttccatacat gttgttatag atttgcttca ttctttgtaa 26941 tcattgacta atattccatt gtatgaatat gctactgcta aacatgtacg ttatttccaa 27001 cctctt atta tcaagaaatg ctgcaatgaa tatccttgta atactttagt ggattcatgt 27061 gcaaaaatat tcataggata aaatcctgaa agttaaattg ctgagctaaa gggtatgtgc 27121 attttaatgc tttatagatt gcccagctgc ctcaaaggag gttataacaa tttacactcc 27181 caagaaaaat gcacaagggt ccccatttcc ccatacccta gctaacacag gatattgcta 27241 aatgctttca tctttgtaaa cat gatgtat tgaaaatggt atctcaaagt tttaatgtgc 27301 atttttctga ttgtgagaag ataaaggaaa tgtagtacaa ctaaacatca gcagtcaaat 27361 gacctggcca tgactcctga gtgaggacac tggtaaacac catcaggatc caaacacctc 27421 tgtatttacg aagaggatgc tccctattgg atagcactaa gcttatttca tgtatgtaca 27481 tatgtagtta gttaattaca tccagcggtg gcaaagggct tgttctgacc caatgaaact 27541 ttctctcctg gcccccttcc agcatgtggt caggagtaga gtgttgtggc catgaggcat 27601 gcatttgtac agatgactac ttactcctcc ttgaaacatt tttttccatt tgcttccctg 27661 ctgtctcact catgggtctg ctcctaattc acaaatc act cttttcccag tcttcttggt 27721 tgggttttct cctcttctgt gcttgtagac atgggggagc cccagggctt ctctcttgaa 27781 ctacagcttc tccctgggtt catctccttg ggatgtctgt tccaatgggt ttaaatacta 27841 gggctaggac tagggagagg t cattgaggc acttagcaca taaagtttaa ggaaacattc 27901 tttatcaggc ccatgcaagt gcaggactgg ccctggaggg tgactaccac cttacctttt 27961 ccaccctagg caccttgttt gccttaccct agccccagtc ctctttaaca ccccagtctt 28021 ctccctggac ctccagaaac ataaatccta tttgacattt ctacttggag gttttaaggt 28081 aactcaaacg taaaatatct aagacagaac tcttgcatca ct tcccatcc tggggcccaa 28141 gcctgtctct tctactagtc tatctcagtt aacagcatca ccatttattc agttgctcag 28201 gacaaaaaat ttgaagtaat ccttgactct tctttttttt tttttgagac ggattctcac 28261 tctgttgccc aggctggagt g cagtggtgg gaccttggct cactgcaacc tctgcctcct 28321 gggttcaagc aattctcctg cctcagtctt ctgacctcgt gatccactcg cctcggcctc 28381 ccaaagtgct gggattacag gcgtgagcca ccgcacccgg cctggattct tttttttttt 28441 tttaaacaag tcctatcttc catctccaaa atgtatccca aatctgacaa cctctcccac 28501 cgtaggccag cccccatctc tcccctctga aaatagcctc ccttagatct ctggac attt 28561 gttcttcccc acccccttgt

- 35 045887 gatcactatt cagcattcag aatgatcttt taatattatg 28621 aaggagactg tgttcctctc ctacttaaaa ttctctagtg gcttcctaat aaatttagaa 28681 taaaaagcca actcctcgcc atggtcacca ggccaggatc cagtgggtac aacaatctg t 28741 tcccagcaca ataatcccac ttctgcctcc ccaccattca ccaggctcca ctgcactggc 28801 tcattcctgc ctcagttgtg cttcttttcc ctggaaagtt ctttctgtag atctttaaag 28861 ggtgatttcc ttctcaacat tcaggtgtca gctcgt ttca ctttcctgac catgcccatc 28921 cactcagaga tcactcaaaa tcccattacc ctattttatt tctccatcat atgtatcact 28981 atctgaaact atcttgttgt tgatgcaggc tattttcttg accccttcat gggactccca 29041 acaggggtac cccatttact cagcctgccc tgctcaacct cttgcaggag ggagcacacg 29101 agtgaacgag tgcaggaacc agctggctgc tttagtgctg tgaggagtaa actccat gca 29161 ggccctgcag cagcaaccag gtaggggtgc ctgcaacccc agggccccag agggtgtgtt 29221 acaatgctct cgtagctctg ccatctgtgg acagcagtgt gttgtcagct cagtgggccc 29281 tttgcttcat catgtagggt ggctgccctc tgcctgt gag ggcaaagggc cagggtgaca 29341 gtctttttgg gtacccacaa tttgtgcatc ctgaattctt gtttggtgcc caagaagaat 29401 ggggtcacac agatgaactg aaggatggtg aatgcagaga attagcaatg aaagtggctc 29461 tcagcagaga gagaagctga aaagggaatg ggaagggcag gtcactctcc cctgaagtca 29521 agtcacatct ctccaatgtc cagccaccat ctctgaagtc aagtttcctc tctctgatgt 2958 2 9761 caggtttcag gcttttcagc tcaaaagtga ggtttttcca gggacctgcc ccgtctgcct 29821 aaaatttcta cacttctgtc attgataccg ctggataaca gctctcctat aaagttcagg 29881 ggcttaaaac aaaaatttac taattcaccc ggacagttct tgatagggtc tctcctaact 29941 gttgcagtta catagcaact gggttggagt catcttttct gggcttgaca tccaggacag 30001 cttcttccct tgtgtgtctg gtgcctcagt gctcctccag gcagcctttc tctccagaag 30061 agtagcctgg acttcttggc aactcaagct tccaaaagaa aaaaaagcag agactgctgg 30121 ttctcttatc aaacaggcct ggaactggca caatgtactt ctgctgccat attcaggagg 3 0181 tcaaagcaat cgaaggccaa tccaagttca aaggcattgg agaaaaatga gaagtgtcac 30241 ttaaatgaga agtgacacat gcgtaaaagg gggaaaagca ttgattgtgg ccatttttgg 30301 agataagcta tcacgtttat ttgtttgttt gctttctaat ggtctgtctt ctcccattag 30361 gttataagct ctgtgagaca acaggaatct tgtccatctt gttttatggc tctacttcca 30421 acacct agaa taatgcctgg cacatagtag gtgctcagtg aataacttaa gcacttgata 30481 catgtttggg gaactaaaat gaacagaatt aaacttcccc agattggtcc tgccagattt 30541 gctgatgcca agcatgctga tgcctcacca gatgaaagaa gccctaaaat gtagggtttc 30601 gctttctctg caaacaagaa aaacttgccc tgaacacaaa atctagaaat agatttggcg 30661 tgttttctac attgaaatat ttcccgtagt accagaaatt attttcccac agctttgtgc 30721 tacattaaaa tattgaagtt gactgaaaat atctccattc tttaatcttg gtgtagacta 30781 gaaacaattt ttttgtaaca aagtaaatat gaaaacttcc taatatttga actccccaga 30841 tatccccaga tatctccaaa cttaa aatat cattgcaagt taagataaat ttttttaaat 30901 gactaccgag aaaggtcatt aaaggcttgg ttattaaaat gtacagattt gggttataaa 30961 gccagaactt atttgtttaa atcattacat atgaccaagc acagaaaata aattacctca 31021 aatctcctct ttgctaattt ttactggtaa actctataaa atgatcctat ctttaaacct 31081 ttttgtaaac cccttataag ttagtaagtg agaatgtatt catcagaagg attttagtga 31141 tgtttgaaat taaaaaagag agatttgatt tttaaaatta tacttgcaga ctactgctaa 31201 tgaaacttct tctaacccta gttttgtctt atcttcagtt tttccagatt tgctcaaagc 31261 aatcccagtg agcatccacg tcaatg tcat tctcttctct gccatcctta ttgtgttaac 31321 catggtgggg acagccttct tcatgtacaa tgcttttgga aaaccttttg aaactctgca 31381 tggtccccta gggctgtacc ttttgagctt catttcaggt aagtacaaaa ttctacctct 31441 gaagacaaat g tgcttttca atatgtcaaa aagaccgtct acctaaatat aaagttataa 31501 tcttaacata tatacatgga tgcacactgt agtattatac ataataacaa aaagtgtgga 31561 aataccacac ttgctcaaca gtagggaatt caataaatac tttatggaca tctatatgaa 31621 taactgtgat gctgacatta aattatattt ttgaagatgt aatcaagagg

- 36 045887 ataaacgctt 31681 gtctcaaaaa gttacatggg aaaagcagta tgtaaactta tataaacatt gtgaacctaa 31741 tttgattata tatataaaat atagggaata tacatataaa atacatatat gtatatatgg 31801 gggctatata tatatatata tgaaagagat agatagatag atagatagat agatagatag 31861 acagacagac agacaataca gactccaatc tgttggtcgt ggttgtctct gacccatgac 31921 actatggggg acttttattt ttgctcatac ttttcaatat ttcttagtgt tcaataatgt 31981 gctattattt atacataata ataaaaataa ataa atggca tcaaaaaaga gtaaagggcc 32041 agtgttccgc ccacatatga gcagccatat tcaagcctgt agacactttg tgtagcctaa 32101 tgctaggtgt atctgggcaa ggataaactc taaagccaga aattagttca tcaataaaca 32161 tgtgctactc aatagctagg gctgatggaa aagaatataa aacccagtct gtgccaaatg 32221 gtgcttacta tctg caagtg ggagaaggag aaagacgaga aaatgaaaaa tgtgtgtata 32281 atttatatgt agctgttctg taggagatct ctgacttcac cccattctaa ctttgcaaaa 32341 agatccaaca ctttgtcaga ttcctgggag gcaagtaatt ttattgatgg tttcatggag 32401 ggatacagaa cgataacaac tcacacaaag caaacaatgt aatgaaaatc tctattcgac 32461 tgtttctttt tctcctgaag ttgccctttg gctgccagct accaggcacc aggctcaagg 32521 tactttcttg ctcttgacac tactcccttc tctcatacaa ttcaacccca accacaaacg 32581 tgtatagatc tctctctcta taaaacaaag gcctgtagtt aacaggaggt cacttgcagt 32641 gtagcctctg ttcattgtta cttgt gcaca ctgcttaggg tctcacccca tccacattct 32701 gctaatcaca ttattcaccc atccaatgta gatctctcca gtggagattc tgctaatatt 32761 ttctttagat ttgtcacaag tatataatac agttttaaat tgtacagatg attatcctat 32821 aacagaagag tctaagcctt ttacat cttt gtatctctaa cgaaagcatt cagcatgaag 32881 ctctgtacac agcagacaat tcaatatgaa tttgctgact tgaaacagca agcctagaaa 32941 ggagatgtta acttggtcac ttagacagaa caggtttcag caatcagaat tcagatgaca 33001 tggaactggt agaacaggcg ctttgaagca ataggacatg agccagtgag gagagggatg 33061 gaatatcata aacaaaggcc aagggctttg caatcagag c tgaagagcca agagcacagg 33121 ctcagggtgt gggcagactg aatgagaaag tgattcaatc acatgtgaaa gtccagatga 33181 gaagagagag ttgggattac ttctgctcac caaacatcca aaaccaaaca ggtggatccg 33241 ggtggtgtgc tgttttactg at gaccatta cacagaattt taacagaagg aatgtaaagc 33301 agtggttctc aaactggagt tcccagatga gcagcgtctg catcatctgg aaacctgata 33361 aagcagcaaa ttctcaggcc ctaccccaga cccactgaat cagaaacttg ggggtctggg 33421 ggaagatggc catctgtatt ttaacaatct cccttcagga gattctgagg ctggctcaag 33481 tttgaactac aggtagttgg ttcaacaggt gttggtggac tgacaaacaa aa agagactc 33541 cgaggtaact ccaagatggt aatgtcagaa agcagctacc acccctaggg cttgggggaa 33601 ccaacaaaag agtttggcat tgccagaacc tagaatcttg aggagaggcc ccagagcatt 33661 gtgtctcaga ccttgaggac ttggcactgg gacaccatga ggggtttct g ggtgtgggaa 33721 agggctggaa actccccagt tgctgccacc agggaact acaagtgaag tggaaggtgt 33781 gggcctttct cccttttctt ttctcgtctt ctctctcccc ctggtgctca tgtttgacag 33841 aaaacagctg aaaaggcaga actagtttgg ggagtcttga cctggcatca taaagcagag 33901 aaaagcaaag ctggagtgaa ggtgagacac aacagctcat tagcag caac agccgtctag 33961 cgctccagct tctgaatgaa attctgaaga acagcgcact tggaagacaa attatttgac 34021 agttctgaca gacgaccaaa ctaacagcat ttgaaaagca agatgactca gagaatacag 34081 aatttaatcc aaatcccaga tcctatctct gcctttggcc aggcc taatg caaggagaac 34141 ctgagcacac aaatatatgc aggaatgatc aggacctgtg cctgcattct attctgtctc 34201 acccaccttc aaatttgttg taaaaacatg ggctcaataa aggtttgtga atcagggaag 34261 gaagagaagg ggagaaagga agggaaggag ccagctccag atctgtgtct tgcagaggat 34321 aaaggccagt gtttttagat cacccagtgt ttttctaagc ccccaatact tattttgaa a 34381 tatcaaaatg ttcaataact aaaaaaaaaa ccgttacaac aataaaacat gtttgaggt 34441 cagatggact ggcagtttgt gacctctggg gataaacagg tcactttgga atcacagact 34501 tcctcattcc ccttaaatct catatggtac ccagaagccc tt ggaacttt ggaaggtgtt 34561 tattcacagt tgtaatgtcc atgcagaccc tggctctaag acccaattgt gtaagggtag 34621 gtttgtagcc cttatcccaa acattctaag tgtgagccaa tgcgtcacac actcagaggc 34681 cagagactgt attggggtcc tttatttcac gtacgagtca cattccatta agagacccca 34741

- 37 045887 gaagtcagct ctcttccact gactggttct cttcccttgt ttctcttgcc aatgtgtgct 34801 gcccaggtgg cagtgctcac tgtcagcaga gaagaaaaat gctttcctcc ttggacctct 34861 tttctctttt tctcctccct actcacattc aggttcccta agcttccccg ctccttgtgc 34921 tgaagtcatt ctatggtcat ttcttcaact gtctacttcc ctgctggatg ggcacccaag 34981 acttggcatc ctggggcatg tagaaagggg aaagggaagg gaagggaaaa gaagtcctcc 35041 caattgtcta tct ggacctt tccacactgc ccagagtact gctatgggca tctccttatg 35101 tctcccgatg tggtgcatgc cagaccctgc aggtagaaaa ggaaagaaag caacccattg 35161 gaccaggcca gcaaaggctt cagtcacaca gctggctcat acttatggct tcatattctg 35221 ttgcctcttg aaccagacat ttcttccact ctcataacct ccagtttagc tcgtattcct 35281 cagcattctc catgtaatat tgttgcatga aacccatgca agtcagccaa tttgctcttt 35341 ctcatcttgt catttataaa ttgatgctga gaagtctttt tcccaaggtt tttagtaata 35401 ccttcatcat cccccatagt tcattttggg cagtgattcg cttctttgac tgtacattag 35461 aatcatctga agaactttct aaaactactg atctcaggt c tcacacaaca ctaattaaat 35521 tatagtctct ggtggggtag ggcttgggca ctgctatttt accttaagct ctctggagtc 35581 attctaattt gtagccagtg ctaagggttg caatataagt gaatatattt cacgtatttg 35641 tcaaacattg actgagtgcc cattatgtgc cagccattat aataggcact ggtgatccca 35701 cagtgaatca ggcacacaat gctgtcttca cggagcttgt tgtctagtgg gagagtcaaa 35761 caaaagtgta tatcaataat taagtgatta cagattgcaa taattacaat aagggtgata 35821 aacaggttgc tataatatac aatagtattg cctttcacca gacatttctt aaagaggtaa 35881 atcatctatc agacaccttt taaaaatctc atctaatttc aaaagtgtac ataaataatt 35941 aagtgattac agtttgcaat aattacaatg agggtgataa acaagttgct atgaaagaga 36001 aagatagcag agatctggct ttgagatggt ggtcagggaa gactgctcca atagctgagt 36061 tctaaagcta agaaggaact gagaaccttc acagaacgtc ccaagtagaa gagaaagcac 36121 actgaagact ctagggaaag aggtctgctt gttgtaggaa ccgaaagaag gccaatgtgg 361 81 ctaggtgctg ggtagtgagg ggaaatggca caaggaaaaa atgaggttag agagatcagt 36241 tgataccagt taatgttgga ccctaaacat taaccatggt aagtctttta gaattgattc 36301 taattgcaat gaaaaccttt tgaaagattt taaaaagata tctgatagct gatt tacctc 36361 tctaagaaat gtctggtgaa agacaatacc atcacattgg agatggaaaa agatgaatgg 36421 attctaaaaa cattctgaaa gtacattcaa aatgtttttc aggtagctta tgcaactaat 36481 aaatagtggt ggcattctgg gtaagacaag ggaggagcag gcttgcagtt tagggcaaga 36541 aaggggtggg gagaagagct cagcactaaa atcatgtgtt ccatttgggg cacatcgagt 36601 ctgagttgct atgagaccac caagtggaga tgccaagtaa atagtcagtt acatgaatct 36661 ggagttcagt gaagaggtct agaagaaaga tgtatatttg ggcattattc ggatatagat 36721 attatgtaaa gcaataaaat tggatgagat cacctaggga gagaatgcac atagataaaa 367 81 actgacctag gaccacttca tgtctaaaac accaaaagca atgtcaacaa aagccaaaat 36841 tgacaaatgg gatctaatta aactaaagag cttctgcaca gcaaaagaat cagagtgaac 36901 aggcaaccca caaaatggaa gaaaattttc acaacctact catctgacaa agggctaata 36961 tccagaatct acagtgaact caaacaaatt tacaagaaaa aaacaaacaa ccccatcaaa 37021 aagtgggtga a ggacatgaa cagacacttc tcaaaagaag acatttatgc agccaaaaaa 37081 cacatgaaaa aatgctcacc atcactggcc atcagagaaa tgcaaatcaa aaccacaatg 37141 agataccatc tcacaccagt tcaaatggca atcattaaaa agtcaggaaa caacaggtgc 37201 t ggagaggat ctggagaaat aggaacactt ttacactgtt ggtgggacta taaactagtt 37261 caaccattgg ggaagtcatt gtggcgattc ctcagggatc tagaactaga aataccattt 37321 gacccagcca tcccattact gggtatatac ccaaaggact ataaatcatg ctgctataaa 37381 gacacatgca catgtatgtt tattgcggca ctattcacaa tagcaaagac ttggaaccaa 37441 cctaaatgtc caacaatgat agactgg att aagaaaatgt ggcacatata caccatggaa 37501 tactatgcag ccataaaaaa tgatgagttc atgtcctttg tagggacatg gatgaagctg 37561 gaaaccatca tcctcagcaa actatcgcaa ggacaaaaaa ccaaacaccg catgttctca 37621 cccataggtg gga attgaac gatgagaaca catggacacg ggaaggggaa catcacacac 37681 tggggactgt tgtggggtgg gaagagggggg gagggatagc attaggagat atacctaatg 37741 ctaaatgacg agttattggg tgcagcacac cagcatggca catgtataca tatgtaccta 37801 acctgcacat tgagcacacg taccctaaaa cttaaagtat

- 38 045887 aataataata aaataaaata 37861 aaataaaaaa acaaaaattg atgtaggacc aattcctgaa gaacactgac agttaatttt 37921 ttggtttagg aggaggagaa gccagcaaac gacactgagt agcaatatcc aaagaaaaag 37981 aggaaaagg aaaactggga gattatgagt gtcccagagg gaatgtttca agattaccat 38041 cagcagtgag ctttgtgtaa aggtggcctc ctgtaataga ggtgcgggca ggagaaggca 38101 gaatagggaa aagggggtga aaaagcttcc ctcaagattt ataatacagt ggaagagaga 38 161 gacagagaga gagaaagaga aagagaga gagaacttaa ggaggtagag gaagagagag 38221 aaccaaaaaa gagggagctg agtatagaag caattagatt catagttttt agttgcggca 38281 gtgatatttg agtgggggcc ttttatatat tccattctag gtgtttccca gttgatggga 38341 gagggtctta cctagatctg catgtaaaag ggagtaggcc agctggcaga cttgacatgg 38401 atcagt ggta gaacatccta gcagttctgt gaatactctc tgagaatgac atgaaaggta 38461 ttggttcagg ccttttggag gtgataaaaa ccaccaaaat gtggacttat tgcaaattgt 38521 atttgttacc atttgcaatg attataatta ttctcttata tataggcttt cttacatata 3 8581 gcttctctta cacatagcgt catgagttat gccttctctt acatatagtg tctgctatga 38641 gttatgccaa gcagggcaaa caaaattgct gcctttcttt aaaaagagga cgctcctagt 38701 atgggcctaa ttaattatga taattacagc tatggcatgg aacataagca cattcatata 38761 cacaaagaca ataaaataaa gaacagttca aaaacagaac agttacatta tatatcagtt 38821 tcagtatgaa taataccctg gactct gaaa tatgtctggg gcacattatt ctgtaattgg 38881 tggtgaaaaa aaatctgcat cttatctcta cgccaatcct tatgaaggag ctgtttttca 38941 ggagttcgag aaagagacac agggatgtcc agtcatcaaa gccgcagagc ctgaggaaga 39001 ataa aggatt tgtggcagga aaacccagta atgaatgtat tctgctagtt tctcagcata 39061 gaacttagaa aagaggccac agaaggaaaa gagaagtaat gttagacagc tgatgttggc 39121 aatgggcaaa gaatttcatt ctcatatgca gggcagtggc taaaggggca gtgttgtgag 39181 gaatcacatt ccaggtcatt catgtccagg gtgtggtagg aggactgtgt ttcatttatt 39241 ttgtacatgg cccagctatg accttgtgca aggaaatgct taatcatttt ctatcacagt 39301 tgcaaagaga ttcttatcct actcagaatg tacgtcttct cttctgtttc atttacagtc 39361 acaacccaag tccttgcttt gacctccaaa gcaccacttg atgtatccac ttcagaaaca 39421 cacacagaca gctcacctct ttctatccct taccttcctc ccctcttcac tcaaaccacc 39481 tacttccttt gcattcactc ttccttcagc ctgaaataat cttcctccaa atatctacct 39541 tctcactccc tcacttctct caagatacac ttaaatgtta tattccctat gaggcctccc 39601 ctggccatcc ctccccagcc ttcctatccc ccctctctgc tttattttat tctccttaat 39661 atatatcaca ctctgataaa ccattgaatg tacttatcaa gt tattgcct ctctctccct 39721 ttccattgtc tccatcactg agagctctgt gaagaaaagg atttgtacct gtttcattta 39781 gtgctgtacc cccagttccc acaacagcgc aacaggcact caataaatag ttgttgaata 39841 agtgaataaa acagaagtag ctgcatatt t tctggtaaca aatgatattc ttctgaaaat 39901 gtcatatttt cagacatatt tccgaaaata aattcaaatt agataaacat tgtattttta 39961 gaccatttct tctttgcatt aatcatcctt ctcaataata taacatttgt aaaacttagg 40021 ttagatatgg gctcttcaac tttccattac agaagataaa gtgaaaaggc tagacccaat 40081 ggtgttattc cttcatctac atctatcctt tggaaacaca tgaccaaatt gctt gccatc 40141 acaatctcaa aatctaccct ttggtattaa ctcacttcac ttgtccctct gtcccttttt 40201 agatggtagc catcggtctc tggagcagtg tagagtcaga acaacttcta tttggggaag 40261 aaatcattgc tggtgacctt actttcaatt actaactttc tag tgacatt tacataattt 40321 tagagaaaat taacacctac acttgtaaag ttgtggcttt cccacaccta tttatcatct 40381 ctcaatattc cttgaaaagg aaattatcaa tttatcattc tatattggca atgaaatgcc 40441 cctaatatct gtcacctata agacaattga agatgatgtg ttgaaagctt tctgaaaatg 40501 ctgatcatta ctttaaatgg aattgaaatt ccagtttatt atttccaaaa atatga tctt 40561 actgatcata ggataacatt tcataacatt tcagagattt cttccccttc gaggagccaa 40621 acccatagga cctctggact cccacagatc ctggcaggga gttcccactc ataaaagcac 40681 aggtgccctc agagtcattc agggatgaag aagcaaccct cattggccat gtcct acgtt 40741 ccccatatag taaggactgg aggagaccag tgctcaattc tgcagtctca gacagctgtc 40801 agaggagagt catgaatgtg cagtgtctag cacattacaa acgtttgtta attgactgat 40861 cattcatggt gtgacagccc tataactcag ctatcctatt cagtcagaaa ttaactcagt 40921 aatcaaagtc attaaaagga agaaaaaaaa aacctacagt accagacaga

- 39 045887 tggtggggaa 40981 atcagacaga tgaaaggaaa aatggctgta ggtcattgag taagacactg ggcagcaaaa 41041 cctgggcctt gtgcctggtt atactccaca ttatagctcc agcaaggttt ggcaggattt 41101 ccacagtcct ggctt attct aacctttctt gggagcagga gcagtgttgg tcagatagac 41161 agacacataa ggaatctgtc caactggcac cgtgtgaatt tgggctcttg gtgtacatgg 41221 ataactggga aaaagaggag agagacatgt aggactgatc ctaccgtttg tgaagtcttg 41281 ggca agagta tgaatgaaaa cccacttctc ttcccctgcc tggctccact gcacacagta 41341 aagagcctca agcataggtg tgtggacatt gcaccatgta tccaagctct gaccatgcct 41401 cttgaaacag ctattcctca gccaccctct gaccatggga ggaatgaccc aggagaaatg 41461 accacatagg tcttgaaaat gggctcaggg ctatttacga agtcaattcc ggggtcccag 41521 gagtatggac taaaatgtga gtca ggcatg ccagatgggt atgttctatt gacttcaagg 41581 attcctcatg ctgtgggaag gaacctctcc agaagagaga cagagcagaa ccctctaaat 41641 gtggggcaca aagcaggagc ccctcttgct ggattcaaag ggtcatactg gaagagtgta 41701 ggttgagtct tatt ctcaca tcactcatat cacttacaca cttcttttat agccttagca 41761 gccatgccac aaagagaaac tcttcatgca tatcttttgg tccataagtc ataaatagtt 41821 atccttgatc ccatgtcttt tttagagcca tggacagaga gaagcaaaaa tataccaagt 41881 tcacactgag ttgtctccct tcatatctct tagcagtcac tgaaaggtta tgagactcag 41941 gctgggtttc tatcctctgt ccctga aacg acaacgttga cctcgtgatc aaccctagaa 42001 tccagagcaa gatctcagac tgtcctctct actaccagac agcacacttt gttttggggg 42061 ctgtgtgctt gaaatattag ctatggcaaa aggctttgag tcttatgaca ccccaagtaa 42121 ctttt acttt aggaatttga aatacagcct tgctgtaatg ctgtctcctt aacaaagcag 42181 tacctttgaa atatttaaca acttgaaaag gaaaccgagc ttgaattttc ctttcaggtg 42241 ctcaggaaat aatgtttcac ttctgtctga aattcaccat ctcctcagac aaagaaggct 42301 cttatggtaa aaggaatggc attttctcca caattttcga ataaaagata aagagaaaac 42361 agcactgcag cctttttgtt aggatcta ac aataaagaaa taatacggtt ttgccagggg 42421 agagctctgg ttttaagctc agaatacaaa aataggctga caaaatttta caaaggaata 42481 ttctcagcta ccactctgag gatggtagaa agtgaaattt caagaaaatt atattatttg 42541 attatttgat gatgattaag ctgatt ggcc agtcctatgt gaaattctaa agtagaagaa 42601 atgtgatgtt gtcttttctg ctcacctctc ccctcattcc tacccccaaa tctctgcctc 42661 taccccaaac ccagcctgac ctttgggaaa ggaatggggg ctgtcacttg caccgtagct 42721 cctcctgcct gcagtactct ccccccacag tccagcctcc ctctgctcag ctaacttttc 42781 ctatagctcc ttctggctac ttctaaggaa ccttccataa tgctg cccac cctctcagta 42841 acagcccctc tactatccct tgattacatg cactgtaatt ggttagtaat tgattttatg 42901 tcctctgcca aattatactc catgagagca aaaatcatga gtattatctt taatgtttaa 42961 atctccacaa ctatccccca tataagtcta gagaataaat gaatgag tga attaatgaat 43021 agaaactcaa gccattatgt tgccactcct aggatatttg gattaacttt aactgaagag 43081 taaaaagcat ttacctgtcc taaaggagac ataaaattag tgggagagta tttggagaaa 43141 aaaaagacac tgtaatacat tcttttgtgt tgcctaccct gatgtagtca ggtgtccctg 43201 atatggggtg ggctgaggat ttgaaataaa atacctaatt tgacattgta ag tggaggaa 43261 tcaggatttg aaaccaaatt ggtttgacct aaatcaagct attatgataa ggacttgcaa 43321 gaaaaaagga atccataaaa accatatgaa tagctaccaa ttagtaagca tttatatgtg 43381 tcaattacaa agccaaatgc aaatcatgct ttatttatat tag ccacctt ttatagatga 43441 agaaattgag acctgaatat taaaattgcc tacttttaca tagtaagtaa aggaatcagg 43501 gtttgaaccc aaattggttt cacctaaggt agaaaaccat cccagcaagt ctcctattaa 43561 ctggaaccct attgtggtgg cctgagatat aacagtagct gtggaagcgc tgtagagtcc 43621 tggccatcct atgtgctcct gatctggtcc ctcctgccac ctgcttctgc tccctgtgcc 43680 taatagtgt 43861 actaaacaaa acaaatgttt atttttctca cacataaaaa tctagaggtt gaagtccagg 43921 gctggtccag aggctccaag gatctgggat ttagactccc tctttcttgt ttttccacag 43981 catatggctt ccatttctgg ggccacattg gtccaaaatg tatgctgggg ctccagccat 44041 tgcatccata tttcagccac aggaaggagg

- 40 045887 aagtggggaa gaaaggacag gcccctaata 44101 cctgtatagt tcaagaagac tatcccgccc atacttccca accaccctta gttgaacaat 44161 gctgtcttaa ttcaagacac tcacatgtct agccaaaaat ctgaattctg ttacaaacaa 44221 gg agaataga gatgtgcgcc acctcaatac ctcatccata gctacctttt cctttgtgca 44281 gctgtggcca agtgaaagct gaaggagctg tggtaaccct tctgaaggga ggctggggcc 44341 tttcacaaga ggctgcatga ttgacattta tcctgcatgg cctgtgaagt acagagaaat 44 401 attttctctt gaagccacat catagcagtg gctgctttgt agcctgattc caccattatg 44461 cctttaaagt gcctagcaat tcagccttca catcatgcaa agaggaatat ctcccagtct 44521 ttgtaagatc agcttaattc taaccacctc cttacctccc actgcactcc tacacgcaca 44581 cacaaatctt cttcactcag agcagaacca taacccaagc cctaccacct agagactgaa 44641 gaat caggct catgattaca aatatgcaat aattttttgt gtggataatg tcaatgggga 44701 tgatggtaag agaattcctt ggtttacaca ttgaccctct tccctgtccc ttacaatcag 44761 gaaatatttg tcccaacacc ttgtttcttc tgttgcaggc tcctgtggct gtcttg tcat 44821 gatattgttt gcctctgaag tgaaaatcca tcacctctca gaaaaaattg caaattataa 44881 agaagggact tatgtctaca aaacgcaaag tgaaaaatat accacctcat tctggggtcat 44941 tttcttttgc ttttttgttc attttctgaa tgggctccta atacgacttg ctggatttca 45001 gttccctttt gcaaaatcta aagacgcaga aacaactaat gtagctgcag atctaatgta 450 61 ctgaaaggca aacctttcta taattttaca agggagtaga cttgctttgg tcacttttag 45121 atgtggttaa ttttgcatat ccttttagtc tgcatatatt aaagcatcag gacccttcgt 45181 gacaatgttt acaaattacg tactaaggat acaggctgga aagtaaggga agcagaagga 45241 aggctttgaa aagttgtttt atctggtggg aaattgcttg acccaggtag tcaaaggcag 45301 ttgactagaa tcgacaaatt gttactccat atatatatat gtgtgtgtgt gtgtgtgtgt 45361 gtgtgtgtaa gatgtcttcc tatcaaaaag atatcaaagg cacatggaat atattttaat 45421 aaaaacaaat aatatctcta atatatccac acatttgttg ccagatttca gaaaactgag 45481 ctg caatcgc tttcctaaaa cagtagtgta ttaaatgaac atctataaaa tgtatcaaca 45541 cacattttaa aaaatttgtt taaagtatac tcttaggcca ggcgtggtga ctcacacctg 45601 taattccagc acttcaggag gccaaggtgg gaagatcatt tgagttcagg agtt cgagtt 45661 acagcctggg caataaagtg agaccctgtc actaacaaaa ttaaaaaata aaataaatat 45721 aaaatatagg ctttaaaaaa gcatagtctt attaaccatg tctgttggtc aaaatctgca 45781 aactctaaaa gaagaaaaga agaaaaaacc aagcttaggg tatttttcct cccgtgcctg 45841 agtcccaatt acattcacga cagtactttc aatgaacata attgttagga ccactgagga 45901 atcatgaaaa atgatctctg cttagta cat ttgatgcaaa atgacttatt aggggctgtt 45961 tttctagcta tagtgtctcg agtactaata tgcaattatg aaaattatat taaatctggg 46021 attatgacgg tatcactgta tcatcttggt cttgttctgg ctgtcaccaa gcatgaccca 46081 ggtcaacttt tt ttttcccc tgaattaccc atcaaattga tctgcagctg actaaaggcc 46141 acagctgagc ctggaactga cccttccttc atcctcaacc tgctgtcctc cagaaagcac 46201 caaggaaaaa gcagagaatg acagcaaaca gatcactagg cctctgacca caggtgctga 46261 gtactcagca gccctcatat aataggtttg aaagtactcc ttaaaataaa acactgtttc 46321 cctttggaac tatttacaag gatgaaacaa ccgtatacct gagaaataac ttgctctggt 46381 gtcaattcgc tattcgccag cagacatcag aacacaccga gtttccagat gctggttttt 46441 ccccttaaat caggaaatac acctggacaa tttctagaag actacaattc agtctagcca 46501 caaaggggat tttttttttt tggtaaca gg ctagagcccg gttctgtaag tctttagctg 46561 aaatggtcca gtacaaaagc actggaaatg agtgggctag gaggacaagg accgtctcct 46621 gcgtgaggag ttggttggag gtccccaagg ccaggtaccc cctgcactct tattggattc 46681 ctctctgtct tcttggagtt ttgaaaaact ccttcgaaca ccaggctttt ttctttagaa 46741 aacaagtctc caatcgttct ctgttccgta gaaagaga aa gaaaacctgg agcagctgct 46801 gaaaaatcta atgaggaact aagaggcaaa cccacca

A non-limiting example of a wild-type human CLRN1 genomic DNA sequence is SEQ ID NO: 9. Exons in SEQ ID NO: 9: nucleotide positions 1-544 (exon 1), nucleotide positions 28764-29180 (exon 2), nucleotide positions 31239-31418 ( exon 3), nucleotide positions 32481-32519 (exon 4), nucleotide positions 44799-46433 (exon 5), nucleotide positions 44799-44935 (exon 6), and nucleotide positions 46128-46837 (exon 7). Introns: located between each pair of these exons in SEQ ID NO: 9, i.e. at nucleotide positions 545-28763 (intron 1), nucleotide positions 29181-31238 (intron 2), nucleotide positions 31419-32480 (intron 3), nucleotide positions 32520-44798 (intron 4) and nucleotide positions 44936-46127 (intron 7) .

Mouse CLRN1 Protein Isoform 1 (SEQ ID NO: 10):

MPSQQKKIIFCMAGVLSFLCALGVVTAVGTPLWVKATILCKTGALLVNASGKEL DKFMGEMQYGLFHGEGVRQCGLGARPFRFSSRSMKERYSLYEDKGETAVFPDLVQAIP VSIHINIILFSMILVVLTMVGTAFFMYNAFGKPFETLHGPLGLYLVSFISGSCGCLVMILFA SEVKVHRLSEKIANFKEGTYAYRT QNENYTTSFWVVFICFFVHF LNGLLIRLAGFQFPFTKSKETETTNVASDLMY

Canine CLRN1 protein (SEQ ID NO: 11):

- 41 045887

MPNQQKKVVFCTAGVLSFVCALGVVTALGTPLWIKATFLCKTGALLVNASGQE LDKFMGEMQYGLFHGEGIRQCGLGARPFRFSLFPDLLKVIPVSIHVNVILFSTILVVLTMV GTAFFMYNAFGKPFETLHGPLGLYLLSFISGCGCLVMILFASEVKIHHLSEKIANYKEGT YAYKTQSEKYTTSFWVV FICFLVHLLNGLLIRLAGFQFPFAKS KDTETTNVAADLMY Vectors.

The compositions provided herein comprise at least two (e.g., two, three, four, five, or six) nucleic acid vectors, wherein at least two different vectors each contain a coding sequence that encodes a different portion of the CLRN1 protein, wherein each of the encoded portions is at least 30 amino acids in length (e.g., about 30 to about 202 amino acids, about 30 to about 200 amino acids, about 30 to about

180 amino acids, from near thirty before near 170 amino acids, from near thirty before near 160 amino acids, from near thirty before near 150 amino acids, from near thirty before near 140 amino acids, from near thirty before near 130 amino acids, from near thirty before near 120 amino acids, from near thirty before near 110 amino acids, from near thirty before near 100 amino acids, from near thirty before near 90 amino acids, from near thirty before near 80 amino acids, from near thirty before near 70 amino acids, from near thirty before near 60 amino acids, from near thirty before near 50 amino acids, from near thirty before near 40 amino acids, from near 60 before near 202 amino acids, from near 60 before near 200 amino acids, from near 60 before near 180 amino acids, from near 60 before near 170 amino acids, from near 60 before near 160 amino acids, from near 60 before near 150 amino acids, from near 60 before near 140 amino acids, from near 60 before near 130 amino acids, from near 60 before near 120 amino acids, from near 60 before near 110 amino acids, from near 60 before near 100 amino acids, from near 60 before near 90 amino acids, from near 60 before near 80 amino acids, from near 60 before near 70 amino acids, from near 90 before near 202 amino acids, from near 90 before near 200 amino acids, from near 90 before near 180 amino acids, from near 90 before near 170 amino acids, from near 90 before near 160 amino acids, from near 90 before near 150 amino acids, from near 90 before near 140 amino acids, from near 90 before near 130 amino acids, from near 90 before near 120 amino acids, from near 90 before near 110 amino acids, from near 90 before near 100 amino acids, from near 100 before near 202 amino acids, from near 100 before near 200 amino acids, from near 100 before near 180 amino acids, from near 100 before near 170 amino acids, from near 100 before near 160 amino acids, from near 100 before near 150 amino acids, from near 100 before near 140 amino acids, from near 100 before near 130 amino acids, from near 100 before near 120 amino acids, from near 90 before near 110 amino acids, from near 120 before near 202 amino acids, from near 120 before near 200 amino acids, from near 120 before near 180 amino acids, from near 120 before near 170 amino acids, from near 120 before near 160 amino acids, from near 120 before near 150 amino acids, from near 120 before near 140 amino acids, from near 120 before near 130 amino acids, from near 150 before near 202 amino acids, from near 150 before near 200 amino acids, from near 150 before near 180 amino acids, from near 150 before near 170 amino acids, from near 150 before near 160 amino acids, from near 170 before near 202 amino acids, from near 170 before near 200 amino acids, from near 170 before near 180 amino acids, from near 190 before near

202 amino acids or about 190 to about 200 amino acids).

In some embodiments of these compositions, at least one of the coding sequences contains a nucleotide sequence spanning two consecutive exons of CLRN1 genomic DNA (e.g., exons 1 and 2 or exons 5 and 6), and does not contain an intronic sequence that naturally occurs between the two consecutive exons.

In some embodiments, the amino acid sequence of no encoded portion overlaps even partially with the amino acid sequence of another encoded portion. In some embodiments, the amino acid sequence of one or more encoded portions partially overlaps with the amino acid sequence of another encoded portion. In some embodiments, the amino acid sequence of one or more encoded portions partially overlaps with the amino acid sequence of another encoded portion.

In some embodiments, the overlapping amino acid sequence has a length of from about 30 amino acid residues to about 202 amino acids (eg, or any subrange of this range described herein).

In some examples, the vectors include two different vectors, each containing different intron segments, wherein the intron contains the nucleotide sequence of an intron that is present in the CLRN1 genomic DNA (e.g., any of the exemplary introns in SEQ ID NO: 9.

- 42 045887 described herein), and where two different segments overlap in sequence by at least 100 nucleotides (e.g., from about 100 to about 10,000 nucleotides, from about 100

before near 5000 nucleotides, from near 100 before near 4500 nucleotides, from near 100 before near 4000 nucleotides, from near 100 before near 3500 nucleotides, from near 100 before near 3000 nucleotides, from near 100 before near 2500 nucleotides, from near 100 before near 2000 nucleotides, from near 100 before near 1500 nucleotides, from near 100 before near 1000 nucleotides, from near 100 before near 800 nucleotides, from near 100 before near 600 nucleotides, from near 100 before near 400 nucleotides, from near 100 before near 200 nucleotides, from near 200 before near 10000 nucleotides, from near 200 before near 5000 nucleotides, from near 200 before near 4500 nucleotides, from near 200 before near 4000 nucleotides, from near 200 before near 3500 nucleotides, from near 200 before near 3000 nucleotides, from near 200 before near 2500 nucleotides, from near 200 before near 2000 nucleotides, from near 200 before near 1500 nucleotides, from near 200 before near 1000 nucleotides, from near 200 before near 800 nucleotides, from near 200 before near 600 nucleotides, from near 200 before near 400 nucleotides, from near 400 before near 10000 nucleotides, from near 400 before near 5000 nucleotides, from near 400 before near 4500 nucleotides, from near 400 before near 4000 nucleotides, from near 400 before near 3500 nucleotides, from near 400 before near 3000 nucleotides, from near 400 before near 2500 nucleotides, from near 400 before near 2000 nucleotides, from near 400 before near 1500 nucleotides, from near 400 before near 1000 nucleotides, from near 400 before near 800 nucleotides, from near 400 before near 600 nucleotides, from near 600 before near 10000 nucleotides, from near 600 before near 5000 nucleotides, from near 600 before near 4500 nucleotides, from near 600 before near 4000 nucleotides, from near 600 before near 3500 nucleotides, from near 600 before near 3000 nucleotides, from near 600 before near 2500 nucleotides, from near 600 before near 2000 nucleotides, from near 600 before near 1500 nucleotides, from near 600 before near 1000 nucleotides, from near 600 before near 800 nucleotides, from near 800 before near 10000 nucleotides, from near 800 before near 5000 nucleotides, from near 800 before near 4500 nucleotides, from near 800 before near 4000 nucleotides, from near 800 before near 3500 nucleotides, from near 800 before near 3000 nucleotides, from near 800 before near 2500 nucleotides, from near 800 before near 2000 nucleotides, from near 800 before near 1500 nucleotides, from near 800 before near 1000 nucleotides, from near 1000 before near 10000 nucleotides, from near 1000 before near 5000 nucleotides, from near 1000 before near 4500 nucleotides, from near 1000 before near 4000 nucleotides, from near 1000 before near 3500 nucleotides, from near 1000 before near 3000 nucleotides, from near 1000 before near 2500 nucleotides, from near 1000 before near 2000 nucleotides, from near 1000 before near 1500 nucleotides, from near 1500 before near 10000 nucleotides, from near 1500 before near 5000 nucleotides, from near 1500 before near 4500 nucleotides, from near 1500 before near 4000 nucleotides, from near 1500 before near 3500 nucleotides, from near 1500 before near 3000 nucleotides, from near 1500 before near 2500 nucleotides, from near 1500 before near 2000 nucleotides, from near 2000 before near 10000 nucleotides, from near 2000 before near 5000 nucleotides, from near 2000 before near 4500 nucleotides, from near 2000 before near 4000 nucleotides, from near 2000 before near 3500 nucleotides, from near 2000 before near 3000 nucleotides, from near 2000 before near 2500 nucleotides, from near 2500 before near 10000 nucleotides, from near 2500 before near 5000 nucleotides, from near 2500 before near 4500 nucleotides, from near 2500 before near 4000 nucleotides, from near 2500 before near 3500 nucleotides, from near 2500 before near 3000 nucleotides, from near 3000 before near 10000 nucleotides, from near 3000 before near 5000 nucleotides, from near 3000 before near 4500 nucleotides, from near 3000 before near 4000 nucleotides, from near 3000 before near 3500 nucleotides, from near 3500 before near 10000 nucleotides, from near 3500 before near 5000 nucleotides, from near 3500 before near 4500 nucleotides, from near 3500 before near 4000 nucleotides, from near 4000 before near 10000 nucleotides, from near 4000 before near 5000 nucleotides, from near 4000 before near 4500 nucleotides, from near 4500 before near 10000 nucleotides, from near 4500

to about 5,000 nucleotides or from about 5,000 to about 10,000 nucleotides) in length.

The overlapping nucleotide sequence in any two of the different vectors may comprise part or all of one or more exons of the CLRN1 gene (eg, any one or more exemplary exons in SEQ ID NO: 9 described herein).

In some embodiments, the number of different vectors in the composition is two, three, four, or five. In compositions in which the number of different vectors in the composition is two, the first of the two different vectors may contain a coding sequence that encodes the N-terminal portion of the CLRN1 protein. In some examples, the N-terminal portion of the CLRN1 gene is from about 30 to about 202 amino acids in length (or any subrange thereof, op.

- 43 045887 above). In some examples, the first vector further comprises a promoter (e.g., any of the promoters described herein or known in the art) and/or a Kozak sequence (e.g., any of the exemplary Kozak sequences described herein or known in the art ). In some examples, the first vector contains a promoter that is an inducible promoter, a constitutive promoter, or a tissue-specific promoter. In some examples, the second of two different vectors contains a coding sequence that encodes the C-terminal portion of the CLRN1 protein. In some examples, the C-terminal portion of the CLRN1 protein ranges from 30 to about 202 amino acids in length (or any subrange of that range described above). In some examples, the second vector further comprises a polyadenylation signal sequence.

In some examples, where the number of different vectors in the composition is two, the N-terminal portion encoded by one of the two vectors may contain a portion containing amino acid position 1 to any of the following: about amino acid position 202, about amino acid position 200, about amino acid 190, near amino acid position 180, near amino acid position

position 170, near amino acid position 160, near amino acid position 150, near amino acid position 140, near amino acid position 130, near amino acid position 120, near amino acid position 110, near amino acid position 100, near amino acid position 90, near amino acid position 80, near amino acid position 70, near amino acid position 60, near amino acid

position 50, about amino acid position 40 of the wild-type CLRN1 protein (e.g., SEQ ID NO: 1, 3, 5, or 7).

In some examples, where the number of different vectors in the composition is two, the N-terminal portion of the CLRN1 precursor protein may comprise a portion comprising amino acid position 1 to amino acid position 202, amino acid position 1 to about

amino acid position 200, With amino acid provisions 1 By near amino acid position 190, With amino acid provisions 1 By near amino acid position 180, With amino acid provisions 1 By near amino acid position 170, With amino acid provisions 1 By near amino acid position 160, With amino acid provisions 1 By near amino acid position 150, With amino acid provisions 1 By near amino acid position 140, With amino acid provisions 1 By near amino acid position 130, With amino acid provisions 1 By near amino acid position 120, With amino acid provisions 1 By near amino acid position 110, With amino acid provisions 1 By near amino acid position 100, With amino acid provisions 1 By near amino acid position 90, With amino acid provisions 1 By near amino acid position 80, With amino acid provisions 1 By near amino acid position 70, With amino acid provisions 1 By near amino acid position 60, With amino acid provisions 1 By near amino acid position 50, With amino acid provisions 1 By near amino acid position 40, With amino acid provisions 1 By near

amino acid position 30 of the wild-type CLRN1 protein (eg, SEQ ID NO: 1, 3, 5 or 7).

As used herein, the term vector means a composition containing a polynucleotide capable of carrying at least one exogenous nucleic acid fragment, such as a plasmid vector, transposon, cosmid, artificial chromosome (e.g., human artificial chromosome (HAC), yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC) or P1-based artificial chromosome (PAC)), viral vector (eg, any adenoviral vectors (eg, pSV or pCMV vectors) or any retroviral vectors as described herein), and any Gateway® vectors . The vector may, for example, contain a sufficient number of cis-acting elements for expression; other elements for expression may be provided by the mammalian host cell or in an in vitro expression system. The term vector includes any genetic element (eg, plasmid, transposon, cosmid, artificial chromosome, viral vector, etc.) that is capable of replicating when associated with appropriate regulatory elements. Thus, the term includes cloning and expression vectors as well as viral vectors (eg, adeno-associated virus (AAV) vector, adenoviral vector, lentiviral vector, or retroviral vector).

Vectors include all vectors known in the art, including cosmids, plasmids (eg, naked or contained in liposomes) and viruses (eg, lentiviruses, retroviruses, adenoviruses and adeno-associated viruses) that contain a recombinant polynucleotide. Those skilled in the art will be able to select suitable vectors and mammalian cells to produce any of the nucleic acids described herein.

- 44 045887

In some embodiments, the vector is a plasmid (ie, a circular DNA molecule that can autonomously replicate within a cell). In some embodiments, the vector may be a cosmid (eg, the pWE and sCos series (Wahl et al. (1987), Evans et al. (1989)).

In some embodiments, the vector(s) is an artificial chromosome. An artificial chromosome is a genetically engineered chromosome that can be used as a vector to transfer large DNA inserts. In some embodiments, the artificial chromosome is a human artificial chromosome (HAC) (see, e.g., Kouprina et al., Expert Opin. Drug Deliv. 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 et al., Mol. Ther. 19(9):1591-1601 , 2011; Kazuki et al., Gen. Ther. 18:384-393, 2011; and Katoh et al., Biochem. Biophys. Res. Commun. 321:280-290, 2004).

In some embodiments, the vector(s) are a yeast artificial chromosome (YAC) (see, e.g., Murray et al., Nature, 305:189-193, 1983; Ikeno et al. (1998), Nat. Biotech. 16 :431-439, 1998). In some embodiments, the vector(s) are a bacterial artificial chromosome (BAC) (eg, pBeloBAC11, pECBAC1, and pBAC108L). In some embodiments, the vector(s) are a P1-based artificial chromosome (PAC). Examples of artificial chromosomes are known in the art.

In some embodiments, the vector(s) is a viral vector (eg, adeno-associated virus, adenovirus, lentivirus, and retrovirus). Non-limiting examples of viral vectors are described herein. In some embodiments, the vector(s) are an adeno-associated virus (AAV) vector (see, e.g., Asokan et al., Mol. Ther. 20:699-7080, 2012). Recombinant vectors based on AAV or rAAV typically consist of, at a minimum, a transgene or part thereof and a regulatory sequence and, optionally, 5' and 3' AAV inverted terminal repeats (ITRs). This recombinant AAV-based vector is packaged in a capsid and delivered to the selected target cell (eg, cochlear hair cell).

AAV vector sequences typically contain cis-acting 5' and 3' ITR sequences (see, for example, B. J. Carter, in Handbook of Parvoviruses, ed., P. Tijsser, CRC Press, pp. 155-168, 1990 ). Typical AAV ITR sequences are approximately 145 nucleotides in length. In some embodiments, at least 75% of the representative ITR sequence (eg, at least 80%, at least 85%, at least 90%, or at least 95%) is included in the AAV-based vector. The ability to modify these ITR sequences is within the skill of the person skilled in the art (see, for example, texts such as Sambrook et al., Molecular Cloning. A Laboratory Manual, ^2nd ed., Cold Spring Harbor Laboratory, New York, 1989 and K. Fisher et al., J Virol 70:520-532, 1996). In some embodiments, any of the coding sequences described herein are flanked by 5' and 3' AAV ITR sequences in AAV-based vectors. AAV ITR sequences can be obtained from any known AAV, including currently identified AAV types.

The AAV-based vectors described herein may contain any of the regulatory elements described herein (eg, one or more of a promoter, a polyadenylation signal sequence (poly(A)) and an IRES).

In some embodiments, the AAV vector is selected from the group consisting of AAV1 vector, AAV2 vector, AAV3 vector, AAV4 vector, AAV5 vector, AAV6 vector, AAV7 vector, AAV8 vector, AAV9 vector, AAV2.7m8 vector, AAV8BP2 vector, and AAV293 vector. Additional exemplary AAV-based vectors that may be used herein are known in the art. See, for example, Kanaan et al., Mol. Ther. Nucleic Acids, 8:184-197, 2017; Li et al., Mol. Ther. 16(7):1252-1260; Adachi et al., Nat. Commun. 5:3075, 2014; Isgrig et al., Nat. Commun. 10(1):427, 2019; and Gao et al., J. Virol. 78(12):6381-6388.

In some embodiments, the AAV-based vector provided herein contains or consists of a sequence that is at least 80% identical (e.g., at least 82%, at least 84%, at least 85%, to at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98%, at least 99 or 100% identical) SEQ ID NO: 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. In some embodiments, the vector(s) are an adenovirus (see, for example, Dmitriev et al. (1998), J. Virol. 72:9706-9713; and Poulin et al., J. Virol. 8:10074-10086 , 2010). In some embodiments, the vector(s) are a retrovirus (see, for example, Maier et al. (2010), Future Microbiol., 5:1507-23).

In some embodiments, the vector(s) are a lentivirus (see, e.g., Matrai et al. (2010), Mol. Ther. 18:477-490; Banasik et al. (2010), Gene Ther. 17:150- 7; and Wanisch et al. (2009), Mol. Ther. 17:1316-32). Lentiviral vector refers to a vector derived from at least a portion of a lentiviral genome, including in particular a self-inactivating lentiviral vector as described by Milone et al., Mol. Ther. 17(8):1453–1464 (2009). Non-restrictive lentiviral vectos

- 45 045887 ry that can be used in clinical practice include Oxford BioMedica's LENTIVECTOR® gene delivery technology, Lentigen's LENTIMAX™ vector system, etc. Other types of lentiviral vectors are also available and known to one skilled in the art.

The vectors presented in this document come in a variety of sizes. The choice of vector that is used in any of the compositions, kits and methods described herein may depend on the size of the vector.

In some embodiments, the vector(s) is a plasmid and may have a total length of up to about 1 kb, up to about 2 kb, up to about 3 kb, up to about 4 k .bp, up to about 5 kb, up to about 6 kb, up to about 7 kb, up to about 8 kb, up to about 9 t .bp, up to about 10 kb, up to about 11 kb, up to about 12 kb, up to about 13 kb, up to about 14 t .p.n. or up to about 15 kb.

In some embodiments, the vector(s) is a plasmid and may have a total length ranging from about 1 to about 2 kb, from about 1 to about 3 kb, from about 1 to about 4 k .bp, about 1 to about 5 kb, about 1 to about 6 kb, about 1 to about 7 kb, about 1 to about 8 kb, from about 1 to about 9 kb, from about 1 to about 10 kb, from about 1 to about 11 kb, from about 1 to about 12 kb, about 1 to about 13 kb, about 1 to about 14 kb. or from about 1 to about 15 kb.

In some embodiments, the vector(s) are a transposon (eg, a PiggyBac™ transposon) and may be greater than 200 kb. In some examples, the vector(s) are a transposon having a total length ranging from about 1 to about 10 kb, from about 1 to about 20 kb, from about 1 to about 30 kb. bp, from about 1 to about 40 kb, from about 1 to about 50 kb, from about 1 to about 60 kb, from about 1 to about 70 kb, from about 1 to about 80 kb, from about 1 to about 90 kb, from about 10 to about 20 kb, from about 10 to about 30 kb, from about 10 to about 40 kb, from about 10 to about 50 kb, from about 10 to about 60 kb, from about 10 to about 70 kb, from about 10 to about 90 kb, from about 10 to about 100 kb, from about 20 to about 30 kb, from about 20 to about 40 kb, from about 20 to about 50 kb, from about 20 to about 60 kb, from about 20 to about 70 kb ., from about 20 to about 80 kb, from about 20 to about 90 kb, from about 20 to about 100 kb, from about 30 to about 40 kb .b., from about 30 to about 50 kb., from about 30 to about 60 kb., from about 30 to about 70 kb., from about 30 to about 80 t. .bp, from about 30 to about 90 kb, from about 30 to about 100 kb, from about 40 to about 50 kb, from about 40 to about 60 kb, from about 40 to about 70 kb, from about 40 to about 80 kb, from about 40 to about 90 kb, from about 40 to about 100 kb, from about 50 to about 60 kb, from about 50 to about 70 kb, from about 50 to about 80 kb, from about 50 to about 90 kb, from about 50 to about 100 kb, from about 60 to about 70 kb, from about 60 to about 80 kb, from about 60 to about 90 kb, from about 60 to about 100 kb, from about 70 to about 80 kb, from about 70 to about 90 kb ., from about 70 to about 100 kb, from about 80 to about 90 kb, from about 80 to about 100 kb, from about 90 to about 100 kb .b., from about 1 to about 100 kb, from about 100 to about 200 kb, from about 100 to about 300 kb, from about 100 to about 400 t .p.n. or from about 100 to about 500 kb.

In some embodiments, the vector is a cosmid and may have a total length of up to 55 kb. In some examples, the vector is a cosmid and has a total number of nucleotides from about 1 to about 10 kb, from about 1 to about 20 kb, from about 1 to about 30 kb. , from about 1 to about 40 kb, from about 1 to about 50 kb, from about 1 to about 55 kb, from about 10 to about 20 kb. b., from about 10 to about 30 kb., from about 10 to about 40 kb., from about 10 to about 50 kb., from about 10 to about 55 kb. bp, from about 15 to about 55 kb, from about 15 to about 50 kb, from about 15 to about 40 kb, from about 15 to about 30 kb, from about 15 to about 20 kb, from about 20 to about 55 kb, from about 20 to about 50 kb, from about 20 to about 40 kb, from about 20 to about 30 kb, from about 25 to about 55 kb, from about 25 to about 50 kb, from about 25 to about 40 kb, from about 25 to about 30 kb, from about 30 to about 55 kb, from about 30 to about 50 kb, from about 30 to about 40 kb, from about 35 to about 55 kb, from about 40 to about 55 kb, from about 40 to about 50 kb . or from about 45 to about 55 kb.

In some embodiments, the vector(s) is an artificial chromosome and may have a total number of nucleotides from about 100 kb to about 2000 kb. In some embodiments, the artificial chromosome(s) is a human artificial chromosome (HAC) and may have a total number of nucleotides ranging from about 1 to about 10 kb, from 1 to about 20 kb, from about 1 to about 30 kb, from about 1 to about 40 kb, from about 1 to about 50 kb, from about 1 to about 60 kb ., from about 10 to about 20 kb, from about 10 to about 30 kb, from about 10 to about 40 kb, from about 10 to about 50 kb .b., from about 10 to about 60 kb., from about 20 to about 30 kb., from about 20 to about 40 kb., from about 20 to about 50 t. .bp, from about 20 to about 60 kb, from about 30 to about 40 kb, from about 30 to about 50 kb, from about 30 to about 60 kb, from about 40 to about 50 kb,

- 46 045887 from about 40 to about 60 kb. or about 50 to about 60 kb.

In some embodiments, the artificial chromosome(s) are a yeast artificial chromosome (YAC) and may have a total number of up to 1000 kb. In some embodiments, the artificial chromosome(s) is a YAC having a total number of nucleotides ranging from about 100 to about 1000 kb, from about 100 to about 900 kb, from about 100 to about 800 kb, from about 100 to about 700 kb, from about 100 to about 600 kb, from about 100 to about 500 kb, from about 100 to about 400 kb, from about 100 to about 300 kb, from about 100 to about 200 kb, from about 200 to about 1,000 kb, from about 200 to about 900 kb, from about 200 to about 800 kb, from about 200 to about 700 kb, from about 200 to about 600 kb, from about 200 to about 500 kb, from about 200 to about 400 kb, from about 200 to about 300 kb, from about 300 to about 1000 kb, from about 300 to about 900 kb, from about 300 to about 800 kb, from about 300 to about 700 kb, from about 300 to about 600 kb, from about 300 to about 500 kb, from about 300 to about 400 kb, from about 400 to about 1000 kb, from about 400 to about 900 kb. , from about 400 to about 800 kb, from about 400 to about 700 kb, from about 400 to about 600 kb, from about 400 to about 500 kb. b., from about 500 to about 1000 kb., from about 500 to about 900 kb., from about 500 to about 800 kb., from about 500 to about 700 kb. .b., from about 500 to about 600 kb, from about 600 to about 1000 kb, from about 600 to about 900 kb, from about 600 to about 800 kb .bp, from about 600 to about 700 kbp, from about 700 to about 1000 kbp, from about 700 to about 900 kbp, from about 700 to about 800 kbp. bp, from about 800 to about 1000 kb, from about 800 to about 900 kb. or from about 900 to about 1000 kb.

In some embodiments, the artificial chromosome(s) are a bacterial artificial chromosome (BAC) and may have a total number of up to 750 kb. In some embodiments, the artificial chromosome(s) is a BAC and may have a total number of nucleotides ranging from about 100 to about 750 kb, from about 100 to about 700 kb, from about 100 to about 600 kb, from about 100 to about 500 kb, from about 100 to about 400 kb, from about 100 to about 300 kb, from about 100 to about 200 kb, from about 150 to about 750 kb, from about 150 to about 700 kb, from about 150 to about 600 kb, from about 150 to about 500 kb, from about 150 to about 400 kb, from about 150 to about 300 kb, from about 150 to about 200 kb, from about 200 to about 750 kb, from about 200 to about 700 kb, from about 200 to about 600 kb, from about 200 to about 500 kb, from about 200 to about 400 kb, from about 200 to about 300 kb, from about 250 to about 750 kb, from about 250 to about 700 kb. , from about 250 to about 600 kb, from about 250 to about 500 kb, from about 250 to about 400 kb, from about 250 to about 300 kb. , from about 300 to about 750 kb, from about 300 to about 700 kb, from about 300 to about 600 kb, from about 300 to about 500 kb ., from about 300 to about 400 kb, from about 350 to about 750 kb, from about 350 to about 700 kb, from about 350 to about 600 kb. b., from about 350 to about 500 kb, from about 350 to about 400 kb, from about 400 to about 750 kb, from about 400 to about 700 kb. b., from about 450 to about 600 kb., from about 450 to about 500 kb., from about 500 to about 750 kb., from about 500 to about 700 kb. .bp, from about 500 to about 600 kbp, from about 550 to about 750 kbp, from about 550 to about 700 kbp, from about 550 to about 600 kbp. bp, from about 600 to about 750 kb, from about 600 to about 700 kb. or from about 650 to about 750 kb.

In some embodiments, the artificial chromosome(s) are P1-based artificial chromosome (PAC) and may have a total number of up to 300 kb. In some embodiments, the P1-based artificial chromosome(s) may have a total number of nucleotides ranging from about 100 kb to about 300 kb, from about 100 kb to about 200 kb. or from about 200 to about 300 kb.

In some embodiments, the vector(s) are a viral vector and may have a total number of up to 10 kb. In some embodiments, the viral vector(s) may have a total number of nucleotides ranging from about 1 kb to about 2 kb, about 1 kb to about 3 kb, or about 1 kb to about 4 kb. bp, from about 1 to about 5 kb, from about 1 to about 6 kb, from about 1 to about 7 kb, from about 1 to about 8 kb, from about 1 to about 9 kb, from about 1 to about 10 kb, from about 2 to about 3 kb, from about 2 to about 4 kb, about 2 to about 5 kb, about 2 to about 6 kb, about 2 to about 7 kb, about 2 to about 8 kb, about 2 to about 9 kb, about 2 to about 10 kb, about 3 to about 4 kb, about 3 to about 5 kb, about 3 to about 6 kb, about 3 to about 7 kb, about 3 to about 8 kb ., from about 3 to about 9 kb, from about 3 to about 10 kb, from about 4 to about 5 kb, from about 4 to about 6 kb .b., from about 4 to about 7 kb., from about 4 to about 8 kb., from about 4 to about 9 kb., from about 4 to about 10 t. .bp, from about 5 to about 6 kb, from about 5 to about 7 kb, from about 5 to about 8 kb, from about 5 to about 9 kb, about 5 to about 10 kb, about 6 to about 7 kb, about 6 to about 8 kb, about 6 to about 9 kb, from about 6 to about 10 kb, from about 7 to about 8 kb, from about 7 to about 9 kb, from about 7 to about 10 kb, about 8 to about 9 kb,

- 47 045887 from about 8 to about 10 kb. or about 9 to about 10 kb.

In some embodiments, the vector(s) are lentivirus and may have a total number of up to 8 kb. In some examples, the lentivirus(es) may have a total number of nucleotides of from about to about 2 kb, from about 1 to about to about to about to about to about to about to about to about to about

5

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from from from from from from from about about about about about about about about about about to to to to to to to to to about about about about about about about about about

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from from from from from from from about about about about about about about about to about 7 kb. or about 7 to about 8 kb.

In some embodiments, the vector(s) are adenoviral and may have a total number of up to 8 kb. In some embodiments, the adenovirus(es) may have a total number of nucleotides ranging from about 1 to about 2 kb, from about 1 to about 3 kb, from about 1 to about 4 kb .b., from about 1 to about 5 kb., from about 1 to about 6 kb., from about 1 to about 7 kb., from about 1 to about 8 t. .bp, from about 2 to about 3 kb, from about 2 to about 4 kb, from about 2 to about 5 kb, from about 2 to about 6 kb, about 2 to about 7 kb, about 2 to about 8 kb, about 3 to about 4 kb, about 3 to about 5 kb, from about 3 to about 6 kb, from about 3 to about 7 kb, from about 3 to about 8 kb, from about 4 to about 5 kb, about 4 to about 6 kb, about 4 to about 7 kb, about 4 to about 8 kb. , from about 5 to about 6 kb, from about 5 to about 7 kb, from about 5 to about 8 kb, from about 6 to about 7 kb. n, from about 6 to about 8 kb. or about 7 to about 8 kb.

In some embodiments, the vector(s) are an adeno-associated virus (AAV-based vector) and may have a total number of up to 5 kb. In some embodiments, the AAV-based vector(s) may contain a total number of nucleotides ranging from about 1 to about 2 kb, from about 1 to about 3 kb, from about 1 to about 4 kb, about 1 to about 5 kb, about 2 to about 3 kb, about 2 to about 4 kb, about 2 to about 5 kb, about 3 to about 4 kb, about 3 to about 5 kb. or about 4 to about 5 kb.

In some embodiments, the vector(s) are a Gateway® vector and may have a total number of up to 5 kb. In some embodiments, each Gateway® vector(s) has a total number of nucleotides ranging from about 1 to about 2 kb, from about 1 to about 3 kb, from about 1 to about 4 k .bp, from about 1 to about 5 kb, from about 2 to about 3 kb, from about 2 to about 4 kb, from about 2 to about 5 kb, about 3 to about 4 kb, about 3 to about 5 kb. or about 4 to about 5 kb.

In some embodiments of any of the compositions, kits and methods provided herein, the at least two different vectors may be substantially the same type of vector and may differ in size. In some embodiments, the at least two different vectors may be different types of vectors and may be substantially the same size or have different sizes.

In some embodiments, either of the at least two vectors may have a total number of nucleotides ranging from about 500 to about 15,000 nucleotides,

from near 500 before near 14500 nucleotides, from near 500 before near 14000 nucleotides, from near 500 before near 13500 nucleotides, from near 500 before near 13000 nucleotides, from near 500 before near 12500 nucleotides, from near 500 before near 12000 nucleotides, from near 500 before near 11500 nucleotides, from near 500 before near 11000 nucleotides, from near 500 before near 10500 nucleotides, from near 500 before near 10000 nucleotides, from near 500 before near 9500 nucleotides, from near 500 before near 9000 nucleotides, from near 500 before near 8500 nucleotides, from near 500 before near 8000 nucleotides, from near 500 before near 7800 nucleotides, from near 500 before near 7600 nucleotides, from near 500 before near 7400 nucleotides, from near 500 before near 7200 nucleotides, from near 500 before near 7000 nucleotides, from near 500 before near 6800 nucleotides, from near 500 before near 6600 nucleotides, from near 500 before near 6400 nucleotides, from near 500 before near 6200 nucleotides, from near 500 before near 6000 nucleotides, from near 500 before near 5800 nucleotides, from near 500 before near 5600 nucleotides, from near 500 before near 5400 nucleotides, from near 500 before near 5200 nucleotides, from near 500 before near 5000 nucleotides, from near 500 before near 4800 nucleotides, from near 500 before near 4600 nucleotides, from near 500 before near 4400 nucleotides,

- 48 045887

from near 500 before near 4200 nucleotides, from near 500 before near 4000 nucleotides, from near 500 before near 3800 nucleotides, from near 500 before near 3600 nucleotides, from near 500 before near 3400 nucleotides, from near 500 before near 3200 nucleotides, from near 500 before near 3000 nucleotides, from near 500 before near 2800 nucleotides, from near 500 before near 2600 nucleotides, from near 500 before near 2400 nucleotides, from near 500 before near 2200 nucleotides, from near 500 before near 2000 nucleotides, from near 500 before near 1800 nucleotides, from near 500 before near 1600 nucleotides, from near 500 before near 1400 nucleotides, from near 500 before near 1200 nucleotides, from near 500 before near 1000 nucleotides, from near 500 before near 800 nucleotides, from near 800 before near 15000 nucleotides, from near 800 before near 14500 nucleotides, from near 800 before near 14000 nucleotides, from near 800 before near 13500 nucleotides, from near 800 before near 13000 nucleotides, from near 800 before near 12500 nucleotides, from near 800 before near 12000 nucleotides, from near 800 before near 11500 nucleotides, from near 800 before near 11000 nucleotides, from near 800 before near 10500 nucleotides, from near 800 before near 10000 nucleotides, from near 800 before near 9500 nucleotides, from near 800 before near 9000 nucleotides, from near 800 before near 8500 nucleotides, from near 800 before near 8000 nucleotides, from near 800 before near 7800 nucleotides, from near 800 before near 7600 nucleotides, from near 800 before near 7400 nucleotides, from near 800 before near 7200 nucleotides, from near 800 before near 7000 nucleotides, from near 800 before near 6800 nucleotides, from near 800 before near 6600 nucleotides, from near 800 before near 6400 nucleotides, from near 800 before near 6200 nucleotides, from near 800 before near 6000 nucleotides, from near 800 before near 5800 nucleotides, from near 800 before near 5600 nucleotides, from near 800 before near 5400 nucleotides, from near 800 before near 5200 nucleotides, from near 800 before near 5000 nucleotides, from near 800 before near 4800 nucleotides, from near 800 before near 4600 nucleotides, from near 800 before near 4400 nucleotides, from near 800 before near 4200 nucleotides, from near 800 before near 4000 nucleotides, from near 800 before near 3800 nucleotides, from near 800 before near 3600 nucleotides, from near 800 before near 3400 nucleotides, from near 800 before near 3200 nucleotides, from near 800 before near 3000 nucleotides, from near 800 before near 2800 nucleotides, from near 800 before near 2600 nucleotides, from near 800 before near 2400 nucleotides, from near 800 before near 2200 nucleotides, from near 800 before near 2000 nucleotides, from near 800 before near 1800 nucleotides, from near 800 before near 1600 nucleotides, from near 800 before near 1400 nucleotides, from near 800 before near 1200 nucleotides, from near 800 before near 1000 nucleotides, from near 1000 before near 15000 nucleotides, from near 1000 before near 14500 nucleotides, from near 1000 before near 14000 nucleotides, from near 1000 before near 13500 nucleotides, from near 1000 before near 13000 nucleotides, from near 1000 before near 12500 nucleotides, from near 1000 before near 12000 nucleotides, from near 1000 before near 11500 nucleotides, from near 1000 before near 11000 nucleotides, from near 1000 before near 10500 nucleotides, from near 1000 before near 10000 nucleotides, from near 1000 before near 9000 nucleotides, from near 1000 before near 8500 nucleotides, from near 1000 before near 8000 nucleotides, from near 1000 before near 7800 nucleotides, from near 1000 before near 7600 nucleotides, from near 1000 before near 7400 nucleotides, from near 1000 before near 7200 nucleotides, from near 1000 before near 7000 nucleotides, from near 1000 before near 6800 nucleotides, from near 1000 before near 6600 nucleotides, from near 1000 before near 6400 nucleotides, from near 1000 before near 6200 nucleotides, from near 1000 before near 6000 nucleotides, from near 1000 before near 5800 nucleotides, from near 1000 before near 5600 nucleotides, from near 1000 before near 5400 nucleotides, from near 1000 before near 5200 nucleotides, from near 1000 before near 5000 nucleotides, from near 1000 before near 4800 nucleotides, from near 1000 before near 4600 nucleotides, from near 1000 before near 4400 nucleotides, from near 1000 before near 4200 nucleotides, from near 1000 before near 4000 nucleotides, from near 1000 before near 3800 nucleotides, from near 1000 before near 3600 nucleotides, from near 1000 before near 3400 nucleotides, from near 1000 before near 3200 nucleotides, from near 1000 before near 3000 nucleotides, from near 1000 before near 2600 nucleotides, from near 1000 before near 2400 nucleotides, from near 1000 before near 2200 nucleotides, from near 1000 before near 2000 nucleotides, from near 1000 before near 1800 nucleotides, from near 1000 before near 1600 nucleotides, from near 1000 before near 1400 nucleotides, from near 1000 before near 1200 nucleotides, from near 1200 before near 15000 nucleotides, from near 1200 before near 14500 nucleotides, from near 1200 before near 14000 nucleotides, from near 1200 before near 13500 nucleotides, from near 1200 before near 13000 nucleotides, from near 1200 before near 12500 nucleotides, from near 1200 before near 12000 nucleotides, from near 1200 before near 11500 nucleotides, from near 1200 before near 11000 nucleotides,

- 49 045887

from near 1200 before near 10500 nucleotides, from near 1200 before near 10000 nucleotides, from near 1200 before near 9500 nucleotides, from near 1200 before near 9000 nucleotides, from near 1200 before near 8500 nucleotides, from near 1200 before near 8000 nucleotides, from near 1200 before near 7800 nucleotides, from near 1200 before near 7600 nucleotides, from near 1200 before near 7400 nucleotides, from near 1200 before near 7200 nucleotides, from near 1200 before near 7000 nucleotides, from near 1200 before near 6800 nucleotides, from near 1200 before near 6600 nucleotides, from near 1200 before near 6400 nucleotides, from near 1200 before near 6200 nucleotides, from near 1200 before near 6000 nucleotides, from near 1200 before near 5800 nucleotides, from near 1200 before near 5600 nucleotides, from near 1200 before near 5400 nucleotides, from near 1200 before near 5000 nucleotides, from near 1200 before near 4800 nucleotides, from near 1200 before near 4600 nucleotides, from near 1200 before near 4400 nucleotides, from near 1200 before near 4200 nucleotides, from near 1200 before near 4000 nucleotides, from near 1200 before near 3800 nucleotides, from near 1200 before near 3600 nucleotides, from near 1200 before near 3400 nucleotides, from near 1200 before near 3200 nucleotides, from near 1200 before near 3000 nucleotides, from near 1200 before near 2800 nucleotides, from near 1200 before near 2600 nucleotides, from near 1200 before near 2400 nucleotides, from near 1200 before near 2200 nucleotides, from near 1200 before near 2000 nucleotides, from near 1200 before near 1800 nucleotides, from near 1200 before near 1600 nucleotides, from near 1200 before near 1400 nucleotides, from near 1400 before near 15000 nucleotides, from near 1400 before near 14500 nucleotides, from near 1400 before near 14000 nucleotides, from near 1400 before near 13500 nucleotides, from near 1400 before near 13000 nucleotides, from near 1400 before near 12500 nucleotides, from near 1400 before near 12000 nucleotides, from near 1400 before near 11500 nucleotides, from near 1400 before near 11000 nucleotides, from near 1400 before near 10500 nucleotides, from near 1400 before near 10000 nucleotides, from near 1400 before near 9500 nucleotides, from near 1400 before near 9000 nucleotides, from near 1400 before near 8500 nucleotides, from near 1400 before near 8000 nucleotides, from near 1400 before near 7800 nucleotides, from near 1400 before near 7600 nucleotides, from near 1400 before near 7400 nucleotides, from near 1400 before near 7200 nucleotides, from near 1400 before near 7000 nucleotides, from near 1400 before near 6800 nucleotides, from near 1400 before near 6600 nucleotides, from near 1400 before near 6400 nucleotides, from near 1400 before near 6200 nucleotides, from near 1400 before near 6000 nucleotides, from near 1400 before near 5800 nucleotides, from near 1400 before near 5600 nucleotides, from near 1400 before near 5400 nucleotides, from near 1400 before near 5200 nucleotides, from near 1400 before near 5000 nucleotides, from near 1400 before near 4800 nucleotides, from near 1400 before near 4600 nucleotides, from near 1400 before near 4400 nucleotides, from near 1400 before near 4200 nucleotides, from near 1400 before near 4000 nucleotides, from near 1400 before near 3800 nucleotides, from near 1400 before near 3600 nucleotides, from near 1400 before near 3400 nucleotides, from near 1400 before near 3200 nucleotides, from near 1400 before near 3000 nucleotides, from near 1400 before near 2600 nucleotides, from near 1400 before near 2400 nucleotides, from near 1400 before near 2200 nucleotides, from near 1400 before near 2000 nucleotides, from near 1400 before near 1800 nucleotides, from near 1400 before near 1600 nucleotides, from near 1600 before near 15000 nucleotides, from near 1600 before near 14500 nucleotides, from near 1600 before near 14000 nucleotides, from near 1600 before near 13500 nucleotides, from near 1600 before near 13000 nucleotides, from near 1600 before near 12500 nucleotides, from near 1600 before near 12000 nucleotides, from near 1600 before near 11500 nucleotides, from near 1600 before near 11000 nucleotides, from near 1600 before near 10500 nucleotides, from near 1600 before near 10000 nucleotides, from near 1600 before near 9500 nucleotides, from near 1600 before near 9000 nucleotides, from near 1600 before near 8500 nucleotides, from near 1600 before near 8000 nucleotides, from near 1600 before near 7800 nucleotides, from near 1600 before near 7600 nucleotides, from near 1600 before near 7400 nucleotides, from near 1600 before near 7200 nucleotides, from near 1600 before near 7000 nucleotides, from near 1600 before near 6800 nucleotides, from near 1600 before near 6400 nucleotides, from near 1600 before near 6200 nucleotides, from near 1600 before near 6000 nucleotides, from near 1600 before near 5800 nucleotides, from near 1600 before near 5600 nucleotides, from near 1600 before near 5400 nucleotides, from near 1600 before near 5200 nucleotides, from near 1600 before near 5000 nucleotides, from near 1600 before near 4800 nucleotides, from near 1600 before near 4600 nucleotides, from near 1600 before near 4400 nucleotides, from near 1600 before near 4200 nucleotides, from near 1600 before near 4000 nucleotides, from near 1600 before near 3800 nucleotides, from near 1600 before near 3600 nucleotides, from near 1600 before near 3400 nucleotides, from near 1600 before near 3200 nucleotides, from near 1600 before near 3000 nucleotides, from near 1600 before near 2800 nucleotides,

- 50 045887

from near 1600 before near 2600 nucleotides, from near 1600 before near 2400 nucleotides, from near 1600 before near 2200 nucleotides, from near 1600 before near 2000 nucleotides, from near 1600 before near 1800 nucleotides, from near 1800 before near 15000 nucleotides, from near 1800 before near 14500 nucleotides, from near 1800 before near 14000 nucleotides, from near 1800 before near 13500 nucleotides, from near 1800 before near 13000 nucleotides, from near 1800 before near 12500 nucleotides, from near 1800 before near 12000 nucleotides, from near 1800 before near 11500 nucleotides, from near 1800 before near 11000 nucleotides, from near 1800 before near 10500 nucleotides, from near 1800 before near 10000 nucleotides, from near 1800 before near 9500 nucleotides, from near 1800 before near 9000 nucleotides, from near 1800 before near 8500 nucleotides, from near 1800 before near 8000 nucleotides, from near 1800 before near 7800 nucleotides, from near 1800 before near 7600 nucleotides, from near 1800 before near 7400 nucleotides, from near 1800 before near 7200 nucleotides, from near 1800 before near 7000 nucleotides, from near 1800 before near 6800 nucleotides, from near 1800 before near 6600 nucleotides, from near 1800 before near 6400 nucleotides, from near 1800 before near 6200 nucleotides, from near 1800 before near 6000 nucleotides, from near 1800 before near 5800 nucleotides, from near 1800 before near 5600 nucleotides, from near 1800 before near 5400 nucleotides, from near 1800 before near 5200 nucleotides, from near 1800 before near 5000 nucleotides, from near 1800 before near 4800 nucleotides, from near 1800 before near 4600 nucleotides, from near 1800 before near 4400 nucleotides, from near 1800 before near 4200 nucleotides, from near 1800 before near 4000 nucleotides, from near 1800 before near 3800 nucleotides, from near 1800 before near 3600 nucleotides, from near 1800 before near 3400 nucleotides, from near 1800 before near 3200 nucleotides, from near 1800 before near 3000 nucleotides, from near 1800 before near 2800 nucleotides, from near 1800 before near 2600 nucleotides, from near 1800 before near 2400 nucleotides, from near 1800 before near 2200 nucleotides, from near 1800 before near 2000 nucleotides, from near 2000 before near 15000 nucleotides, from near 2000 before near 14500 nucleotides, from near 2000 before near 14000 nucleotides, from near 2000 before near 13500 nucleotides, from near 2000 before near 13000 nucleotides, from near 2000 before near 12500 nucleotides, from near 2000 before near 12000 nucleotides, from near 2000 before near 11500 nucleotides, from near 2000 before near 11000 nucleotides, from near 2000 before near 10500 nucleotides, from near 2000 before near 10000 nucleotides, from near 2000 before near 9500 nucleotides, from near 2000 before near 9000 nucleotides, from near 2000 before near 8500 nucleotides, from near 2000 before near 8000 nucleotides, from near 2000 before near 7800 nucleotides, from near 2000 before near 7600 nucleotides, from near 2000 before near 7400 nucleotides, from near 2000 before near 7200 nucleotides, from near 2000 before near 7000 nucleotides, from near 2000 before near 6800 nucleotides, from near 2000 before near 6600 nucleotides, from near 2000 before near 6400 nucleotides, from near 2000 before near 6200 nucleotides, from near 2000 before near 6000 nucleotides, from near 2000 before near 5800 nucleotides, from near 2000 before near 5600 nucleotides, from near 2000 before near 5400 nucleotides, from near 2000 before near 5200 nucleotides, from near 2000 before near 5000 nucleotides, from near 2000 before near 4800 nucleotides, from near 2000 before near 4600 nucleotides, from near 2000 before near 4400 nucleotides, from near 2000 before near 4200 nucleotides, from near 2000 before near 4000 nucleotides, from near 2000 before near 3800 nucleotides, from near 2000 before near 3600 nucleotides, from near 2000 before near 3400 nucleotides, from near 2000 before near 3200 nucleotides, from near 2000 before near 3000 nucleotides, from near 2000 before near 2800 nucleotides, from near 2000 before near 2600 nucleotides, from near 2000 before near 2400 nucleotides, from near 2000 before near 2200 nucleotides, from near 2200 before near 15000 nucleotides, from near 2200 before near 14500 nucleotides, from near 2200 before near 14000 nucleotides, from near 2200 before near 13500 nucleotides, from near 2200 before near 13000 nucleotides, from near 2200 before near 12500 nucleotides, from near 2200 before near 12000 nucleotides, from near 2200 before near 11500 nucleotides, from near 2200 before near 11000 nucleotides, from near 2200 before near 10500 nucleotides, from about 2200 to about 10,000 nucleotides, from about 9500 nucleotides, from about 9000 nucleotides, from near 8500 nucleotides, from about 8000 nucleotides, from near 7800 nucleotides, from near 7600 nucleotides, from about 7400 nucleotides, from near 7200 nucleotides, from near 7000 nucleotides, from about 6800 nucleotides, from near 6600 nucleotides, from near 6400 nucleotides, from about 6200 nucleotides, from near 6000 nucleotides, from near 5800 nucleotides, from about 5600 nucleotides, from near 5400 nucleotides, from near 5200 nucleotides, from about 5000 nucleotides, from near 4800 nucleotides, from near 4600 nucleotides, from about 4400 nucleotides, from near 4200 nucleotides, from near 4000 nucleotides, from about 3800 nucleotides, from near 3600 nucleotides, from near 3400 nucleotides, from about 3200 nucleotides, from near 3000 nucleotides,

- 51 045887

from near 2800 nucleotides, from about 2600 nucleotides, from near 2400 nucleotides, from near 2400 before near 15000 nucleotides, from near 2400 before near 14500 nucleotides, from near 2400 before near 14000 nucleotides, from near 2400 before near 13500 nucleotides, from near 2400 before near 13000 nucleotides, from near 2400 before near 12500 nucleotides, from near 2400 before near 12000 nucleotides, from near 2400 before near 11500 nucleotides, from near 2400 before near 11000 nucleotides, from near 2400 before near 10500 nucleotides, from near 2400 before near 10000 nucleotides, from near 2400 before near 9500 nucleotides, from near 2400 before near 9000 nucleotides, from near 2400 before near 8500 nucleotides, from near 2400 before near 8000 nucleotides, from near 2400 before near 7800 nucleotides, from near 2400 before near 7600 nucleotides, from near 2400 before near 7400 nucleotides, from near 2400 before near 7200 nucleotides, from near 2400 before near 7000 nucleotides, from near 2400 before near 6800 nucleotides, from near 2400 before near 6600 nucleotides, from near 2400 before near 6400 nucleotides, from near 2400 before near 6200 nucleotides, from near 2400 before near 6000 nucleotides, from near 2400 before near 5800 nucleotides, from near 2400 before near 5600 nucleotides, from near 2400 before near 5400 nucleotides, from near 2400 before near 5200 nucleotides, from near 2400 before near 5000 nucleotides, from near 2400 before near 4800 nucleotides, from near 2400 before near 4600 nucleotides, from near 2400 before near 4400 nucleotides, from near 2400 before near 4200 nucleotides, from near 2400 before near 4000 nucleotides, from near 2400 before near 3800 nucleotides, from near 2400 before near 3600 nucleotides, from near 2400 before near 3400 nucleotides, from near 2400 before near 3200 nucleotides, from near 2400 before near 3000 nucleotides, from near 2400 before near 2800 nucleotides, from near 2400 before near 2600 nucleotides, from near 2600 before near 15000 nucleotides, from near 2600 before near 14500 nucleotides, from near 2600 before near 14000 nucleotides, from near 2600 before near 13500 nucleotides, from near 2600 before near 13000 nucleotides, from near 2600 before near 12500 nucleotides, from near 2600 before near 12000 nucleotides, from near 2600 before near 11500 nucleotides, from near 2600 before near 11000 nucleotides, from near 2600 before near 10500 nucleotides, from near 2600 before near 10000 nucleotides, from near 2600 before near 9500 nucleotides, from near 2600 before near 9000 nucleotides, from near 2600 before near 8500 nucleotides, from near 2600 before near 8000 nucleotides, from near 2600 before near 7800 nucleotides, from near 2600 before near 7600 nucleotides, from near 2600 before near 7400 nucleotides, from near 2600 before near 7200 nucleotides, from near 2600 before near 7000 nucleotides, from near 2600 before near 6800 nucleotides, from near 2600 before near 6600 nucleotides, from near 2600 before near 6400 nucleotides, from near 2600 before near 6200 nucleotides, from near 2600 before near 6000 nucleotides, from near 2600 before near 5800 nucleotides, from near 2600 before near 5600 nucleotides, from near 2600 before near 5400 nucleotides, from near 2600 before near 5200 nucleotides, from near 2600 before near 5000 nucleotides, from near 2600 before near 4800 nucleotides, from near 2600 before near 4600 nucleotides, from near 2600 before near 4400 nucleotides, from near 2600 before near 4200 nucleotides, from near 2600 before near 4000 nucleotides, from near 2600 before near 3800 nucleotides, from near 2600 before near 3600 nucleotides, from near 2600 before near 3400 nucleotides, from near 2600 before near 3200 nucleotides, from near 2600 before near 3000 nucleotides, from near 2600 before near 2800 nucleotides, from near 2800 before near 15000 nucleotides, from near 2800 before near 14500 nucleotides, from near 2800 before near 14000 nucleotides, from near 2800 before near 13500 nucleotides, from near 2800 before near 13000 nucleotides, from near 2800 before near 12500 nucleotides, from near 2800 before near 12000 nucleotides, from near 2800 before near 11500 nucleotides, from near 2800 before near 11000 nucleotides, from near 2800 before near 10500 nucleotides, from near 2800 before near 10000 nucleotides, from near 2800 before near 9500 nucleotides, from near 2800 before near 9000 nucleotides, from near 2800 before near 8500 nucleotides, from near 2800 before near 8000 nucleotides, from near 2800 before near 7800 nucleotides, from near 2800 before near 7600 nucleotides, from near 2800 before near 7400 nucleotides, from near 2800 before near 7200 nucleotides, from near 2800 before near 7000 nucleotides, from near 2800 before near 6800 nucleotides, from near 2800 before near 6600 nucleotides, from near 2800 before near 6400 nucleotides, from near 2800 before near 6200 nucleotides, from near 2800 before near 6000 nucleotides, from near 2800 before near 5800 nucleotides, from near 2800 before near 5600 nucleotides, from near 2800 before near 5400 nucleotides, from near 2800 before near 5200 nucleotides, from near 2800 before near 5000 nucleotides, from near 2800 before near 4800 nucleotides, from near 2800 before near 4600 nucleotides, from near 2800 before near 4400 nucleotides, from near 2800 before near 4200 nucleotides, from near 2800 before near 4000 nucleotides, from near 2800 before near 3800 nucleotides, from near 2800 before near 3600 nucleotides, from near 2800 before near 3400 nucleotides, from near 2800 before near 3200 nucleotides,

- 52 045887

from near 2800 before near 3000 nucleotides, from near 3000 before near 15000 nucleotides, from near 3000 before near 14500 nucleotides, from near 3000 before near 14000 nucleotides, from near 3000 before near 13500 nucleotides, from near 3000 before near 13000 nucleotides, from near 3000 before near 12500 nucleotides, from near 3000 before near 12000 nucleotides, from near 3000 before near 11500 nucleotides, from near 3000 before near 11000 nucleotides, from near 3000 before near 10500 nucleotides, from near 3000 before near 10000 nucleotides, from near 3000 before near 9500 nucleotides, from near 3000 before near 9000 nucleotides, from near 3000 before near 8500 nucleotides, from near 3000 before near 8000 nucleotides, from near 3000 before near 7800 nucleotides, from near 3000 before near 7600 nucleotides, from near 3000 before near 7400 nucleotides, from near 3000 before near 7200 nucleotides, from near 3000 before near 7000 nucleotides, from near 3000 before near 6800 nucleotides, from near 3000 before near 6600 nucleotides, from near 3000 before near 6400 nucleotides, from near 3000 before near 6200 nucleotides, from near 3000 before near 6000 nucleotides, from near 3000 before near 5800 nucleotides, from near 3000 before near 5600 nucleotides, from near 3000 before near 5400 nucleotides, from near 3000 before near 5200 nucleotides, from near 3000 before near 5000 nucleotides, from near 3000 before near 4800 nucleotides, from near 3000 before near 4600 nucleotides, from near 3000 before near 4400 nucleotides, from near 3000 before near 4200 nucleotides, from near 3000 before near 4000 nucleotides, from near 3000 before near 3800 nucleotides, from near 3000 before near 3600 nucleotides, from near 3000 before near 3400 nucleotides, from near 3000 before near 3200 nucleotides, from near 3200 before near 15000 nucleotides, from near 3200 before near 14500 nucleotides, from near 3200 before near 14000 nucleotides, from near 3200 before near 13500 nucleotides, from near 3200 before near 13000 nucleotides, from near 3200 before near 12500 nucleotides, from near 3200 before near 12000 nucleotides, from near 3200 before near 11500 nucleotides, from near 3200 before near 11000 nucleotides, from near 3200 before near 10500 nucleotides, from near 3200 before near 10000 nucleotides, from near 3200 before near 9500 nucleotides, from near 3200 before near 9000 nucleotides, from near 3200 before near 8500 nucleotides, from near 3200 before near 8000 nucleotides, from near 3200 before near 7800 nucleotides, from near 3200 before near 7600 nucleotides, from near 3200 before near 7400 nucleotides, from near 3200 before near 7200 nucleotides, from near 3200 before near 7000 nucleotides, from near 3200 before near 6800 nucleotides, from near 3200 before near 6600 nucleotides, from near 3200 before near 6400 nucleotides, from near 3200 before near 6200 nucleotides, from near 3200 before near 6000 nucleotides, from near 3200 before near 5800 nucleotides, from near 3200 before near 5600 nucleotides, from near 3200 before near 5400 nucleotides, from near 3200 before near 5200 nucleotides, from near 3200 before near 5000 nucleotides, from near 3200 before near 4800 nucleotides, from near 3200 before near 4600 nucleotides, from near 3200 before near 4400 nucleotides, from near 3200 before near 4200 nucleotides, from near 3200 before near 4000 nucleotides, from near 3200 before near 3800 nucleotides, from near 3200 before near 3600 nucleotides, from near 3200 before near 3400 nucleotides, from near 3400 before near 15000 nucleotides, from near 3400 before near 14500 nucleotides, from near 3400 before near 14000 nucleotides, from near 3400 before near 13500 nucleotides, from near 3400 before near 13000 nucleotides, from near 3400 before near 12500 nucleotides, from near 3400 before near 12000 nucleotides, from near 3400 before near 11500 nucleotides, from near 3400 before near 11000 nucleotides, from near 3400 before near 10500 nucleotides, from near 3400 before near 10000 nucleotides, from near 3400 before near 9500 nucleotides, from near 3400 before near 9000 nucleotides, from near 3400 before near 8500 nucleotides, from near 3400 before near 8000 nucleotides, from near 3400 before near 7800 nucleotides, from near 3400 before near 7600 nucleotides, from near 3400 before near 7400 nucleotides, from near 3400 before near 7200 nucleotides, from near 3400 before near 7000 nucleotides, from near 3400 before near 6800 nucleotides, from near 3400 before near 6600 nucleotides, from near 3400 before near 6400 nucleotides, from near 3400 before near 6200 nucleotides, from near 3400 before near 6000 nucleotides, from near 3400 before near 5800 nucleotides, from near 3400 before near 5600 nucleotides, from near 3400 before near 5400 nucleotides, from near 3400 before near 5200 nucleotides, from near 3400 before near 5000 nucleotides, from near 3400 before near 4800 nucleotides, from near 3400 before near 4600 nucleotides, from near 3400 before near 4400 nucleotides, from near 3400 before near 4200 nucleotides, from near 3400 before near 4000 nucleotides, from near 3400 before near 3800 nucleotides, from near 3400 before near 3600 nucleotides, from near 3600 before near 15000 nucleotides, from near 3600 before near 14500 nucleotides, from near 3600 before near 14000 nucleotides, from near 3600 before near 13500 nucleotides, from near 3600 before near 13000 nucleotides, from near 3600 before near 12500 nucleotides, from near 3600 before near 12000 nucleotides, from near 3600 before near 11500 nucleotides, from near 3600 before near 11000 nucleotides,

- 53 045887

from near 3600 before near 10500 nucleotides, from near 3600 before near 10000 nucleotides, from near 3600 before near 9500 nucleotides, from near 3600 before near 9000 nucleotides, from near 3600 before near 8500 nucleotides, from near 3600 before near 8000 nucleotides, from near 3600 before near 7800 nucleotides, from near 3600 before near 7600 nucleotides, from near 3600 before near 7400 nucleotides, from near 3600 before near 7200 nucleotides, from near 3600 before near 7000 nucleotides, from near 3600 before near 6800 nucleotides, from near 3600 before near 6600 nucleotides, from near 3600 before near 6400 nucleotides, from near 3600 before near 6200 nucleotides, from near 3600 before near 6000 nucleotides, from near 3600 before near 5800 nucleotides, from near 3600 before near 5600 nucleotides, from near 3600 before near 5400 nucleotides, from near 3600 before near 5200 nucleotides, from near 3600 before near 5000 nucleotides, from near 3600 before near 4800 nucleotides, from near 3600 before near 4600 nucleotides, from near 3600 before near 4400 nucleotides, from near 3600 before near 4200 nucleotides, from near 3600 before near 4000 nucleotides, from near 3600 before near 3800 nucleotides, from near 3800 before near 15000 nucleotides, from near 3800 before near 14500 nucleotides, from near 3800 before near 14000 nucleotides, from near 3800 before near 13500 nucleotides, from near 3800 before near 13000 nucleotides, from near 3800 before near 12500 nucleotides, from near 3800 before near 12000 nucleotides, from near 3800 before near 11500 nucleotides, from near 3800 before near 11000 nucleotides, from near 3800 before near 10500 nucleotides, from near 3800 before near 10000 nucleotides, from near 3800 before near 9500 nucleotides, from near 3800 before near 9000 nucleotides, from near 3800 before near 8500 nucleotides, from near 3800 before near 8000 nucleotides, from near 3800 before near 7800 nucleotides, from near 3800 before near 7600 nucleotides, from near 3800 before near 7400 nucleotides, from near 3800 before near 7200 nucleotides, from near 3800 before near 7000 nucleotides, from near 3800 before near 6800 nucleotides, from near 3800 before near 6600 nucleotides, from near 3800 before near 6400 nucleotides, from near 3800 before near 6200 nucleotides, from near 3800 before near 6000 nucleotides, from near 3800 before near 5800 nucleotides, from near 3800 before near 5600 nucleotides, from near 3800 before near 5400 nucleotides, from near 3800 before near 5200 nucleotides, from near 3800 before near 5000 nucleotides, from near 3800 before near 4800 nucleotides, from near 3800 before near 4600 nucleotides, from near 3800 before near 4200 nucleotides, from near 3800 before near 4000 nucleotides, from near 4000 before near 15000 nucleotides, from near 4000 before near 14500 nucleotides, from near 4000 before near 14000 nucleotides, from near 4000 before near 13500 nucleotides, from near 4000 before near 13000 nucleotides, from near 4000 before near 12500 nucleotides, from near 4000 before near 12000 nucleotides, from near 4000 before near 11500 nucleotides, from near 4000 before near 11000 nucleotides, from near 4000 before near 10500 nucleotides, from near 4000 before near 10000 nucleotides, from near 4000 before near 9500 nucleotides, from near 4000 before near 9000 nucleotides, from near 4000 before near 8500 nucleotides, from near 4000 before near 8000 nucleotides, from near 4000 before near 7800 nucleotides, from near 4000 before near 7600 nucleotides, from near 4000 before near 7400 nucleotides, from near 4000 before near 7200 nucleotides, from near 4000 before near 7000 nucleotides, from near 4000 before near 6800 nucleotides, from near 4000 before near 6600 nucleotides, from near 4000 before near 6400 nucleotides, from near 4000 before near 6200 nucleotides, from near 4000 before near 6000 nucleotides, from near 4000 before near 5800 nucleotides, from near 4000 before near 5600 nucleotides, from near 4000 before near 5400 nucleotides, from near 4000 before near 5200 nucleotides, from near 4000 before near 5000 nucleotides, from near 4000 before near 4800 nucleotides, from near 4000 before near 4600 nucleotides, from near 4000 before near 4400 nucleotides, from near 4000 before near 4200 nucleotides, from near 4200 before near 15000 nucleotides, from near 4200 before near 14500 nucleotides, from near 4200 before near 14000 nucleotides, from near 4200 before near 13500 nucleotides, from near 4200 before near 13000 nucleotides, from near 4200 before near 12500 nucleotides, from near 4200 before near 12000 nucleotides, from near 4200 before near 11500 nucleotides, from near 4200 before near 11000 nucleotides, from near 4200 before near 10500 nucleotides, from near 4200 before near 10000 nucleotides, from near 4200 before near 9500 nucleotides, from near 4200 before near 9000 nucleotides, from near 4200 before near 8500 nucleotides, from near 4200 before near 8000 nucleotides, from near 4200 before near 7800 nucleotides, from near 4200 before near 7600 nucleotides, from near 4200 before near 7400 nucleotides, from near 4200 before near 7200 nucleotides, from near 4200 before near 7000 nucleotides, from near 4200 before near 6800 nucleotides, from near 4200 before near 6600 nucleotides, from near 4200 before near 6400 nucleotides, from near 4200 before near 6200 nucleotides, from near 4200 before near 6000 nucleotides, from near 4200 before near 5800 nucleotides, from near 4200 before near 5600 nucleotides, from near 4200 before near 5400 nucleotides, from near 4200 before near 5200 nucleotides,

- 54 045887

from near 4200 before near 5000 nucleotides, from near 4200 before near 4800 nucleotides, from near 4200 before near 4600 nucleotides, from near 4200 before near 4400 nucleotides, from near 4400 before near 15000 nucleotides, from near 4400 before near 14500 nucleotides, from near 4400 before near 14000 nucleotides, from near 4400 before near 13500 nucleotides, from near 4400 before near 13000 nucleotides, from near 4400 before near 12500 nucleotides, from near 4400 before near 12000 nucleotides, from near 4400 before near 11500 nucleotides, from near 4400 before near 11000 nucleotides, from near 4400 before near 10500 nucleotides, from near 4400 before near 10000 nucleotides, from near 4400 before near 9500 nucleotides, from near 4400 before near 9000 nucleotides, from near 4400 before near 8500 nucleotides, from near 4400 before near 8000 nucleotides, from near 4400 before near 7800 nucleotides, from near 4400 before near 7600 nucleotides, from near 4400 before near 7400 nucleotides, from near 4400 before near 7200 nucleotides, from near 4400 before near 7000 nucleotides, from near 4400 before near 6800 nucleotides, from near 4400 before near 6600 nucleotides, from near 4400 before near 6400 nucleotides, from near 4400 before near 6200 nucleotides, from near 4400 before near 6000 nucleotides, from near 4400 before near 5800 nucleotides, from near 4400 before near 5600 nucleotides, from near 4400 before near 5400 nucleotides, from near 4400 before near 5200 nucleotides, from near 4400 before near 5000 nucleotides, from near 4400 before near 4800 nucleotides, from near 4400 before near 4600 nucleotides, from near 4600 before near 15000 nucleotides, from near 4600 before near 14500 nucleotides, from near 4600 before near 14000 nucleotides, from near 4600 before near 13500 nucleotides, from near 4600 before near 13000 nucleotides, from near 4600 before near 12500 nucleotides, from near 4600 before near 12000 nucleotides, from near 4600 before near 11500 nucleotides, from near 4600 before near 11000 nucleotides, from near 4600 before near 10500 nucleotides, from near 4600 before near 10000 nucleotides, from near 4600 before near 9500 nucleotides, from near 4600 before near 9000 nucleotides, from near 4600 before near 8500 nucleotides, from near 4600 before near 8000 nucleotides, from near 4600 before near 7800 nucleotides, from near 4600 before near 7600 nucleotides, from near 4600 before near 7400 nucleotides, from near 4600 before near 7200 nucleotides, from near 4600 before near 7000 nucleotides, from near 4600 before near 6800 nucleotides, from near 4600 before near 6600 nucleotides, from near 4600 before near 6400 nucleotides, from near 4600 before near 6200 nucleotides, from near 4600 before near 6000 nucleotides, from near 4600 before near 5800 nucleotides, from near 4600 before near 5600 nucleotides, from near 4600 before near 5400 nucleotides, from near 4600 before near 5200 nucleotides, from near 4600 before near 5000 nucleotides, from near 4600 before near 4800 nucleotides, from near 4800 before near 15000 nucleotides, from near 4800 before near 14500 nucleotides, from near 4800 before near 14000 nucleotides, from near 4800 before near 13500 nucleotides, from near 4800 before near 13000 nucleotides, from near 4800 before near 12500 nucleotides, from near 4800 before near 12000 nucleotides, from near 4800 before near 11500 nucleotides, from near 4800 before near 11000 nucleotides, from near 4800 before near 10500 nucleotides, from near 4800 before near 10000 nucleotides, from near 4800 before near 9500 nucleotides, from near 4800 before near 9000 nucleotides, from near 4800 before near 8500 nucleotides, from near 4800 before near 8000 nucleotides, from near 4800 before near 7800 nucleotides, from near 4800 before near 7600 nucleotides, from near 4800 before near 7400 nucleotides, from near 4800 before near 7200 nucleotides, from near 4800 before near 7000 nucleotides, from near 4800 before near 6800 nucleotides, from near 4800 before near 6600 nucleotides, from near 4800 before near 6400 nucleotides, from near 4800 before near 6200 nucleotides, from near 4800 before near 6000 nucleotides, from near 4800 before near 5800 nucleotides, from near 4800 before near 5600 nucleotides, from near 4800 before near 5400 nucleotides, from near 4800 before near 5200 nucleotides, from near 4800 before near 5000 nucleotides, from near 5000 before near 15000 nucleotides, from near 5000 before near 14500 nucleotides, from near 5000 before near 14000 nucleotides, from near 5000 before near 13500 nucleotides, from near 5000 before near 13000 nucleotides, from near 5000 before near 12500 nucleotides, from near 5000 before near 12000 nucleotides, from near 5000 before near 11500 nucleotides, from near 5000 before near 11000 nucleotides, from near 5000 before near 10500 nucleotides, from near 5000 before near 10000 nucleotides, from near 5000 before near 9500 nucleotides, from near 5000 before near 9000 nucleotides, from near 5000 before near 8500 nucleotides, from near 5000 before near 8000 nucleotides, from near 5000 before near 7800 nucleotides, from near 5000 before near 7600 nucleotides, from near 5000 before near 7400 nucleotides, from near 5000 before near 7200 nucleotides, from near 5000 before near 7000 nucleotides, from near 5000 before near 6800 nucleotides, from near 5000 before near 6600 nucleotides, from near 5000 before near 6400 nucleotides, from near 5000 before near 6200 nucleotides, from near 5000 before near 6000 nucleotides, from near 5000 before near 5800 nucleotides, from near 5000 before near 5600 nucleotides,

- 55 045887

from near 5000 before near 5400 nucleotides, from near 5000 before near 5200 nucleotides, from near 5200 before near 15000 nucleotides, from near 5200 before near 14500 nucleotides, from near 5200 before near 14000 nucleotides, from near 5200 before near 13500 nucleotides, from near 5200 before near 13000 nucleotides, from near 5200 before near 12500 nucleotides, from near 5200 before near 12000 nucleotides, from near 5200 before near 11500 nucleotides, from near 5200 before near 11000 nucleotides, from near 5200 before near 10500 nucleotides, from near 5200 before near 10000 nucleotides, from near 5200 before near 9500 nucleotides, from near 5200 before near 9000 nucleotides, from near 5200 before near 8500 nucleotides, from near 5200 before near 8000 nucleotides, from near 5200 before near 7800 nucleotides, from near 5200 before near 7600 nucleotides, from near 5200 before near 7400 nucleotides, from near 5200 before near 7200 nucleotides, from near 5200 before near 7000 nucleotides, from near 5200 before near 6800 nucleotides, from near 5200 before near 6600 nucleotides, from near 5200 before near 6400 nucleotides, from near 5200 before near 6200 nucleotides, from near 5200 before near 6000 nucleotides, from near 5200 before near 5800 nucleotides, from near 5200 before near 5600 nucleotides, from near 5200 before near 5400 nucleotides, from near 5400 before near 15000 nucleotides, from near 5400 before near 14500 nucleotides, from near 5400 before near 14000 nucleotides, from near 5400 before near 13500 nucleotides, from near 5400 before near 13000 nucleotides, from near 5400 before near 12500 nucleotides, from near 5400 before near 12000 nucleotides, from near 5400 before near 11500 nucleotides, from near 5400 before near 11000 nucleotides, from near 5400 before near 10500 nucleotides, from near 5400 before near 10000 nucleotides, from near 5400 before near 9500 nucleotides, from near 5400 before near 9000 nucleotides, from near 5400 before near 8500 nucleotides, from near 5400 before near 8000 nucleotides, from near 5400 before near 7800 nucleotides, from near 5400 before near 7600 nucleotides, from near 5400 before near 7400 nucleotides, from near 5400 before near 7200 nucleotides, from near 5400 before near 7000 nucleotides, from near 5400 before near 6800 nucleotides, from near 5400 before near 6600 nucleotides, from near 5400 before near 6400 nucleotides, from near 5400 before near 6200 nucleotides, from near 5400 before near 6000 nucleotides, from near 5400 before near 5800 nucleotides, from near 5400 before near 5600 nucleotides, from near 5600 before near 15000 nucleotides, from near 5600 before near 14500 nucleotides, from near 5600 before near 14000 nucleotides, from near 5600 before near 13500 nucleotides, from near 5600 before near 13000 nucleotides, from near 5600 before near 12500 nucleotides, from near 5600 before near 12000 nucleotides, from near 5600 before near 11500 nucleotides, from near 5600 before near 11000 nucleotides, from near 5600 before near 10500 nucleotides, from near 5600 before near 10000 nucleotides, from near 5600 before near 9500 nucleotides, from near 5600 before near 9000 nucleotides, from near 5600 before near 8500 nucleotides, from near 5600 before near 8000 nucleotides, from near 5600 before near 7800 nucleotides, from near 5600 before near 7600 nucleotides, from near 5600 before near 7400 nucleotides, from near 5600 before near 7200 nucleotides, from near 5600 before near 7000 nucleotides, from near 5600 before near 6800 nucleotides, from near 5600 before near 6600 nucleotides, from near 5600 before near 6400 nucleotides, from near 5600 before near 6200 nucleotides, from near 5600 before near 6000 nucleotides, from near 5600 before near 5800 nucleotides, from near 5800 before near 15000 nucleotides, from near 5800 before near 14500 nucleotides, from near 5800 before near 14000 nucleotides, from near 5800 before near 13500 nucleotides, from near 5800 before near 13000 nucleotides, from near 5800 before near 12500 nucleotides, from near 5800 before near 12000 nucleotides, from near 5800 before near 11500 nucleotides, from near 5800 before near 11000 nucleotides, from near 5800 before near 10500 nucleotides, from near 5800 before near 10000 nucleotides, from near 5800 before near 9500 nucleotides, from near 5800 before near 9000 nucleotides, from near 5800 before near 8500 nucleotides, from near 5800 before near 8000 nucleotides, from near 5800 before near 7800 nucleotides, from near 5800 before near 7600 nucleotides, from near 5800 before near 7400 nucleotides, from near 5800 before near 7200 nucleotides, from near 5800 before near 7000 nucleotides, from near 5800 before near 6800 nucleotides, from near 5800 before near 6600 nucleotides, from near 5800 before near 6400 nucleotides, from near 5800 before near 6200 nucleotides, from near 5800 before near 6000 nucleotides, from near 6000 before near 15000 nucleotides, from near 6000 before near 14500 nucleotides, from near 6000 before near 14000 nucleotides, from near 6000 before near 13500 nucleotides, from near 6000 before near 13000 nucleotides, from near 6000 before near 12500 nucleotides, from near 6000 before near 12000 nucleotides, from near 6000 before near 11500 nucleotides, from near 6000 before near 11000 nucleotides, from near 6000 before near 10500 nucleotides, from near 6000 before near 10000 nucleotides, from near 6000 before near 9500 nucleotides, from near 6000 before near 9000 nucleotides, from near 6000 before near 8500 nucleotides, from near 6000 before near 8000 nucleotides, from near 6000 before near 7800 nucleotides,

- 56 045887

from near 6000 before near 7600 nucleotides, from near 6000 before near 7400 nucleotides, from near 6000 before near 7200 nucleotides, from near 6000 before near 7000 nucleotides, from near 6000 before near 6800 nucleotides, from near 6000 before near 6600 nucleotides, from near 6000 before near 6400 nucleotides, from near 6000 before near 6200 nucleotides, from near 6200 before near 15000 nucleotides, from near 6200 before near 14500 nucleotides, from near 6200 before near 14000 nucleotides, from near 6200 before near 13500 nucleotides, from near 6200 before near 13000 nucleotides, from near 6200 before near 12500 nucleotides, from near 6200 before near 12000 nucleotides, from near 6200 before near 11500 nucleotides, from near 6200 before near 11000 nucleotides, from near 6200 before near 10500 nucleotides, from near 6200 before near 10000 nucleotides, from near 6200 before near 9000 nucleotides, from near 6200 before near 8500 nucleotides, from near 6200 before near 8000 nucleotides, from near 6200 before near 7800 nucleotides, from near 6200 before near 7600 nucleotides, from near 6200 before near 7400 nucleotides, from near 6200 before near 7200 nucleotides, from near 6200 before near 7000 nucleotides, from near 6200 before near 6800 nucleotides, from near 6200 before near 6600 nucleotides, from near 6200 before near 6400 nucleotides, from near 6400 before near 15000 nucleotides, from near 6400 before near 14500 nucleotides, from near 6400 before near 14000 nucleotides, from near 6400 before near 13500 nucleotides, from near 6400 before near 13000 nucleotides, from near 6400 before near 12500 nucleotides, from near 6400 before near 12000 nucleotides, from near 6400 before near 11500 nucleotides, from near 6400 before near 11000 nucleotides, from near 6400 before near 10500 nucleotides, from near 6400 before near 10000 nucleotides, from near 6400 before near 9500 nucleotides, from near 6400 before near 9000 nucleotides, from near 6400 before near 8500 nucleotides, from near 6400 before near 8000 nucleotides, from near 6400 before near 7800 nucleotides, from near 6400 before near 7600 nucleotides, from near 6400 before near 7400 nucleotides, from near 6400 before near 7200 nucleotides, from near 6400 before near 7000 nucleotides, from near 6400 before near 6800 nucleotides, from near 6400 before near 6600 nucleotides, from near 6600 before near 15000 nucleotides, from near 6600 before near 14500 nucleotides, from near 6600 before near 14000 nucleotides, from near 6600 before near 13500 nucleotides, from near 6600 before near 13000 nucleotides, from near 6600 before near 12500 nucleotides, from near 6600 before near 12000 nucleotides, from near 6600 before near 11500 nucleotides, from near 6600 before near 11000 nucleotides, from near 6600 before near 10500 nucleotides, from near 6600 before near 10000 nucleotides, from near 6600 before near 9500 nucleotides, from near 6600 before near 9000 nucleotides, from near 6600 before near 8500 nucleotides, from near 6600 before near 8000 nucleotides, from near 6600 before near 7800 nucleotides, from near 6600 before near 7600 nucleotides, from near 6600 before near 7400 nucleotides, from near 6600 before near 7200 nucleotides, from near 6600 before near 7000 nucleotides, from near 6600 before near 6800 nucleotides, from near 6800 before near 15000 nucleotides, from near 6800 before near 14500 nucleotides, from near 6800 before near 14000 nucleotides, from near 6800 before near 13500 nucleotides, from near 6800 before near 13000 nucleotides, from near 6800 before near 12500 nucleotides, from near 6800 before near 12000 nucleotides, from near 6800 before near 11500 nucleotides, from near 6800 before near 11000 nucleotides, from near 6800 before near 10500 nucleotides, from near 6800 before near 10000 nucleotides, from near 6800 before near 9500 nucleotides, from near 6800 before near 9000 nucleotides, from near 6800 before near 8500 nucleotides, from near 6800 before near 8000 nucleotides, from near 6800 before near 7800 nucleotides, from near 6800 before near 7600 nucleotides, from near 6800 before near 7400 nucleotides, from near 6800 before near 7200 nucleotides, from near 6800 before near 7000 nucleotides, from near 7000 before near 15000 nucleotides, from near 7000 before near 14500 nucleotides, from near 7000 before near 14000 nucleotides, from near 7000 before near 13500 nucleotides, from near 7000 before near 13000 nucleotides, from near 7000 before near 12500 nucleotides, from near 7000 before near 12000 nucleotides, from near 7000 before near 11500 nucleotides, from near 7000 before near 11000 nucleotides, from near 7000 before near 10500 nucleotides, from near 7000 before near 10000 nucleotides, from near 7000 before near 9500 nucleotides, from near 7000 before near 9000 nucleotides, from near 7000 before near 8500 nucleotides, from near 7000 before near 8000 nucleotides, from near 7000 before near 7800 nucleotides, from near 7000 before near 7600 nucleotides, from near 7000 before near 7400 nucleotides, from near 7000 before near 7200 nucleotides, from near 7200 before near 15000 nucleotides, from near 7200 before near 14500 nucleotides, from near 7200 before near 14000 nucleotides, from near 7200 before near 13500 nucleotides, from near 7200 before near 13000 nucleotides, from near 7200 before near 12500 nucleotides, from near 7200 before near 12000 nucleotides, from near 7200 before near 11500 nucleotides, from near 7200 before near 11000 nucleotides, from near 7200 before near 10500 nucleotides, from near 7200 before near 10000 nucleotides, from near 7200 before near 9500 nucleotides,

- 57 045887

from near 7200 before near 9000 nucleotides, from near 7200 before near 8500 nucleotides, from near 7200 before near 8000 nucleotides, from near 7200 before near 7800 nucleotides, from near 7200 before near 7600 nucleotides, from near 7200 before near 7400 nucleotides, from near 7400 before near 15000 nucleotides, from near 7400 before near 14500 nucleotides, from near 7400 before near 14000 nucleotides, from near 7400 before near 13500 nucleotides, from near 7400 before near 13000 nucleotides, from near 7400 before near 12500 nucleotides, from near 7400 before near 12000 nucleotides, from near 7400 before near 11500 nucleotides, from near 7400 before near 11000 nucleotides, from near 7400 before near 10500 nucleotides, from near 7400 before near 10000 nucleotides, from near 7400 before near 9500 nucleotides, from near 7400 before near 9000 nucleotides, from near 7400 before near 8500 nucleotides, from near 7400 before near 8000 nucleotides, from near 7400 before near 7800 nucleotides, from near 7400 before near 7600 nucleotides, from near 7600 before near 15000 nucleotides, from near 7600 before near 14500 nucleotides, from near 7600 before near 14000 nucleotides, from near 7600 before near 13500 nucleotides, from near 7600 before near 13000 nucleotides, from near 7600 before near 12500 nucleotides, from near 7600 before near 12000 nucleotides, from near 7600 before near 11500 nucleotides, from near 7600 before near 11000 nucleotides, from near 7600 before near 10500 nucleotides, from near 7600 before near 10000 nucleotides, from near 7600 before near 9500 nucleotides, from near 7600 before near 9000 nucleotides, from near 7600 before near 8500 nucleotides, from near 7600 before near 8000 nucleotides, from near 7600 before near 7800 nucleotides, from near 7800 before near 15000 nucleotides, from near 7800 before near 14500 nucleotides, from near 7800 before near 14000 nucleotides, from near 7800 before near 13500 nucleotides, from near 7800 before near 13000 nucleotides, from near 7800 before near 12500 nucleotides, from near 7800 before near 12000 nucleotides, from near 7800 before near 11500 nucleotides, from near 7800 before near 11000 nucleotides, from near 7800 before near 10500 nucleotides, from near 7800 before near 10000 nucleotides, from near 7800 before near 9500 nucleotides, from near 7800 before near 9000 nucleotides, from near 7800 before near 8500 nucleotides, from near 7800 before near 8000 nucleotides, from near 8000 before near 15000 nucleotides, from near 8000 before near 14500 nucleotides, from near 8000 before near 14000 nucleotides, from near 8000 before near 13500 nucleotides, from near 8000 before near 13000 nucleotides, from near 8000 before near 12500 nucleotides, from near 8000 before near 12000 nucleotides, from near 8000 before near 11500 nucleotides, from near 8000 before near 11000 nucleotides, from near 8000 before near 10500 nucleotides, from near 8000 before near 10000 nucleotides, from near 8000 before near 9500 nucleotides, from near 8000 before near 9000 nucleotides, from near 8000 before near 8500 nucleotides, from near 8500 before near 15000 nucleotides, from near 8500 before near 14500 nucleotides, from near 8500 before near 14000 nucleotides, from near 8500 before near 13500 nucleotides, from near 8500 before near 13000 nucleotides, from near 8500 before near 12500 nucleotides, from near 8500 before near 12000 nucleotides, from near 8500 before near 11500 nucleotides, from near 8500 before near 11000 nucleotides, from near 8500 before near 10500 nucleotides, from near 8500 before near 10000 nucleotides, from near 8500 before near 9500 nucleotides, from near 8500 before near 9000 nucleotides, from near 9000 before near 15000 nucleotides, from near 9000 before near 14500 nucleotides, from near 9000 before near 14000 nucleotides, from near 9000 before near 13500 nucleotides, from near 9000 before near 13000 nucleotides, from near 9000 before near 12500 nucleotides, from near 9000 before near 12000 nucleotides, from near 9000 before near 11500 nucleotides, from near 9000 before near 11000 nucleotides, from near 9000 before near 10500 nucleotides, from near 9000 before near 10000 nucleotides, from near 9000 before near 9500 nucleotides, from near 9500 before near 10000 nucleotides, from near 10000 before near 15000 nucleotides, from near 10000 before near 14500 nucleotides, from near 10000 before near 14000 nucleotides, from near 10000 before near 13500 nucleotides, from near 10000 before near 13000 nucleotides, from near 10000 before near 12500 nucleotides, from near 10000 before near 12000 nucleotides, from near 10000 before near 11500 nucleotides, from near 10000 before near 11000 nucleotides, from near 10000 before near 10500 nucleotides, from near 10500 before near 15000 nucleotides, from near 10500 before near 14500 nucleotides, from near 10500 before near 14000 nucleotides, from near 10500 before near 13500 nucleotides, from near 10500 before near 13000 nucleotides, from near 10500 before near 12500 nucleotides, from near 10500 before near 12000 nucleotides, from near 10500 before near 11500 nucleotides, from near 10500 before near 11000 nucleotides, from near 11000 before near 15000 nucleotides, from near 11000 before near 14500 nucleotides, from near 11000 before near 14000 nucleotides, from near 11000 before near 13500 nucleotides, from near 11000 before near 13000 nucleotides, from near 11000 before near 12500 nucleotides, from near 11000 before near 12000 nucleotides, from near 11000 before near 11500 nucleotides, from near 11500 before near 15000 nucleotides, from near 11500 before near 14500 nucleotides, from near 11500 before near 14000 nucleotides,

- 58 045887 from from from from from from from from from from from from from

near 11500 before near 13500 nucleotides, from near 11500 before near 13000 nucleotides, near 11500 before near 12500 nucleotides, from near 11500 before near 12000 nucleotides, near 12000 before near 15000 nucleotides, from near 12000 before near 14500 nucleotides, near 12000 before near 14000 nucleotides, from near 12000 before near 13500 nucleotides, near 12000 before near 13000 nucleotides, from near 12000 before near 12500 nucleotides, near 12500 before near 15000 nucleotides, from near 12500 before near 14500 nucleotides, near 12500 before near 14000 nucleotides, from near 12500 before near 13500 nucleotides, near 12500 before near 13000 nucleotides, from near 13000 before near 15000 nucleotides, near 13000 before near 14500 nucleotides, from near 13000 before near 14000 nucleotides, near 13000 before near 13500 nucleotides, from near 13500 before near 15000 nucleotides, near 13500 before near 14500 nucleotides, from near 13500 before near 14000 nucleotides,

about 14,000 to about 15,000 nucleotides, about 14,000 to about 14,500 nucleotides, or about 14,500 to about 15,000 nucleotides (inclusive).

Provided herein are illustrative vectors that can be used in any of the compositions and methods described herein, see, for example, FIG. 1-24.

To introduce any of the vectors described herein into a mammalian cell (eg, inner cochlear hair cell, outer cochlear hair cell, retinal cell), many different methods known in the art can be used. Non-limiting examples of methods for introducing a nucleic acid into a mammalian cell include lipofection, transfection (e.g., calcium phosphate transfection, highly branched organic transfection, transfection using cationic polymers, dendrimer-based transfection, optical transfection, particle-based transfection (e.g., nanoparticle transfection ) or transfection using liposomes (eg cationic liposomes)), microinjection, electroporation, cell compression, sonoporation, protoplast fusion, impalefection, hydrodynamic delivery, gene gun, magnetofection, viral transfection and nucleofection.

Those skilled in the art will appreciate that any of the vectors described herein can be introduced into a mammalian cell, for example, by lipofection, and can be stably integrated into an endogenous gene locus (eg, the CLRN1 gene locus). In some embodiments, the vectors provided herein stably integrate into the endogenous defective CLRN1 gene locus and thereby replace the defective CLRN1 gene with a nucleic acid encoding a functional (eg, wild-type) CLRN1 protein.

Various molecular biology techniques are also known in the art that can be used to introduce mutation(s) and/or deletion(s) into an endogenous gene. Non-limiting examples of such methods include site-directed mutagenesis, CRISPR (eg, CRISPR/Cas9-induced knock-in mutations and CRISPR/Cas9-induced knock-in mutations) and TALEN. These methods can be used to correct the sequence of a defective endogenous gene present on the chromosome of a target cell.

Any of the vectors described herein may further comprise a control sequence, for example a control sequence selected from the group of a transcription initiation sequence, a transcription termination sequence, a promoter sequence, an enhancer sequence, an RNA splicing sequence, a polyadenylation (polyA) sequence, and a Kozak consensus sequence. Non-limiting examples of these control sequences are described herein. In some embodiments, the promoter may be a native promoter, a constitutive promoter, an inducible promoter, and/or a tissue-specific promoter.

Promoters.

The term promoter means a DNA sequence recognized by enzymes/proteins in a mammalian cell necessary to initiate transcription of a particular gene (eg, the CLRN1 gene). A promoter generally refers, for example, to a nucleotide sequence to which RNA polymerase and/or any associated factor binds and with which transcription is initiated. Non-limiting examples of promoters are described herein. Additional examples of promoters are known in the art.

In some embodiments, a vector encoding the N-terminal portion of a CLRN1 protein (eg, human CLRN1 protein) may contain a promoter and/or enhancer. The vector encoding the N-terminal portion of the CLRN1 protein may contain any of the promoters and/or enhancers described herein or known in the art.

In some embodiments, the promoter is an inducible promoter, a constitutive promoter, a mammalian cell promoter, a viral promoter, a chimeric promoter, an engineered promoter, a tissue-specific promoter, or any other type of promoter known in the art. In some embodiments, the promoter is an RNA polymerase II promoter, such as a mammalian RNA polymerase II promoter. In some

- 59 045887 embodiments, the promoter is an RNA polymerase III promoter, including, but not limited to, the H1 promoter, the human U6 promoter, the mouse U6 promoter, or the porcine U6 promoter. The promoter will typically be one that is capable of stimulating transcription in the inner hair cell. In some examples, the promoter is a snail-specific promoter or a snail-specific promoter.

There are many promoters known in the art that can be used herein. Non-limiting examples of promoters that may be used herein include promoters from human EF1a, human cytomegalovirus (CMV) (U.S. Patent No. 5,168,062), human ubiquitin C (UBC), mouse phosphoglycerate kinase 1, polyoma adenovirus, simian virus 40 (SV40) , β-globin, β-actin, α-fetoprotein, γ-globin, β-interferon, γ-glutamyltransferase, mouse mammary tumor virus (MMTV), Rous sarcoma virus, rat insulin, glyceraldehyde-3-phosphate dehydrogenase, metallothionein II ( MT II), amylase, cathepsin, muscarinic receptor MI, retroviral LTR (e.g. human T-cell leukemia virus HTLV), AAV ITR, interleukin-2, collagenase, platelet-derived growth factor, adenovirus 5 E2, stromelysin, mouse MX gene, glucose-regulated proteins (GRP78 and GRP94), α-2-macroglobulin, vimentin, MHC class I gene, H-2k b, HSP70, proliferin, tumor necrosis factor, thyroid-stimulating hormone α gene, immunoglobulin light chain, T-cell receptor, DQa and DQe HLA, interleukin-2 receptor, MHC class II, HLA-DRa MHC class II, muscle creatine kinase, prealbumin (transthyretin), elastase I, albumin gene, c-fos, c-HA-ras, nerve cell adhesion molecule ( NCAM), histone H2B (TH2B), rat growth hormone, human serum amyloid (SAA), troponin I (TN I), Duchenne muscular dystrophy, human immunodeficiency virus and gibbon leukemia virus (GALV). Additional examples of promoters are known in the art, see, for example, Lodish, Molecular Cell Biology, Freeman and Company, New York, 2007. In some embodiments, the promoter is a CMV immediate-early promoter. In some embodiments, the promoter is a CAG promoter or a CAG/CBA promoter. In some embodiments, the promoter is a CBA promoter, such as a CBA promoter comprising or consisting of SEQ ID NO: 18.

The term constitutive promoter refers to a nucleotide sequence that, when operably linked to a protein-encoding nucleic acid (eg, the CLRN1 protein), causes the transcription of RNA from the nucleic acid in a mammalian cell under most or all physiological conditions.

Examples of constitutive promoters include, but are not limited to, the retroviral Rous sarcoma virus (RSV) LTR promoter, the cytomegalovirus (CMV) promoter (see, e.g., Boshart et al., Cell, 41:521-530, 1985), the SV40 promoter, the dihydrofolate reductase promoter , beta-actin promoter, phosphoglycerol kinase (PGK) promoter, and EF1-alpha promoter (Invitrogen).

Inducible promoters allow regulation of gene expression and can be regulated by exogenously supplied compounds, environmental factors such as temperature, or the presence of a specific physiological condition, such as acute phase, a particular cell differentiation state, or only in replicating cells. Inducible promoters and inducible systems are available from a variety of commercial sources, including, but not limited to, Invitrogen, Clontech and Ariad. Additional examples of inducible promoters are known in the art.

Examples of inducible promoters regulated by exogenously supplied compounds include the zinc-inducible ovine metallothionein (MT) promoter, the dexamethasone (Dex)-inducible mouse mammary tumor virus (MMTV) promoter, the T7 polymerase promoter system (WO 98/10088); insect ecdysone promoter (No et al. Proc. Natl. Acad. Sci. U.S.A., 93:33463351, 1996), tetracycline-repressible system (Gossen et al. Proc. Natl. Acad. Sci. U.S.A., 89:55475551, 1992) , tetracycline-inducible system (Gossen et al. Science, 268:1766-1769, 1995, see also Harvey et al. Curr. Opin. Chem. Biol. 2:512-518, 1998), RU486-inducible system (Wang et al., Nat. Biotech. 15:239-243, 1997) and Wang et al., Gene Ther. 4:432-441, 1997) and the rapamycin-inducible system (Magari et al., J. Clin. Invest. 100:2865-2872, 1997).

The term tissue-specific promoter refers to a promoter that is active only in certain cell types and/or tissues (eg, transcription of a particular gene occurs only in cells expressing transcriptional regulatory proteins that bind to the tissue-specific promoter).

In some embodiments, regulatory sequences provide tissue-specific gene expression capabilities. In some cases, tissue-specific regulatory sequences bind tissue-specific transcription factors that induce transcription in a tissue-specific manner.

Typical tissue-specific promoters include, but are not limited to, liver-specific thyroxine-binding globulin (TBG) promoter, insulin promoter, glucagon promoter,

- 60 045887 somatostatin promoter, pancreatic polypeptide (PPY) promoter, synapsin-1 (Syn) promoter, creatine kinase (MCC) promoter, mammalian desmin (DES) promoter, alpha-myosin heavy chain (α-MHC) promoter and cardiac troponin T promoter (sTpT). Additional exemplary promoters include the beta-actin promoter, the hepatitis B virus core promoter (Sandig et al., Gene Ther. 3:1002-1009, 1996), the alpha-fetoprotein (AFP) promoter (Arbuthnot et al., Hum. Gene Ther. 7:15031514, 1996), bone osteocalcin promoter (Stein et al., Mol. Biol. Rep. 24:185-196, 1997); bone sialoprotein promoter (Chen et al., J. Bone Miner. Res. 11:654-664, 1996), CD2 promoter (Hansal et al., J. Immunol. 161:1063-1068, 1998); immunoglobulin heavy chain promoter; T cell receptor alpha chain promoter, neuronal promoter such as neuron-specific enolase (NSE) promoter (Andersen et al., Cell. Mol. Neurobiol. 13:503-515, 1993), neurofilament light chain gene promoter (Piccioli et al., Proc. Natl. Acad. Sci. U.S.A., 88:5611-5615, 1991) and the neuron-specific vgf gene promoter (Piccioli et al., Neuron, 15:373-384, 1995).

In some embodiments, the tissue-specific promoter is a snail-specific promoter. In some embodiments, the tissue-specific promoter is a promoter specific for cochlear hair cells. Non-limiting examples of cochlear hair cell-specific promoters include, but are not limited to, the ATOH1 promoter, the POU4F3 promoter, the LHX3 promoter, the MYO7A promoter, the MYO6 promoter, the a9ACHR promoter, and the a10ACHR promoter. In some embodiments, the promoter is a cochlear hair cell-specific promoter, such as the PRESTIN promoter or the ONCOMOD promoter. See, for example, Zheng et al., Nature, 405:149-155, 2000; Tian et al., Dev. Dyn. 231:199-203, 2004 and Ryan et al., Adv. Otorhinolaryngol. 66:99-115, 2009.

Enhancers.

In some cases, the vector may contain an enhancer sequence. The term enhancer refers to a nucleotide sequence that can increase the level of transcription of a nucleic acid encoding a protein of interest (eg, the CLRN1 protein). Enhancer sequences (50–1500 bp in length) typically increase the level of transcription by providing additional binding sites for transcription-related proteins (eg, transcription factors). In some embodiments, the enhancer sequence is within an intron sequence. Unlike promoter sequences, enhancer sequences can act at a much greater distance from the transcription start site (eg, compared to the promoter). Non-limiting examples of enhancers include the RSV enhancer, the CMV enhancer, and the SV40 enhancer. In some embodiments, the CMV enhancer sequence comprises or consists of SEQ ID NO: 17.

Poly(A) signal.

In some embodiments, any of the vectors provided herein may contain a polyadenylation (poly(A)) signal sequence. Most nascent eukaryotic mRNAs have a poly(A) tail at their 3' end, which is added during a complex process that involves cleavage of the primary transcript and the associated polyadenylation reaction caused by the poly(A) signal sequence (see, for example, Proudfoot et al., Cell 108:501-512, 2002). The poly(A) tail confers stability and transportability on the mRNA (Molecular Biology of the Cell, Third Edition by B. Alberts et al., Garland Publishing, 1994). In some embodiments, the poly(A) signal sequence is located 3' to a nucleic acid sequence encoding the C terminus of the CLRN1 protein.

As used herein, the term polyadenylation refers to the covalent bonding of a polyadenyl moiety or a modified version thereof to a messenger RNA molecule. In eukaryotes, most messenger RNA (mRNA) molecules are polyadenylated at the 3' end. The 3'-poly(A) tail is a long sequence of adenine nucleotides (e.g., 50, 60, 70, 100, 200, 500, 1000, 2000, 3000, 4000, or 5000) added to the pre-mRNA by the action of the enzyme polyadenylate -polymerases. In higher eukaryotes, a poly(A) tail is added to transcripts that contain a specific sequence, the polyadenylation (or poly(A)) signal. The poly(A) tail and its associated protein help protect the mRNA from degradation by exonucleases. Polyadenylation is also important for transcription termination, nuclear export of mRNA, and translation. Polyadenylation occurs in the nucleus immediately after transcription of DNA into RNA, but can also occur later in the cytoplasm. After transcription ends, the mRNA strand is cleaved by the action of an endonuclease complex associated with RNA polymerase. A cleavage site is typically characterized by the presence of the base sequence AAUAAA near the cleavage site. After mRNA cleavage, adenosine residues are added to the free 3' end at the cleavage site.

As used herein, a poly(A) signal sequence or polyadenylation signal sequence is a sequence that triggers endonuclease cleavage of the mRNA and the addition of a series of adenosines to the 3' end of the cleavage.

- 61 045887 mRNA.

There are several poly(A) signal sequences that can be used, including those derived from bovine growth hormone (bgh) (Woychik et al., Proc. Natl. Acad. Sci. U.S.A., 81(13):3944-3948, 1984 ; US patent No. 5122458), mouse β-globin, mouse α-globin (Orkin et al., EMBO J. 4(2):453-456, 1985; Thein et al., Blood, 71(2):313- 319, 1988), human collagen, polyoma virus (Batt et al., Mol. Cell Biol. 15(9):4783-4790, 1995), herpes simplex virus thymidine kinase gene (HSV TK), IgG heavy chain gene polyadenylation signal ( US 2006/0040354), human growth hormone (hGH) (Szymanski et al., Mol. Therapy, 15(7):1340-1347, 2007), a group consisting of the SV40 poly(A) site, such as late and early poly(A) site of SV40 (Schek et al., Mol. Cell Biol. 12(12):5386-5393, 1992).

The poly(A) signal sequence may be AATAAAA. The AATAAAA sequence may be replaced by other hexanucleotide sequences that are homologous to AATAAAA and capable of signaling polyadenylation, including ATTAAA, AGTAAA, CATAAA, TATAAA, GATAAA, ACTAAA, AATATA, AAGAAA, AATAAT, AAAAAA, AATGAA, AATCAA, AACAAA, AATCAA, AATAAC, AATAGA, AATTAA or AATAAG (see for example WO 06/12414).

In some embodiments, the poly(A) signal sequence may be a synthetic polyadenylation site (see, for example, the pCl-neo Promega expression vector, which is based on Levitt el al., Genes Dev. 3(7):1019-1025, 1989) . In some embodiments, the poly(A) signal sequence is a bovine growth hormone polyadenylation signal:

(CTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGAC

CCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCA

TTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGG

GGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGG (seq id NO: 20)).

In some embodiments, the poly(A) signal sequence is a soluble neuropilin-1 polyadenylation (sNRP) signal (AAATAAAATACGAAATG (SEQ ID NO: 21)) (see, for example, WO 05/073384). Additional examples of poly(A) signal sequences are known in the art.

Internal ribosome entry sites (IRES).

In some embodiments, the vector encoding the C-terminal portion of the CLRN1 protein may comprise a polynucleotide internal ribosome entry site (IRES). The IRES sequence is used to produce more than one polypeptide from a single gene transcript. The IRES forms a complex secondary structure that allows translation to be initiated from any position with an mRNA located immediately downstream of the IRES (see, e.g., Pelletier and Sonenberg, Mol. Cell. Biol. 8(3) :1103-1112, 1988).

Several IRES sequences are known to those skilled in the art, including sequences from, for example, foot-and-mouth disease virus (FMDV), encephalomyocarditis virus (EMCV), human rhinovirus (HRV), cricket paralysis virus, human immunodeficiency virus (HIV), hepatitis A virus (HAV) ), hepatitis C virus (HCV) and poliovirus (PV). See, for example, Alberts, Molecular Biology of the Cell, Garland Science, 2002 and Hellen et al., Genes Dev. 15(13):1593-612, 2001.

In some embodiments, the IRES sequence that is included in the vector encoding the C-terminal portion of the CLRN1 protein is a foot-and-mouth disease virus (FMDV) 2A sequence. The foot-and-mouth disease virus 2A sequence is a small peptide (approximately 18 amino acids in length) that has been shown to mediate the cleavage of polyproteins (Ryan, M.D. et al., EMBO, 4:928-933, 1994; Mattion et al., J. Virology, 70:8124-8127, 1996; Furler et al., Gene Therapy, 8:864-873, 2001; and Halpin et al., Plant Journal, 4:453-459, 1999). 2A sequence cleavage activity has previously been demonstrated in artificial systems, including plasmids and gene therapy vectors (AAV and retroviruses) (Ryan et al., EMBO, 4:928-933, 1994; Mattion et al., J. Virology, 70: 8124-8127, 1996; Furler et al., Gene Therapy 8:864-873, 2001; and Halpin et al., Plant Journal, 4:453-459, 1999; de Felipe et al., Gene Therapy, 6:198 -208, 1999; de Felipe et al., Human Gene Therapy, 11:1921-1931, 2000; and Klump et al., Gene Therapy, 8:811-817, 2001).

Reporter sequences.

Any of the vectors provided herein may optionally contain a sequence encoding a reporter protein (reporter sequence). Non-limiting examples of reporter sequences include DNA sequences encoding betalactamase, beta-galactosidase (LacZ), alkaline phosphatase, thymidine kinase, green fluorescent protein (GFP), red fluorescent protein, mCherry fluorescent protein, yellow fluorescent protein, chloramphenicol acetyltransferase (CAT), and luciferase. Additional examples of reporter sequences are known in the art. When bound to regulatory elements that control their expression, the reporter sequence can provide signals detectable by conventional methods, including enzymatic, x-ray, colorimetric, fluorescence or other spectrographic assays; fluorescent sorting assays

- 62 045887 but activated cells (FACS); immunoassays (eg, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and immunohistochemistry).

In some embodiments, the reporter sequence is tGFP (SEQ ID NO: 19). In some embodiments, the reporter sequence is a LacZ gene, and the presence of a vector carrying the LacZ gene in a mammalian cell (eg, a cochlear hair cell, an eye cell such as a retinal cell) is determined using beta-galactosidase activity assays. When the reporter is a fluorescent protein (eg, green fluorescent protein) or luciferase, the presence of the vector carrying the fluorescent protein or luciferase in a mammalian cell (eg, a cochlear hair cell, an eye cell such as a retinal cell) can be measured by fluorescent methods (eg , fluorescence microscopy or FACS) or light production in a luminometer (eg, spectrophotometer or IVIS imager). In some embodiments, a reporter sequence can be used to test the tissue specificity targeting ability and regulatory activity of a tissue specific promoter of any of the vectors described herein.

Flanking regions, untranslated regions (UTRs).

In some embodiments, any of the vectors described herein (eg, any of at least two different vectors) may contain an untranslated region, such as a 5'UTR or 3'UTR.

Untranslated regions (UTRs) of a gene are transcribed but not translated. The 5'UTR begins at the transcription start site and continues to the start codon, but does not include the start codon. The 3'UTR begins immediately after the stop codon and continues until the transcription termination signal. There is increasing evidence regarding the regulatory roles that UTRs play in terms of nucleic acid molecule stability and translation. UTR regulatory properties can be included in any of the vectors, compositions, kits or methods as described herein to enhance CLRN1 protein expression.

The natural 5'UTR contains a sequence that plays a role in translation initiation. They contain signatures such as Kozak sequences, which are known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus sequence CCR (A/G) CCAUGG, where R is a purine (A or G) three bases upstream of the start codon (AUG), and the start codon is followed by another G. It is also known that The 5'-UTRs form secondary structures that are involved in elongation factor binding.

In some embodiments, the 5'UTR is included in any of the vectors described herein. Non-limiting examples of 5'UTRs, including those from the following genes: albumin, serum amyloid A, apolipoprotein A/B/E, transferrin, alpha-fetoprotein, erythropoietin and factor VIII can be used to enhance the expression of a nucleic acid molecule, such as mRNA.

In some embodiments, the 5'UTR from an mRNA that is transcribed by a cell in the cochlea or retina may be included in any of the vectors, compositions, kits, and methods described herein.

3'-UTRs are known to contain regions of adenosines and uridines (in the form of RNA) or thymidines (in the form of DNA). These AU-rich signatures are particularly common in genes with high levels of turnover. Based on their sequence features and functional properties, AU-rich elements (AREs) can be divided into three classes (Chen et al., Mol. Cell. Biol. 15:5777-5788, 1995; Chen et al., Mol. Cell Biol. 15:2010-2018, 1995): Class I AREs contain multiple scattered copies of the AUUUA motif in U-rich regions. For example, c-Myc and MyoD mRNAs contain class I AREs. Class II AREs have two or more overlapping UUAUUUA nonamers (U/ A) (U/A). GM-CSF and TNF-alpha mRNAs are examples that contain class II AREs. Class III AREs are less well defined. These U-rich regions do not contain the AUUUA motif. Two well-studied examples of this class are c-Jun and myogenin mRNAs.

Most ARE-binding proteins are known to destabilize the template, whereas members of the ELAV family, especially HuR, have been reported to increase mRNA stability. HuR binds to all three classes of AREs. Integration of specific HuR binding sites into the 3′-UTR of nucleic acid molecules will result in HuR binding and thus template stabilization in vivo.

An exemplary wild-type human 5'-UTR is or contains the sequence of SEQ ID NO: 12 or SEQ ID NO: 13. An exemplary wild-type human 5'-UTR is or contains the sequence of SEQ ID NO: 14 or SEQ ID NO: 15.

In some embodiments, any of the compositions described herein, the 5' untranslated region (UTR), the 3' UTR, or both are included in a vector (eg, any of the vectors described herein). For example, any of the 5'UTRs described herein may be operably linked to a start codon in any of the codes described herein.

- 63 045887 routing sequences. For example, any of the 3'UTRs may be operably linked to the 3'-terminal codon (last codon) in any of the coding sequences described herein.

In some embodiments, any of the 5'-UTR compositions described herein contains at least 10 contiguous (e.g., at least 15 contiguous, at least 20 contiguous, at least 25 contiguous, at least 30 contiguous, at least at least 35 adjacent, at least 40 adjacent, at least 45 adjacent, at least adjacent, at least 55 adjacent, at least 60 adjacent, at least adjacent, at least 70 adjacent, at least 75 adjacent, at least adjacent, at least 85 adjacent, at least 90 adjacent, at least

100 adjacent, at least 105 adjacent, at least 110 adjacent, at least

115 adjacent, at least 120 adjacent, at least 125 adjacent, at least

130 adjacent, at least 135 adjacent, at least 140 adjacent, at least

145 adjacent, at least 150 adjacent, at least 155 adjacent, at least

160 adjacent, at least 165 adjacent, at least 170 adjacent, at least

175 adjacent, at least 180 adjacent, at least 185 adjacent, at least

190 adjacent, at least 195 adjacent, at least 200 adjacent, at least

205 adjacent, at least 210 adjacent, at least 215 adjacent, at least

220 adjacent, at least 225 adjacent, at least 230 adjacent, at least

235 adjacent, at least 240 adjacent, at least 245 adjacent, at least

250 contiguous, at least 255 contiguous, or at least 260 contiguous) nucleotides anywhere in SEQ ID NO: 12 or SEQ ID NO: 13.

For example, the 5'-UTR may contain or consist of one or more of the following: nucleotide positions 1 to 291, nucleotide positions 1 to 290, nucleotide positions 1 to 280, nucleotide positions 1 to 270, nucleotide positions 1 to 260, nucleotide positions 1 to 250, nucleotide positions 1 to 240, nucleotide positions 1 to 230, nucleotide positions 1 to 220, nucleotide positions 1 to 210, nucleotide positions 1 to 200, nucleotide positions 1 to 190 , nucleotide positions 1 to 180, nucleotide positions 1 to 170, nucleotide positions 1 to 160, nucleotide positions 1 to 150, nucleotide positions 1 to 140, nucleotide positions 1 to 130, nucleotide positions 1 to 120, nucleotide positions 1 to 110, nucleotide positions 1 to 100, nucleotide positions 1 to 90, nucleotide positions 1 to 80, nucleotide positions 1 to 70, nucleotide positions 1 to 60, nucleotide positions 1 to 50, nucleotide positions 1 to 40, nucleotide positions 1 to 30, nucleotide positions 1 to 20, nucleotide positions 1 to 10, nucleotide positions 10 to 291, nucleotide positions 10 to 290, nucleotide positions 10 to 280, nucleotide positions 10 to 270, nucleotide positions 10 to 260, nucleotide positions 10 to 250, nucleotide positions 10 to 240, nucleotide positions 10 to 230, nucleotide positions 10 to 220, nucleotide positions 10 to 210, nucleotide positions c 10 to 200, nucleotide positions 10 to 190, nucleotide positions 10 to 180, nucleotide positions 10 to 170, nucleotide positions 10 to 160, nucleotide positions 10 to 150, nucleotide positions 10 to 140, nucleotide positions 10 to 130, nucleotide positions 10 to 120, nucleotide positions 10 to 110, nucleotide positions 10 to 100, nucleotide positions 10 to 90, nucleotide positions 10 to 80, nucleotide positions 10 to 70, nucleotide positions 10 to 60, nucleotide positions 10 to 50, nucleotide positions 10 to 40, nucleotide positions 10 to 30, nucleotide positions 10 to 20, nucleotide positions 20 to 291, nucleotide positions 20 to 290, nucleotide positions 20 to 280 , nucleotide positions 20 to 270, nucleotide positions 20 to 260, nucleotide positions 20 to 250, nucleotide positions 20 to 240, nucleotide positions 20 to 230, nucleotide positions 20 to 220, nucleotide positions 20 to 210, nucleotide positions 20 to 200, nucleotide positions 20 to 190, nucleotide positions 20 to 180, nucleotide positions 20 to 170, nucleotide positions 20 to 160, nucleotide positions 20 to 150, nucleotide positions 20 to 140, nucleotide positions 20 to 130, nucleotide positions 20 to 120, nucleotide positions 20 to 110, nucleotide positions 20 to 100, nucleotide positions 20 to 90, nucleotide positions 20 to 80, nucleotide positions 20 to 70, nucleotide positions 20 to 60, nucleotide positions 20 to 50, nucleotide positions 20 to 40, nucleotide positions 20 to 30, nucleotide positions 30 to 291, nucleotide positions 30 to 290, nucleotide positions 30 to 280, nucleotide positions c 30 to 270, nucleotide positions 30 to 260, nucleotide positions 30 to 250, nucleotide positions 30 to 240, nucleotide positions 30 to 230, nucleotide positions 30 to 220, nucleotide positions 30 to 210, nucleotide positions 30 200, nucleotide positions 30 to 190, nucleotide positions 30 to 180, nucleotide positions 30 to 170, nucleotide positions 30 to 160, nucleotide positions 30 to 150, nucleotide positions 30 to 140, nucleotide

- 64 045887 positions 30 to 130, nucleotide positions 30 to 120, nucleotide positions 30 to 110, nucleotide positions 30 to 100, nucleotide positions 30 to 90, nucleotide positions 30 to 80, nucleotide positions 30 to 70 , nucleotide positions 30 to 60, nucleotide positions 30 to 50, nucleotide positions 30 to 40, nucleotide positions 40 to 291, nucleotide positions 40 to 290, nucleotide positions 40 to 280, nucleotide positions 40 to 270, nucleotide positions 40 to 260, nucleotide positions 40 to 250, nucleotide positions 40 to 240, nucleotide positions 40 to 230, nucleotide positions 40 to 220, nucleotide positions 40 to 210, nucleotide positions 40 to 200, nucleotide positions 40 to 190, nucleotide positions 40 to 180, nucleotide positions 40 to 170, nucleotide positions 40 to 160, nucleotide positions 40 to 150, nucleotide positions 40 to 140, nucleotide positions 40 to 130, nucleotide positions 40 to 120, nucleotide positions 40 to 110, nucleotide positions 40 to 100, nucleotide positions 40 to 90, nucleotide positions 40 to 80, nucleotide positions 40 to 70, nucleotide positions 40 to 60, nucleotide positions c 40 to 50, nucleotide positions 50 to 291, nucleotide positions 50 to 290, nucleotide positions 50 to 280, nucleotide positions 50 to 270, nucleotide positions 50 to 260, nucleotide positions 50 to 250, nucleotide positions 50 to 240, nucleotide positions 50 to 230, nucleotide positions 50 to 220, nucleotide positions 50 to 210, nucleotide positions 50 to 200, nucleotide positions 50 to 190, nucleotide positions 50 to 180, nucleotide positions 50 to 170, nucleotide positions 50 to 160, nucleotide positions 50 to 150, nucleotide positions 50 to 140, nucleotide positions 50 to 130, nucleotide positions 50 to 120, nucleotide positions 50 to 110, nucleotide positions 50 to 100 , nucleotide positions 50 to 90, nucleotide positions 50 to 80, nucleotide positions 50 to 70, nucleotide positions 50 to 60, nucleotide positions 60 to 291, nucleotide positions 60 to 290, nucleotide positions 60 to 280, nucleotide positions 60 to 270, nucleotide positions 60 to 260, nucleotide positions 60 to 250, nucleotide positions 60 to 240, nucleotide positions 60 to 230, nucleotide positions 60 to 220, nucleotide positions 60 to 210, nucleotide positions 60 to 200, nucleotide positions 60 to 190, nucleotide positions 60 to 180, nucleotide positions 60 to 170, nucleotide positions 60 to 160, nucleotide positions 60 to 150, nucleotide positions 60 to 140, nucleotide positions 60 to 130, nucleotide positions 60 to 120, nucleotide positions 60 to 110, nucleotide positions 60 to 100, nucleotide positions 60 to 90, nucleotide positions 60 to 80, nucleotide positions 60 to 70, nucleotide positions c 70 to 291, nucleotide positions 70 to 290, nucleotide positions 70 to 280, nucleotide positions 70 to 270, nucleotide positions 70 to 260, nucleotide positions 70 to 250, nucleotide positions 70 to 240, nucleotide positions 70 to 230, nucleotide positions 70 to 220, nucleotide positions 70 to 210, nucleotide positions 70 to 200, nucleotide positions 70 to 190, nucleotide positions 70 to 180, nucleotide positions 70 to 170, nucleotide positions 70 to 160, nucleotide positions 70 to 150, nucleotide positions 70 to 140, nucleotide positions 70 to 130, nucleotide positions 70 to 120, nucleotide positions 70 to 110, nucleotide positions 70 to 100, nucleotide positions 70 to 90 , nucleotide positions 70 to 80, nucleotide positions 80 to 291, nucleotide positions 80 to 290, nucleotide positions 80 to 280, nucleotide positions 80 to 270, nucleotide positions 80 to 260, nucleotide positions 80 to 250, nucleotide positions 80 to 240, nucleotide positions 80 to 230, nucleotide positions 80 to 220, nucleotide positions 80 to 210, nucleotide positions 80 to 200, nucleotide positions 80 to 190, nucleotide positions 80 to 180, nucleotide positions 80 to 170, nucleotide positions 80 to 160, nucleotide positions 80 to 150, nucleotide positions 80 to 140, nucleotide positions 80 to 130, nucleotide positions 80 to 120, nucleotide positions 80 to 110, nucleotide positions 80 to 100, nucleotide positions 80 to 90, nucleotide positions 90 to 291, nucleotide positions 90 to 290, nucleotide positions 90 to 280, nucleotide positions 90 to 270, nucleotide positions 90 to 260, nucleotide positions c 90 to 250, nucleotide positions 90 to 240, nucleotide positions 90 to 230, nucleotide positions 90 to 220, nucleotide positions 90 to 210, nucleotide positions 90 to 200, nucleotide positions 90 to 190, nucleotide positions 90 to 180, nucleotide positions 90 to 170, nucleotide positions 90 to 160, nucleotide positions 90 to 150, nucleotide positions 90 to 140, nucleotide positions 90 to 130, nucleotide positions 90 to 120, nucleotide positions 90 to 110, nucleotide positions 90 to 100, nucleotide positions 100 to 291, nucleotide positions 100 to 290, nucleotide positions 100 to 280, nucleotide positions 100 to 270, nucleotide positions 100 to 260, nucleotide positions 100 to 250 , nucleotide positions 100 to 240, nucleotide positions 100 to 230, nucleotide positions 100 to 220, nucleotide positions 100 to 210, nucleotide positions 100 to 200, nucleotide positions 100 to 190, nucleotide positions 100 to 180, nucleotide

- 65 045887 positions 100 to 170, nucleotide positions 100 to 160, nucleotide positions 100 to 150, nucleotide positions 100 to 140, nucleotide positions 100 to 130, nucleotide positions 100 to 120, nucleotide positions 100 to 110 , nucleotide positions 110 to 291, nucleotide positions 110 to 290, nucleotide positions 110 to 280, nucleotide positions 110 to 270, nucleotide positions 110 to 260, nucleotide positions 110 to 250, nucleotide positions 110 to 240, nucleotide positions 110 to 230, nucleotide positions 110 to 220, nucleotide positions 110 to 210, nucleotide positions 110 to 200, nucleotide positions 110 to 190, nucleotide positions 110 to 180, nucleotide positions 110 to 170, nucleotide positions 110 to 160, nucleotide positions 110 to 150, nucleotide positions 110 to 140, nucleotide positions 110 to 130, nucleotide positions 110 to 120, nucleotide positions 120 to 291, nucleotide positions 120 to 290, nucleotide positions nucleotide positions 120 to 280, nucleotide positions 120 to 270, nucleotide positions 120 to 260, nucleotide positions 120 to 250, nucleotide positions 120 to 240, nucleotide positions 120 to 230, nucleotide positions 120 to 220, nucleotide positions c 120 to 210, nucleotide positions 120 to 200, nucleotide positions 120 to 190, nucleotide positions 120 to 180, nucleotide positions 120 to 170, nucleotide positions 120 to 160, nucleotide positions 120 to 150, nucleotide positions 120 to 140, nucleotide positions 120 to 130, nucleotide positions 130 to 291, nucleotide positions 130 to 290, nucleotide positions 130 to 280, nucleotide positions 130 to 270, nucleotide positions 130 to 260, nucleotide positions 130 to 250, nucleotide positions 130 to 240, nucleotide positions 130 to 230, nucleotide positions 130 to 220, nucleotide positions 130 to 210, nucleotide positions 130 to 200, nucleotide positions 130 to 190, nucleotide positions 130 to 180 , nucleotide positions 130 to 170, nucleotide positions 130 to 160, nucleotide positions 130 to 150, nucleotide positions 130 to 140, nucleotide positions 140 to 291, nucleotide positions 140 to 290, nucleotide positions 140 to 280, nucleotide positions 140 to 270, nucleotide positions 140 to 260, nucleotide positions 140 to 250, nucleotide positions 140 to 240, nucleotide positions 140 to 230, nucleotide positions 140 to 220, nucleotide positions 140 to 210, nucleotide positions 140 to 200, nucleotide positions 140 to 190, nucleotide positions 140 to 180, nucleotide positions 140 to 170, nucleotide positions 140 to 160, nucleotide positions 140 to 150, nucleotide positions 150 to 291, nucleotide positions nucleotide positions 150 to 290, nucleotide positions 150 to 280, nucleotide positions 150 to 270, nucleotide positions 150 to 260, nucleotide positions 150 to 250, nucleotide positions 150 to 240, nucleotide positions 150 to 230, nucleotide positions c 150 to 220, nucleotide positions 150 to 210, nucleotide positions 150 to 200, nucleotide positions 150 to 190, nucleotide positions 150 to 180, nucleotide positions 150 to 170, nucleotide positions 150 to 160, nucleotide positions 160 to 291, nucleotide positions 160 to 290, nucleotide positions 160 to 280, nucleotide positions 160 to 270, nucleotide positions 160 to 260, nucleotide positions 160 to 250, nucleotide positions 160 to 240, nucleotide positions 160 to 230, nucleotide positions 160 to 220, nucleotide positions 160 to 210, nucleotide positions 160 to 200, nucleotide positions 160 to 190, nucleotide positions 160 to 180, nucleotide positions 160 to 170, nucleotide positions 170 to 291 , nucleotide positions 170 to 290, nucleotide positions 170 to 280, nucleotide positions 170 to 270, nucleotide positions 170 to 260, nucleotide positions 170 to 250, nucleotide positions 170 to 240, nucleotide positions 170 to 230, nucleotide positions 170 to 220, nucleotide positions 170 to 210, nucleotide positions 170 to 200, nucleotide positions 170 to 190, nucleotide positions 170 to 180, nucleotide positions 180 to 291, nucleotide positions 180 to 290, nucleotide positions 180 to 280, nucleotide positions 180 to 270, nucleotide positions 180 to 260, nucleotide positions 180 to 250, nucleotide positions 180 to 240, nucleotide positions 180 to 230, nucleotide positions 180 to 220, nucleotide positions 180 to 210, nucleotide positions 180 to 200, nucleotide positions 180 to 190, nucleotide positions 190 to 291, nucleotide positions 190 to 290, nucleotide positions 190 to 280, nucleotide positions 190 to 270, nucleotide positions c 190 to 260, nucleotide positions 190 to 250, nucleotide positions 190 to 240, nucleotide positions 190 to 230, nucleotide positions 190 to 220, nucleotide positions 190 to 210, nucleotide positions 190 to 200, nucleotide positions 200 to 291, nucleotide positions 200 to 290, nucleotide positions 200 to 280, nucleotide positions 200 to 270, nucleotide positions 200 to 260, nucleotide positions 200 to 250, nucleotide positions 200 to 240, nucleotide positions 200 to 230, nucleotide positions 200 to 220, nucleotide positions 200 to 210, nucleotide positions 210 to 291, nucleotide positions 210 to 290, nucleotide positions 210 to 280, nucleotide

- 66 045887 positions 210 to 270, nucleotide positions 210 to 260, nucleotide positions 210 to 250, nucleotide positions 210 to 240, nucleotide positions 210 to 230, nucleotide positions 210 to 220, nucleotide positions 220 to 291 , nucleotide positions 220 to 290, nucleotide positions 220 to 280, nucleotide positions 220 to 270, nucleotide positions 220 to 260, nucleotide positions 220 to 250, nucleotide positions 220 to 240, nucleotide positions 220 to 230, nucleotide positions 230 to 291, nucleotide positions 230 to 290, nucleotide positions 230 to 280, nucleotide positions 230 to 270, nucleotide positions 230 to 260, nucleotide positions 230 to 250, nucleotide positions 230 to 240, nucleotide positions 240 to 291, nucleotide positions 240 to 290, nucleotide positions 240 to 280, nucleotide positions 240 to 270, nucleotide positions 240 to 260, nucleotide positions 240 to 250, nucleotide positions 250 to 291, nucleotide positions 250 to 290, nucleotide positions 250 to 280, nucleotide positions 250 to 270, nucleotide positions 250 to 260, nucleotide positions 260 to 291, nucleotide positions 260 to 290, nucleotide positions 260 to 280, nucleotide positions c 260 to 270, nucleotide positions 270 to 291, nucleotide positions 270 to 290, nucleotide positions 270 to 280, nucleotide positions 280 to 291, or nucleotide positions 280 to 290 SEQ ID NO: 12 or 13.

In some embodiments, any of the 5'-UTR compositions described herein comprises a sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90 %, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%), identical to SEQ ID NO: 12 or 13.

In some embodiments, any of the compositions described herein

3'-UTR contains at at at at by at at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least less less less less less less less than less less than less less less less than less less less less than least less than to the best of my ability

35

80

100 115

130 145

160 175

190 205

220 235

250 265

280 295

310 325

340 355

370 385

400 550

700 850

1000 1150

1300 1450 less adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent , adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, at least 10 adjacent by by by by by by by by by by by by by by by by by by by by by by by by by according to according to at least less less less less less less less less less less less less less less less less than less less less less less less than less less less less less than less less than at least at least at least at least at least at least at least at least at least at least at least at least at least at least : 25 : 40 : 55 : 85

105 120 135

150 165

180 195 210 225 240 255 270 285 300 315 330 345 360 375 390 450 600 750 900

1050 1200 1350 1500 adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, by by by by by by by by by by by by by by by by by by by by by by by by by by at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at at least at least at least at least at least at least at least at at least at least at least at least at least at least at least at least at our least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at our at least at least at least at least at least at least at least at least at least at best with at least 1 at least 1 at least 1 at least 1 at least 1

110

125

140

155

170

185

200

215

230

245

260

275

290

305

320

335

350

365

380

395

500

650

800

950

1100

1250

1400

1550 adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent, adjacent , contiguous, contiguous, contiguous, contiguous, contiguous, contiguous, contiguous, contiguous, contiguous, at least 1600 contiguous, at least 1650 contiguous, at least 1700 contiguous or at least 1750 contiguous) nucleotides anywhere SEQ ID NO: 14 or 15.

For example, the 5'UTR may contain or consist of one or more of the following:

nucleotide positions 1 to 1773, nucleotide positions 1 to 1770, nucleotide positions

- 67 045887 from 1 to 1750, nucleotide positions from 1 to 1700, nucleotide positions from 1 to 1650, nucleotide positions from 1 to 1600, nucleotide positions from 1 to 1550, nucleotide positions from 1 to 1500, nucleotide positions from 1 to 1450, nucleotide positions 1 to 1400, nucleotide positions 1 to 1350, nucleotide positions 1 to 1300, nucleotide positions 1 to 1250, nucleotide positions 1 to 1200, nucleotide positions 1 to 1150, nucleotide positions 1 to 1100, nucleotide nucleotide positions 1 to 1050, nucleotide positions 1 to 1000, nucleotide positions 1 to 950, nucleotide positions 1 to 900, nucleotide positions 1 to 850, nucleotide positions 1 to 800, nucleotide positions 1 to 750, nucleotide positions 1 to 700, nucleotide positions 1 to 650, nucleotide positions 1 to 600, nucleotide positions 1 to 550, nucleotide positions 1 to 500, nucleotide positions 1 to 450, nucleotide positions 1 to 400, nucleotide positions c 1 to 350, nucleotide positions 1 to 300, nucleotide positions 1 to 250, nucleotide positions 1 to 200, nucleotide positions 1 to 150, nucleotide positions 1 to 100, nucleotide positions 1 to 50, nucleotide positions 1 to 25, nucleotide positions 25 to 1773, nucleotide positions 25 to 1770, nucleotide positions 25 to 1750, nucleotide positions 25 to 1700, nucleotide positions 25 to 1650, nucleotide positions 25 to 1600, nucleotide positions 25 to 1550, nucleotide positions 25 to 1500, nucleotide positions 25 to 1450, nucleotide positions 25 to 1400, nucleotide positions 25 to 1350, nucleotide positions 25 to 1300, nucleotide positions 25 to 1250, nucleotide positions 25 to 1200 , nucleotide positions 25 to 1150, nucleotide positions 25 to 1100, nucleotide positions 25 to 1050, nucleotide positions 25 to 1000, nucleotide positions 25 to 950, nucleotide positions 25 to 900, nucleotide positions 25 to 850, nucleotide positions 25 to 800, nucleotide positions 25 to 750, nucleotide positions 25 to 700, nucleotide positions 25 to 650, nucleotide positions 25 to 600, nucleotide positions 25 to 550, nucleotide positions 25 to 500, nucleotide positions 25 to 450, nucleotide positions 25 to 400, nucleotide positions 25 to 350, nucleotide positions 25 to 300, nucleotide positions 25 to 250, nucleotide positions 25 to 200, nucleotide positions 25 to 150, nucleotide positions 25 to 100, nucleotide positions 25 to 50, nucleotide positions 50 to 1773, nucleotide positions 50 to 1770, nucleotide positions 50 to 1750, nucleotide positions 50 to 1700, nucleotide positions 50 to 1650, nucleotide positions c 50 to 1600, nucleotide positions 50 to 1550, nucleotide positions 50 to 1500, nucleotide positions 50 to 1450, nucleotide positions 50 to 1400, nucleotide positions 50 to 1350, nucleotide positions 50 to 1300, nucleotide positions 50 to 1250, nucleotide positions 50 to 1200, nucleotide positions 50 to 1150, nucleotide positions 50 to 1100, nucleotide positions 50 to 1050, nucleotide positions 50 to 1000, nucleotide positions 50 to 950, nucleotide positions 50 to 900, nucleotide positions 50 to 850, nucleotide positions 50 to 800, nucleotide positions 50 to 750, nucleotide positions 50 to 700, nucleotide positions 50 to 650, nucleotide positions 50 to 600, nucleotide positions 50 to 550 , nucleotide positions 50 to 500, nucleotide positions 50 to 450, nucleotide positions 50 to 400, nucleotide positions 50 to 350, nucleotide positions 50 to 300, nucleotide positions 50 to 250, nucleotide positions 50 to 200, nucleotide positions 50 to 150, nucleotide positions 50 to 100, nucleotide positions 100 to 1773, nucleotide positions 100 to 1770, nucleotide positions 100 to 1750, nucleotide positions 100 to 1700, nucleotide positions 100 to 1650, nucleotide positions 100 to 1600, nucleotide positions 100 to 1550, nucleotide positions 100 to 1500, nucleotide positions 100 to 1450, nucleotide positions 100 to 1400, nucleotide positions 100 to 1350, nucleotide positions 100 to 1300, nucleotide positions 100 to 1250, nucleotide positions 100 to 1200, nucleotide positions 100 to 1150, nucleotide positions 100 to 1100, nucleotide positions 100 to 1050, nucleotide positions 100 to 1000, nucleotide positions 100 to 950, nucleotide positions c 100 to 900, nucleotide positions 100 to 850, nucleotide positions 100 to 800, nucleotide positions 100 to 750, nucleotide positions 100 to 700, nucleotide positions 100 to 650, nucleotide positions 100 to 600, nucleotide positions 100 to 550, nucleotide positions 100 to 500, nucleotide positions 100 to 450, nucleotide positions 100 to 400, nucleotide positions 100 to 350, nucleotide positions 100 to 300, nucleotide positions 100 to 250, nucleotide positions 100 to 200, nucleotide positions 100 to 150, nucleotide positions 150 to 1773, nucleotide positions 150 to 1770, nucleotide positions 150 to 1750, nucleotide positions 150 to 1700, nucleotide positions 150 to 1650, nucleotide positions 150 to 1600 , nucleotide positions 150 to 1550, nucleotide positions 150 to 1500, nucleotide positions 150 to 1450, nucleotide positions 150 to 1400, nucleotide positions 150 to 1350, nucleotide

- 68 045887 positions from 150 to 1300, nucleotide positions from 150 to 1250, nucleotide positions from 150 to 1200, nucleotide positions from 150 to 1150, nucleotide positions from 150 to 1100, nucleotide positions from 150 to 1050, nucleotide positions from 150 to 1000 , nucleotide positions 150 to 950, nucleotide positions 150 to 900, nucleotide positions 150 to 850, nucleotide positions 150 to 800, nucleotide positions 150 to 750, nucleotide positions 150 to 700, nucleotide positions 150 to 650, nucleotide positions 150 to 600, nucleotide positions 150 to 550, nucleotide positions 150 to 500, nucleotide positions 150 to 450, nucleotide positions 150 to 400, nucleotide positions 150 to 350, nucleotide positions 150 to 300, nucleotide positions 150 to 250, nucleotide positions 150 to 200, nucleotide positions 200 to 1773, nucleotide positions 200 to 1770, nucleotide positions 200 to 1750, nucleotide positions 200 to 1700, nucleotide positions 200 to 1650, nucleotide positions nucleotide positions 200 to 1600, nucleotide positions 200 to 1550, nucleotide positions 200 to 1500, nucleotide positions 200 to 1450, nucleotide positions 200 to 1400, nucleotide positions 200 to 1350, nucleotide positions 200 to 1300, nucleotide positions c 200 to 1250, nucleotide positions 200 to 1200, nucleotide positions 200 to 1150, nucleotide positions 200 to 1100, nucleotide positions 200 to 1050, nucleotide positions 200 to 1000, nucleotide positions 200 to 950, nucleotide positions 200 to 900, nucleotide positions 200 to 850, nucleotide positions 200 to 800, nucleotide positions 200 to 750, nucleotide positions 200 to 700, nucleotide positions 200 to 650, nucleotide positions 200 to 600, nucleotide positions 200 to 550, nucleotide positions 200 to 500, nucleotide positions 200 to 450, nucleotide positions 200 to 400, nucleotide positions 200 to 350, nucleotide positions 200 to 300, nucleotide positions 200 to 250, nucleotide positions 250 to 1773 , nucleotide positions 250 to 1770, nucleotide positions 250 to 1750, nucleotide positions 250 to 1700, nucleotide positions 250 to 1650, nucleotide positions 250 to 1600, nucleotide positions 250 to 1550, nucleotide positions 250 to 1500, nucleotide positions 250 to 1450, nucleotide positions 250 to 1400, nucleotide positions 250 to 1350, nucleotide positions 250 to 1300, nucleotide positions 250 to 1250, nucleotide positions 250 to 1200, nucleotide positions 250 to 1150, nucleotide positions 250 to 1100, nucleotide positions 250 to 1050, nucleotide positions 250 to 1000, nucleotide positions 250 to 950, nucleotide positions 250 to 900, nucleotide positions 250 to 850, nucleotide positions 250 to 800, nucleotide positions 250 to 750, nucleotide positions 250 to 700, nucleotide positions 250 to 650, nucleotide positions 250 to 600, nucleotide positions 250 to 550, nucleotide positions 250 to 500, nucleotide positions 250 to 450, nucleotide positions c 250 to 400, nucleotide positions 250 to 350, nucleotide positions 250 to 300, nucleotide positions 300 to 1773, nucleotide positions 300 to 1770, nucleotide positions 300 to 1750, nucleotide positions 300 to 1700, nucleotide positions 300 to 1650, nucleotide positions 300 to 1600, nucleotide positions 300 to 1550, nucleotide positions 300 to 1500, nucleotide positions 300 to 1450, nucleotide positions 300 to 1400, nucleotide positions 300 to 1350, nucleotide positions 300 to 1300, nucleotide positions 300 to 1250, nucleotide positions 300 to 1200, nucleotide positions 300 to 1150, nucleotide positions 300 to 1100, nucleotide positions 300 to 1050, nucleotide positions 300 to 1000, nucleotide positions 300 to 950 , nucleotide positions 300 to 900, nucleotide positions 300 to 850, nucleotide positions 300 to 800, nucleotide positions 300 to 750, nucleotide positions 300 to 700, nucleotide positions 300 to 650, nucleotide positions 300 to 600, nucleotide positions 300 to 550, nucleotide positions 300 to 500, nucleotide positions 300 to 450, nucleotide positions 300 to 400, nucleotide positions 300 to 350, nucleotide positions 350 to 1773, nucleotide positions 350 to 1770, nucleotide positions 350 to 1750, nucleotide positions 350 to 1700, nucleotide positions 350 to 1650, nucleotide positions 350 to 1600, nucleotide positions 350 to 1550, nucleotide positions 350 to 1500, nucleotide positions 350 to 1450, nucleotide positions 350 to 1400, nucleotide positions 350 to 1350, nucleotide positions 350 to 1300, nucleotide positions 350 to 1250, nucleotide positions 350 to 1200, nucleotide positions 350 to 1150, nucleotide positions 350 to 1100, nucleotide positions c 350 to 1050, nucleotide positions 350 to 1000, nucleotide positions 350 to 950, nucleotide positions 350 to 900, nucleotide positions 350 to 850, nucleotide positions 350 to 800, nucleotide positions 350 to 750, nucleotide positions 350 to 700, nucleotide positions 350 to 650, nucleotide positions 350 to 600, nucleotide positions 350 to 550, nucleotide positions 350 to 500, nucleotide positions 350 to 450, nucleotide positions 350 to 400, nucleotide positions 400 to 1773, nucleotide positions 400 to 1770, nucleotide

- 69 045887 positions from 400 to 1750, nucleotide positions from 400 to 1700, nucleotide positions from 400 to 1650, nucleotide positions from 400 to 1600, nucleotide positions from 400 to 1550, nucleotide positions from 400 to 1500, nucleotide positions from 400 to 1450 , nucleotide positions 400 to 1400, nucleotide positions 400 to 1350, nucleotide positions 400 to 1300, nucleotide positions 400 to 1250, nucleotide positions 400 to 1200, nucleotide positions 400 to 1150, nucleotide positions 400 to 1100, nucleotide positions 400 to 1050, nucleotide positions 400 to 1000, nucleotide positions 400 to 950, nucleotide positions 400 to 900, nucleotide positions 400 to 850, nucleotide positions 400 to 800, nucleotide positions 400 to 750, nucleotide positions 400 to 700, nucleotide positions 400 to 650, nucleotide positions 400 to 600, nucleotide positions 400 to 550, nucleotide positions 400 to 500, nucleotide positions 400 to 450, nucleotide positions 450 to 1773, nucleotide positions 450 to 1770, nucleotide positions 450 to 1750, nucleotide positions 450 to 1700, nucleotide positions 450 to 1650, nucleotide positions 450 to 1600, nucleotide positions 450 to 1550, nucleotide positions 450 to 1500, nucleotide positions c 450 to 1450, nucleotide positions 450 to 1400, nucleotide positions 450 to 1350, nucleotide positions 450 to 1300, nucleotide positions 450 to 1250, nucleotide positions 450 to 1200, nucleotide positions 450 to 1150, nucleotide positions 450 to 1100, nucleotide positions 450 to 1050, nucleotide positions 450 to 1000, nucleotide positions 450 to 950, nucleotide positions 450 to 900, nucleotide positions 450 to 850, nucleotide positions 450 to 800, nucleotide positions 450 to 750, nucleotide positions 450 to 700, nucleotide positions 450 to 650, nucleotide positions 450 to 600, nucleotide positions 450 to 550, nucleotide positions 450 to 500, nucleotide positions 500 to 1773, nucleotide positions 500 to 1770 , nucleotide positions 500 to 1750, nucleotide positions 500 to 1700, nucleotide positions 500 to 1650, nucleotide positions 500 to 1600, nucleotide positions 500 to 1550, nucleotide positions 500 to 1500, nucleotide positions 500 to 1450, nucleotide positions 500 to 1400, nucleotide positions 500 to 1350, nucleotide positions 500 to 1300, nucleotide positions 500 to 1250, nucleotide positions 500 to 1200, nucleotide positions 500 to 1150, nucleotide positions 500 to 1100, nucleotide positions 500 to 1050, nucleotide positions 500 to 1000, nucleotide positions 500 to 950, nucleotide positions 500 to 900, nucleotide positions 500 to 850, nucleotide positions 500 to 800, nucleotide positions 500 to 750, nucleotide positions 500 to 700, nucleotide positions 500 to 650, nucleotide positions 500 to 600, nucleotide positions 500 to 550, nucleotide positions 550 to 1773, nucleotide positions 550 to 1770, nucleotide positions 550 to 1750, nucleotide positions c 550 to 1700, nucleotide positions 550 to 1650, nucleotide positions 550 to 1600, nucleotide positions 550 to 1550, nucleotide positions 550 to 1500, nucleotide positions 550 to 1450, nucleotide positions 550 to 1400, nucleotide positions 550 to 1350, nucleotide positions 550 to 1300, nucleotide positions 550 to 1250, nucleotide positions 550 to 1200, nucleotide positions 550 to 1150, nucleotide positions 550 to 1100, nucleotide positions 550 to 1050, nucleotide positions 550 to 1000, nucleotide positions 550 to 950, nucleotide positions 550 to 900, nucleotide positions 550 to 850, nucleotide positions 550 to 800, nucleotide positions 550 to 750, nucleotide positions 550 to 700, nucleotide positions 550 to 650 , nucleotide positions 550 to 600, nucleotide positions 600 to 1773, nucleotide positions 600 to 1770, nucleotide positions 600 to 1750, nucleotide positions 600 to 1700, nucleotide positions 600 to 1650, nucleotide positions 600 to 1600, nucleotide positions 600 to 1550, nucleotide positions 600 to 1500, nucleotide positions 600 to 1450, nucleotide positions 600 to 1400, nucleotide positions 600 to 1350, nucleotide positions 600 to 1300, nucleotide positions 600 to 1250, nucleotide positions 600 to 1200, nucleotide positions 600 to 1150, nucleotide positions 600 to 1100, nucleotide positions 600 to 1050, nucleotide positions 600 to 1000, nucleotide positions 600 to 950, nucleotide positions 600 to 900, nucleotide positions 600 to 850, nucleotide positions 600 to 800, nucleotide positions 600 to 750, nucleotide positions 600 to 700, nucleotide positions 600 to 650, nucleotide positions 650 to 1773, nucleotide positions 650 to 1770, nucleotide positions c 650 to 1750, nucleotide positions 650 to 1700, nucleotide positions 650 to 1650, nucleotide positions 650 to 1600, nucleotide positions 650 to 1550, nucleotide positions 650 to 1500, nucleotide positions 650 to 1450, nucleotide positions 650 to 1400, nucleotide positions 650 to 1350, nucleotide positions 650 to 1300, nucleotide positions 650 to 1250, nucleotide positions 650 to 1200, nucleotide positions 650 to 1150,

- 70 045887 nucleotide positions 650 to 1100, nucleotide positions 650 to 1050, nucleotide positions 650 to 1000, nucleotide positions 650 to 950, nucleotide positions 650 to 900, nucleotide positions 650 to 850, nucleotide positions 650 to 800, nucleotide positions 650 to 750, nucleotide positions 650 to 700, nucleotide positions 700 to 1773, nucleotide positions 700 to 1770, nucleotide positions 700 to 1750, nucleotide positions 700 to 1700, nucleotide positions 700 to 1650 , nucleotide positions 700 to 1600, nucleotide positions 700 to 1550, nucleotide positions 700 to 1500, nucleotide positions 700 to 1450, nucleotide positions 700 to 1400, nucleotide positions 700 to 1350, nucleotide positions 700 to 1300, nucleotide positions 700 to 1250, nucleotide positions 700 to 1200, nucleotide positions 700 to 1150, nucleotide positions 700 to 1100, nucleotide positions 700 to 1050, nucleotide positions 700 to 1000, nucleotide positions 700 to 950, nucleotide positions 700 to 900, nucleotide positions 700 to 850, nucleotide positions 700 to 800, nucleotide positions 700 to 750, nucleotide positions 750 to 1773, nucleotide positions 750 to 1770, nucleotide positions 750 to 1750, nucleotide positions 750 to 1700, nucleotide positions 750 to 1650, nucleotide positions 750 to 1600, nucleotide positions 750 to 1550, nucleotide positions 750 to 1500, nucleotide positions 750 to 1450, nucleotide positions 750 to 1400, nucleotide positions c 750 to 1350, nucleotide positions 750 to 1300, nucleotide positions 750 to 1250, nucleotide positions 750 to 1200, nucleotide positions 750 to 1150, nucleotide positions 750 to 1100, nucleotide positions 750 to 1050, nucleotide positions 750 to 1000, nucleotide positions 750 to 950, nucleotide positions 750 to 900, nucleotide positions 750 to 850, nucleotide positions 750 to 800, nucleotide positions 800 to 1773, nucleotide positions 800 to 1770, nucleotide positions 800 to 1750, nucleotide positions 800 to 1700, nucleotide positions 800 to 1650, nucleotide positions 800 to 1600, nucleotide positions 800 to 1550, nucleotide positions 800 to 1500, nucleotide positions 800 to 1450, nucleotide positions 800 to 1400 , nucleotide positions 800 to 1350, nucleotide positions 800 to 1300, nucleotide positions 800 to 1250, nucleotide positions 800 to 1200, nucleotide positions 800 to 1150, nucleotide positions 800 to 1100, nucleotide positions 800 to 1050, nucleotide positions 800 to 1000, nucleotide positions 800 to 950, nucleotide positions 800 to 900, nucleotide positions 800 to 850, nucleotide positions 850 to 1773, nucleotide positions 850 to 1770, nucleotide positions 850 to 1750, nucleotide positions 850 to 1700, nucleotide positions 850 to 1650, nucleotide positions 850 to 1600, nucleotide positions 850 to 1550, nucleotide positions 850 to 1500, nucleotide positions 850 to 1450, nucleotide positions 850 to 1400, nucleotide positions 850 to 1350, nucleotide positions 850 to 1300, nucleotide positions 850 to 1250, nucleotide positions 850 to 1200, nucleotide positions 850 to 1150, nucleotide positions 850 to 1100, nucleotide positions 850 to 1050, nucleotide positions c 850 to 1000, nucleotide positions 850 to 950, nucleotide positions 850 to 900, nucleotide positions 900 to 1773, nucleotide positions 900 to 1770, nucleotide positions 900 to 1750, nucleotide positions 900 to 1700, nucleotide positions 900 to 1650, nucleotide positions 900 to 1600, nucleotide positions 900 to 1550, nucleotide positions 900 to 1500, nucleotide positions 900 to 1450, nucleotide positions 900 to 1400, nucleotide positions 900 to 1350, nucleotide positions 900 to 1300, nucleotide positions 900 to 1250, nucleotide positions 900 to 1200, nucleotide positions 900 to 1150, nucleotide positions 900 to 1100, nucleotide positions 900 to 1050, nucleotide positions 900 to 1000, nucleotide positions 900 to 950 , nucleotide positions 950 to 1773, nucleotide positions 950 to 1770, nucleotide positions 950 to 1750, nucleotide positions 950 to 1700, nucleotide positions 950 to 1650, nucleotide positions 950 to 1600, nucleotide positions 950 to 1550, nucleotide positions 950 to 1500, nucleotide positions 950 to 1450, nucleotide positions 950 to 1400, nucleotide positions 950 to 1350, nucleotide positions 950 to 1300, nucleotide positions 950 to 1250, nucleotide positions 950 to 1200, nucleotide positions 950 to 1150, nucleotide positions 950 to 1100, nucleotide positions 950 to 1050, nucleotide positions 950 to 1000, nucleotide positions 1000 to 1773, nucleotide positions 1000 to 1770, nucleotide positions 1000 to 1750, nucleotide positions 1000 to 1700, nucleotide positions 1000 to 1650, nucleotide positions 1000 to 1600, nucleotide positions 1000 to 1550, nucleotide positions 1000 to 1500, nucleotide positions 1000 to 1450, nucleotide positions 1000 to 1400, nucleotide positions c 1000 to 1350, nucleotide positions 1000 to 1300, nucleotide positions 1000 to 1250, nucleotide positions 1000 to 1200, nucleotide positions

- 71 045887 from 1000 to 1150, nucleotide positions from 1000 to 1100, nucleotide positions from 1000 to 1050, nucleotide positions from 1050 to 1773, nucleotide positions from 1050 to 1770, nucleotide positions from 1050 to 1750, nucleotide positions from 1050 to 170 0, nucleotide positions 1050 to 1650, nucleotide positions 1050 to 1600, nucleotide positions 1050 to 1550, nucleotide positions 1050 to 1500, nucleotide positions 1050 to 1450, nucleotide positions 1050 to 1400, nucleotide positions 1050 to 1350, nucleotide positions 1050 to 1300, nucleotide positions 1050 to 1250, nucleotide positions 1050 to 1200, nucleotide positions 1050 to 1150, nucleotide positions 1050 to 1100, nucleotide positions 1100 to 1773, nucleotide positions 1100 to 1770, nucleotide positions 1100 to 1750, nucleotide positions 1100 to 1700, nucleotide positions 1100 to 1650, nucleotide positions 1100 to 1600, nucleotide positions 1100 to 1550, nucleotide positions 1100 to 1500, nucleotide positions 1100 to 1450, nucleotide positions c 1100 to 1400, nucleotide provisions from 1100 to 1350, nucleotide provisions from 1100 to 1300, nucleotide positions from 1100 to 1250, nucleotide positions from 1100 to 1200, nucleotide positions from 1100 to 1150, nucleotide positions from 1150 to 1773, nucleotide positions from 1150 to 1770, nucleotide positions 1150 to 1750, nucleotide positions 1150 to 1700, nucleotide positions 1150 to 1650, nucleotide positions 1150 to 1600, nucleotide positions 1150 to 1550, nucleotide positions 1150 to 1500, nucleotide positions 1150 to 1450, nucleotide provisions from 1150 to 1400, nucleotide positions from 1150 to 1350, nucleotide positions from 1150 to 1300, nucleotide positions from 1150 to 1250, nucleotide positions from 1150 to 1200, nucleotide positions from 1200 to 1773, nucleotide positions from 1200 to 1770 , nucleotide positions 1200 to 1750, nucleotide positions 1200 to 1700, nucleotide positions 1200 to 1650, nucleotide positions 1200 to 1600, nucleotide positions 1200 to 1550, nucleotide positions 1200 to 1500, nucleotide positions 1200 to 1450, nucleotide positions 1200 to 1400, nucleotide positions 1200 to 1350, nucleotide positions 1200 to 1300, nucleotide positions 1200 to 1250, nucleotide positions 1250 to 1773, nucleotide positions 1250 to 1770, nucleotide positions 1250 to 1750, nucleotide positions 1250 to 1700, nucleotide positions 1250 to 1650, nucleotide positions 1250 to 1600, nucleotide positions 1250 to 1550, nucleotide positions 1250 to 1500, nucleotide positions 1250 to 1450, nucleotide positions 1250 to 1400, nucleotide positions 1250 to 1350, nucleotide positions 1250 to 1300, nucleotide positions 1300 to 1773, nucleotide positions 1300 to 1770, nucleotide positions 1300 to 1750, nucleotide positions 1300 to 1700, nucleotide positions 1300 to 1650, nucleotide positions c 1300 to 1600, nucleotide provisions from 1300 to 1550, nucleotide provisions from 1300 to 1500, nucleotide provisions from 1300 to 1450, nucleotide positions from 1300 to 1400, nucleotide positions from 1300 to 1350, nucleotide positions from 1350 to 1773, nucleotide positions from 1350 to 1770, nucleotide positions 1350 to 1750, nucleotide positions 1350 to 1700, nucleotide positions 1350 to 1650, nucleotide positions 1350 to 1600, nucleotide positions 1350 to 1550, nucleotide positions 1350 to 1500, nucleotide positions 1350 to 1450, nucleotide provisions from 1350 to 1400, nucleotide provisions from 1400 to 1773, nucleotide positions from 1400 to 1770, nucleotide positions from 1400 to 1750, nucleotide positions from 1400 to 1700, nucleotide positions from 1400 to 1650, nucleotide positions from 1400 to 1600 , nucleotide positions 1400 to 1550, nucleotide positions 1400 to 1500, nucleotide positions 1400 to 1450, nucleotide positions 1450 to 1773, nucleotide positions 1450 to 1770, nucleotide positions 1450 to 1750, nucleotide positions 1450 to 1700, nucleotide positions 1450 to 1650, nucleotide positions 1450 to 1600, nucleotide positions 1450 to 1550, nucleotide positions 1450 to 1500, nucleotide positions 1500 to 1773, nucleotide positions 1500 to 1770, nucleotide positions 1500 to 1750, nucleotide positions 1500 to 1700, nucleotide positions 1500 to 1650, nucleotide positions 1500 to 1600, nucleotide positions 1500 to 1550, nucleotide positions 1550 to 1773, nucleotide positions 1550 to 1770, nucleotide positions 1550 to 1750, nucleotide positions 1550 to 1700, nucleotide positions 1550 to 1650, nucleotide positions 1550 to 1600, nucleotide positions 1600 to 1773, nucleotide positions 1600 to 1770, nucleotide positions 1600 to 1750, nucleotide positions 1600 to 1700, nucleotide positions c 1600 to 1650, nucleotide provisions from 1650 to 1773, nucleotide provisions from 1650 to 1770, nucleotide provisions from 1650 to 1750, nucleotide positions from 1650 to 1700, nucleotide positions from 1700 to 1773, nucleotide positions from 1700 to 1770, nucleotide positions from 1700 to 1750, nucleotide positions 1750 to 1773, or nucleotide positions 1750 to 1770 SEQ ID NO: 14 or 15.

In some embodiments, any of the 3'-UTR compositions described herein contains a sequence that is at least 70% (e.g., at least

- 72 045887

75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95% , at least 96%, at least 97%, at least 98%, or at least 99%) is identical to SEQ ID NO: 14 or 15.

Human CLRN1 5'-UTR (SEQ ID NO: 12):

AGGAGATACTTGAAGGCAGTTTGAAAGACTTGTTTTACAGATTCTTAGTCCA AAGATTTCCAATTAGGGAGAAGAAGCAGCAGAAAAGGAGAAAAGCCAAGTATGAG TGATGATGAGGCCTTCATCTACTGACATTTAACCTGGCGAGAACCGTCGATGGTGAA GTTGCCTTTTCAGCTGGGAGCTGTCCGTTCAGCTTCCGTAATAAATGCAGTCAAAGA GGCAGTCCCTTCCCATTGCTCACAAAGG TCTTGTTTTTGAACCTCGCCCTCACAGAA GCCGTTTCTCATC

Human CLRN1 5'-UTR (SEQ ID NO: 13):

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCT

Human CLRN1 3'-UTR (SEQ ID NO: 14):

AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTC ACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTC AGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

Human CLRN1 3'-UTR (SEQ ID NO: 15):

AAGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTT TAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCC TTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAA GCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGT AGTCAAAGGCAGTTGACTAG AATCGACAAATTGTTACTCCATATATATATATGTGTG TGTGTGTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATATCAAAGGCA CATGGAATATATTTTTAATAAAAACAAAATAATATCTCTAATATATCCACACATTTGTT GCCAGATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATTAAAT GAACATCTATAAAATGTATCAACACACATTTTTAAAAAATTTGTTTAAAAG TATACTCT TAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTG GGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGCCTGGGCAATAAAGTGAGACC CTGTCACTAACAAAATTAAAAAATAAAATAAATATAAAATATAGGCTTTAAAAAAG CATAGTCTTATTAACCATGTCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGAAAA GAAGAAAAAACCAAGCTTAGGGTA TTTTTCCTCCCGTGCCTGAGTCCCAATTACATT CACGACAGTACTTTCAATGAACATAATTGTTAGGACCACTGAGGAATCATGAAAAA TGATCTCTGCTTAGTACATTTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAGCT ATAGTGTCTCGAGTACTAATATGCAATTATGAAAATTATATTAAATCTGGGATTATG ACGGTATCACTGTATCATCTTGGTCTTGTTCTGGCTGTCACCAAG CATGACCCAGGT CAACTTTTTTTTCCCCTGAATTACCCATCAAATTGATCTGCAGCTGACTAAAGGCCA CAGCTGAGCCTGGAACTGACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAAGC ACCAAGGAAAAAGCAGAGAATGACAGCAAACAGATCACTAGGCCTCTGACCACAG GTGCTGAGTACTCAGCAGCCCTCATATAATAGGTTTGAAAGTACTCCTTAAAATAAA ACACTGTTTCCCTTTGGAACTAT TTACAAGGATGAAACAACCGTATACCTGAGAAAT AACTTGCTCTGGTGTCAATTCGCTATTCGCCAGCAGACATCAGAACACACCGAGTTT CCAGATGCTGGTTTTTCCCCTTAAAATCAGGAAATACACCTGGACAATTTCTAGAAGA CTACAATTCAGTCTAGCCACAAAGGGGATTTTTTTTTTTTGGTAACAGGCTAGAGCC CGGTTCTGTAAGTCTTTAGCTGAAATGGTCCAGTACA AAAGCACTGGAAATGAGTG GGCTAGGAGGACAAGGACCGTCTCCTGCGTGAGGAGTTGGTTGGAGGTCCCCAAGG CCAGGTACCCCCTGCACTCTTATTGGATTCCTCTCTGTCTTCTTGGAGTTTTGAAAAA CTCCTTCGAACACCAGGCTTTTTTCTTTAGAAAACAAGTCTCCAATCGTTCTCTGTTC CGTAGAAAGAGAAAGAAAACCTGGAGCAGCTGCTGAAAAATCTAATGAGGA ACTA AGAGGCAAACCCACCA

In some embodiments, introduction, deletion, or modification of the ARE 3'-UTR can be used to modulate the stability of the mRNA encoding the CLRN1 protein. In other embodiments, the AREs may be deleted or mutated to increase intracellular stability and thereby increase translation and production of the CLRN1 protein.

In other embodiments, non-ARE sequences may be included in the 5' or 3' UTR. In some embodiments, introns or portions of intronic sequences may be included in the flanking regions of polynucleotides in any of the vectors, compositions, kits, and methods provided herein. Inclusion of intronic sequences can increase protein production as well as mRNA levels.

- 73 045887

In some embodiments of any of the vectors described herein, the vector contains a chimeric intronic sequence (SEQ ID NO: 16).

Mammalian cells.

Also provided herein is a cell (eg, a mammalian cell) that contains any of the nucleic acids, vectors (eg, at least two different vectors described herein) or compositions described herein. Those skilled in the art will appreciate that the nucleic acids and vectors described herein can be introduced into any mammalian cell. Described herein are non-limiting examples of vectors and methods for introducing vectors into mammalian cells.

In some embodiments, the cell is a human cell, a mouse cell, a pig cell, a rabbit cell, a dog cell, a cat cell, a rat cell, or a non-human primate cell. In some embodiments, the cell is a specialized cochlear cell. In some embodiments, the cell is a cochlear hair cell, such as an inner cochlear hair cell or an outer cochlear hair cell. In some embodiments, the cell is an eye cell (eg, a retinal cell, a retinal ganglion cell, an amacrine cell, a horizontal cell, a bipolar cell, a photoreceptor cell).

In some embodiments, the mammalian cell is in vitro. In some embodiments, the mammalian cell is present in a mammal. In some embodiments, the mammalian cell is an autologous cell obtained from a subject and cultured ex vivo.

Ways.

Also provided herein are methods that include administering to the cochlea of a mammal (eg, a human) a therapeutically effective amount of any of the compositions described herein.

Also provided herein are methods of increasing the expression of full-length CLRN1 protein in a mammalian cell, which include introducing any of the compositions described herein into a mammalian cell.

Also provided herein are methods of increasing the expression of full-length CLRN1 protein in an inner hair cell, an outer hair cell, or both cells in the cochlea of a mammal (e.g., a human), which comprises administering to the cochlea of the mammal a therapeutically effective amount of any of the compositions described herein.

Also provided herein are methods of increasing the expression of full-length CLRN1 protein in the eye of a mammal (eg, a human), which comprise intraocular administration to the eye of the mammal of a therapeutically effective amount of any of the compositions described herein.

Also provided herein are methods of treating hearing loss in a subject who has been identified as having a defective CLRN1 gene, which comprises administering a therapeutically effective amount of any of the compositions described herein to the cochlea of the subject.

Also provided herein are methods of treating vision loss in a subject who has been identified as having a defective CLRN1 gene, which comprises administering a therapeutically effective amount of any of the compositions described herein to the eye of the subject.

In some embodiments of any of these methods, the mammal has previously been identified as having a defective CLRN1 gene (eg, a CLRN1 gene having a mutation that results in decreased expression and/or activity of the CLRN1 protein encoded by the gene). Some embodiments of any of these methods further include, prior to the application or administration step, determining that the subject has a defective CLRN1 gene. Some embodiments of any of these methods may further include detecting a mutation in the CLRN1 gene in the subject. Some embodiments of any of the methods may further include identifying or diagnosing a subject with hearing and/or vision loss.

In some embodiments of any of these methods, two or more doses of any of the compositions described herein are applied or administered to the cochlea of a mammal or subject. Some embodiments of any of these methods may include administering or administering a first dose of the composition to the cochlea of a mammal or subject, assessing the visual function of the mammal or subject after administration or administration of the first dose, and administering an additional dose of the composition to the cochlea of a mammal or subject found to lack hearing function. within the normal range (eg, as determined using any hearing test known in the art).

In some embodiments of any of the methods described herein, the composition may be formulated for intracochlear administration. In some embodiments of any of the methods described herein, the compositions described herein can be administered via intracochlear administration or topical administration. In some embodiments it is possible to

- 74 045887 Following any of the methods described herein, the compositions are administered using a medical device (eg, any of the typical medical devices described herein).

In some embodiments, intracochlear administration can be performed using any of the methods described herein or known in the art. For example, the composition can be introduced or applied to the cochlea using the following surgical technique: first using visualization using a 2.5 mm rigid endoscope with a 0° field of view, the external auditory canal is cleared and a round knife is used to clearly delineate the eardrum with a diameter of about 5 mm . The eardrum is raised and inserted into the middle ear from behind. The nerves of the tympanic membrane are identified and divided, and a curette is used to remove the scutal bone, exposing the round window membrane. To improve the apical distribution of the injected or applied composition, a surgical laser can be used to make a small 2-mm fenestration in the oval window to ensure perilymph displacement during the infusion of the membrane through the round window of the composition. The microinfusion device is then loaded and delivered to the surgical site. The device is directed to the round window and the tip is placed inside the bony round window to allow penetration of the microneedle(s) into the membrane. A foot pedal is activated to provide a measurable, steady infusion of the composition. The device is then removed, and the round window and stapes are sealed with gel foam.

In some embodiments of any of these methods, two or more doses of any of the compositions described herein are applied or administered to the eye of a mammal or subject. Some embodiments of any of these methods may include administering or administering a first dose of the composition to the eye (e.g., intraocular space) of the mammal or subject, assessing the auditory function of the mammal or subject after administration or administration of the first dose, and administering an additional dose of the composition to the eye of the mammal or subject, who is found to lack visual function within the normal range (eg, as determined using any visual test known in the art).

In some embodiments of any of the methods described herein, the composition may be formulated for intraocular administration. In some embodiments of any of the methods described herein, the compositions described herein can be administered via intraocular administration or local administration.

In some embodiments, intraocular administration can be performed using any of the methods described herein or known in the art.

In some embodiments of any of the methods described herein, the subject or mammal is a rodent, non-human primate, or a human. In some embodiments of any of the methods described herein, the subject or mammal is an adult, adolescent, youth, child, toddler, infant, or newborn. In some embodiments of any of the methods described herein, the subject or mammal is 1-5, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-110, 2-5, 2-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70- 80, 80-90, 90-100, 100-110, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-110, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-110, 30-50, 30-60, 30-70, 30-80, 30- 90, 30-100, 40-60, 40-70, 40-80, 40-90, 40-100, 50-70, 50-80, 50-90, 50-100, 60-80, 60-90, 60-100, 70-90, 70-100, 70-110, 80-100, 80-110 or 90-110 years. In some embodiments of any of the methods described herein, the age of the subject or mammal is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 months.

In some embodiments of any of the methods described herein, the subject or mammal has or is at risk of developing hearing loss and/or vision loss (eg, Usher syndrome type III, retinitis pigmentosa). In some embodiments of any of the methods described herein, the subject or mammal has previously been identified as having a mutation in the CLRN1 gene. In some embodiments of any of the methods described herein, the subject or mammal has any of the mutations in the CLRN1 gene that are described herein or known in the art to be associated with hearing loss and/or vision loss.

In some embodiments of any of the methods described herein, a subject or mammal has been identified as carriers of a mutation in the CLRN1 gene (eg, through genetic testing). In some embodiments of any of the methods described herein, a subject or person has been identified as having a mutation in the CLRN1 gene and has been diagnosed with hearing loss and/or vision loss (eg, Usher syndrome type III, retinitis pigmentosa). In some embodiments of any of the methods described herein, the subject or person has been identified as having hearing loss and/or vision loss (eg, Usher syndrome type III, retinitis pigmentosa).

In some embodiments, successful treatment of hearing loss (eg, Usher syndrome type III) can be determined in a subject using any of the traditional functions

- 75 045887 hearing tests known in the art. Non-limiting examples of functional hearing tests include various types of audiometric tests (eg, pure tone testing, speech testing, middle ear testing, auditory brainstem response, and otoacoustic emissions).

In some embodiments, successful treatment of vision loss can be determined in a subject using any of the conventional functional visual tests known in the art. Non-limiting examples of retinal and vision functional tests include visual acuity testing, intraocular pressure (IOP) testing, and electroretinogram (ERG).

Also provided herein are methods of increasing the expression of active CLRN1 (eg, full-length CLRN1) in a mammalian cell, which include introducing any of the compositions described herein into a mammalian cell. In some embodiments of these methods, the mammalian cell is a cochlear hair cell (eg, inner hair cell, outer hair cell) or an eye cell (eg, retinal cell). In some embodiments of these methods, the mammalian cell is a human cell (eg, a human cochlear hair cell). In some embodiments of these methods, the mammalian cell is maintained in vitro. In some embodiments of these methods, the mammalian cell is located in a mammal. In some embodiments of these methods, the mammalian cell is initially obtained from a mammal and is cultured ex vivo. In some embodiments, the mammalian cell has previously been determined to have a defective CLRN1 gene.

Methods for introducing any of the compositions described herein into a mammalian cell are known in the art (eg, through lipofection or the use of a viral vector, such as any of the viral vectors described herein).

The increase in expression of active CLRN1 protein (eg, full-length CLRN1 protein) as described herein is, for example, compared to control or the level of expression of active CLRN1 protein (eg, full-length CLRN1 protein) before administration of the vector(s).

Methods for determining the expression and/or activity of CLRN1 are known in the art. In some embodiments, the expression level of CLRN1 protein can be determined directly (eg, by detecting CLRN1 protein or by detecting CLRN1 mRNA). Non-limiting examples of methods that can be used to directly detect CLRN1 expression and/or activity include real-time PLR, Western blotting, immunoprecipitation, immunohistochemistry, or immunofluorescence. In some embodiments, CLRN1 protein expression may be detected indirectly (eg, by functional auditory, retinal, and vision functional tests).

Pharmaceutical compositions and kits.

In some embodiments, any of the compositions described herein may further include one or more agents that promote entry of a nucleic acid or any of the vectors described herein into a mammalian cell (eg, a liposome or a cationic lipid).

In some embodiments, any of the vectors described herein can be formulated using natural and/or synthetic polymers. Non-limiting examples of polymers that may be included in any of the compositions described herein may include, without limitation, DYNAMIC POLYCONJUGATE® (Arrowhead Research Corp., Pasadena, Calif.), formulations from Minis Bio (Madison, Wis.), and Roche Madison (Madison, WI), PhaseRX polymer formulations such as, but not limited to, SMARTT POLYMER TECHNOLOGY® (PhaseRX, Seattle, WA), DMRI/DOPE, poloxamer, VAXFECTIN® adjuvant from Vical (San Diego, CA ), chitosan, cyclodextrin from Calando Pharmaceuticals (Pasadena, CA), lactic-glycolic acid (PLGA) dendrimers and polymers, RONDEL (RNA/Oligonucleotide Nanoparticle Delivery) polymers (Arrowhead Research Corporation, Pasadena, CA), and pH-sensitive copolymers polymers, such as, but not limited to, those manufactured by PhaseRX (Seattle, Washington). Many of these polymers have demonstrated effectiveness in delivering oligonucleotides in vivo into mammalian cells (see, e.g., deFougerolles, Human Gene Ther. 19:125-132, 2008; Rozema et al., Proc. Natl. Acad. Sci. U.S.A., 104 Heidel et al. al., Proc. Natl. Acad. Sci. U.S.A., 104:5715-5721, 2007).

Any of the compositions described herein may be, for example, a pharmaceutical composition. The pharmaceutical composition may contain any of the compositions described herein and one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Such compositions may contain one or more buffers, such as neutral-buffered saline, phosphate-buffered saline, and the like; one or more carbohydrates such as glucose, mannose, sucrose and dextran; mannitol; one or more white

- 76 045887 coves, polypeptides or amino acids, such as glycine; one or more antioxidants; one or more chelating agents such as EDTA or glutathione; and/or one or more preservatives.

In some embodiments, the composition contains a pharmaceutically acceptable carrier (eg, phosphate buffered saline, saline, or bacteriostatic water). Once prepared, the solutions will be administered in a manner consistent with the dosage composition and in an amount that is therapeutically effective. The compositions are easily administered in various dosage forms such as injection solutions, injection gels, drug release capsules, and the like.

As used herein, the term pharmaceutically acceptable carrier includes solvents, dispersion media, coating agents, antibacterial agents, antifungal agents and the like that are compatible with pharmaceutical administration. Additional active compounds may also be included in any of the formulations described herein.

In some embodiments, a single dose of any of the compositions described herein may contain a total combined amount of at least two different vectors equal to at least 1 ng, at least 2 ng, at least 4 ng, about 6 ng, about 8 to at least 10 ng, at least 20 ng, at least 30 ng, at least 40 at least 50 ng, at least 60 ng, at least 70 ng, at least 80 at least 90 ng, at least 100 ng, at least 200 ng, at least 300 ng, ng, ng, ng, at least 400 ng, at least 500 ng, at least 1 μg, at least 2 μg,

at least 4 mcg, at least at least 6 mcg, at least 8 μg, at least 10 μg, at least 12 mcg, at least at least 14 mcg , at least 16 mcg, at least 18 mcg, at least 20 mcg, at least at least 22 mcg , at least 24 mcg, at least 26 mcg, at least 28 mcg, at least 30 mcg at least 32 mcg, at least 34 mcg, at least 36 mcg, at least at least 38 mcg , at least 40 µg, at least 42 µg, at least 44 mcg, at least at least 46 mcg , at least 48 mcg, at least 50 mcg, at least 52 mcg, at least at least 54 mcg , at least 56 mcg, at least 58 mcg, at least 60 mcg, at least at least 62 mcg , at least 64 mcg, at least 66 mcg, at least 68 mcg, at least at least 70 mcg , at least 72 mcg, at least 74 mcg, at least 76 mcg, at least at least 78 mcg , at least 80 mcg, at least 82 mcg, at least 84 mcg, at least at least 86 mcg , at least 88 mcg, at least 90 mcg, at least 92 mcg, at least 94 mcg , at least 96 mcg, at least 98 mcg, at least 100 mcg, according to less at least 102 mcg, at least 104 mcg, at least 106 mcg, according to less at least 108 mcg, at least 110 mcg, at least 112 mcg, according to less at least 114 mcg, at least 116 mcg, at least 118 mcg, according to less at least 120 mcg, at least 122 mcg, at least 124 mcg, according to less at least 126 mcg, at least 128 mcg, at least 130 mcg less at least 132 mcg, at least 134 mcg, at least 136 mcg, according to less at least 138 mcg, at least 140 mcg, at least 142 mcg, according to less at least 144 mcg, at least 146 mcg, at least 148 mcg, according to less at least 150 mcg, at least 152 mcg, at least 154 mcg, according to less at least 156 mcg, at least 158 mcg, at least 160 mcg, according to less at least 162 mcg, at least 164 mcg, at least 166 mcg, according to less at least 168 mcg, at least 170 mcg, at least 172 mcg, according to less at least 174 mcg, at least 176 mcg, at least 178 mcg, according to less at least 180 mcg, at least 182 mcg, at least 184 mcg, according to less at least 186 mcg, at least 188 mcg, at least 190 mcg, according to less at least 192 mcg, at least 194 mcg,

at least 196 µg, at least 198 µg or at least 200 µg, for example in a buffer solution.

The compositions provided herein may, for example, be formulated to be compatible with the intended route of administration. A non-limiting example of a proposed route of administration is local administration (eg, intracochlear administration).

In some embodiments, the therapeutic compositions comprise a lipid nanoparticle. In some embodiments, the therapeutic compositions comprise a polymer nanoparticle. In some embodiments, the therapeutic compositions are formulated to contain minicircular DNA. In some embodiments, the therapeutic compositions are formulated to contain CELiD DNA. In some embodiments, the therapeutic compositions are formulated to contain a synthetic perilymph solution. Exemplary synthetic solutions of translymph include 20-200 mM NaCl; 1-5 mM KCl; 0.1-10 mM CaCl ₂ ; 1-10 mM glucose; 2-50 mM HEPES having a pH of about 6 to about 9.

Kits containing any of the compositions described herein are also provided. In some embodiments, the kit may contain a solid composition (for example, lyophilis

- 77 045887 a lyophilized composition containing at least two different vectors described herein) and a liquid for solubilizing the lyophilized composition. In some embodiments, the kit may contain a pre-filled syringe containing any of the compositions described herein.

In some embodiments, the kit contains a vial containing any of the compositions described herein (eg, formulated as an aqueous composition, eg, an aqueous pharmaceutical composition).

In some embodiments, the kits may contain instructions for performing any of the methods described herein.

Devices and surgical methods.

Presented herein are therapeutic delivery systems for the treatment of hearing loss and/or vision loss (eg, Usher syndrome type III, retinitis pigmentosa). In one aspect, therapeutic delivery systems comprise i) a medical device capable of creating one or multiple incisions in the membrane of the round window of the inner ear of a person in need thereof, and ii) an effective dose of a composition (eg, any of the compositions described herein). In some embodiments, the medical device includes a plurality of microneedles.

This document also presents surgical options for treating hearing loss (eg, Usher syndrome type III). In some embodiments, the methods include the steps of: making a first incision in the human cochlea at a first incision point and intracochlear administration of a therapeutically effective amount of any of the compositions provided herein. In some embodiments, the composition is administered to the subject at a first incision site. In some embodiments, the composition is administered to the subject at or through the first incision.

In some embodiments of any of the methods described herein, any of the compositions described herein are administered to a subject at or through the oval window membrane of the cochlea. In some embodiments of any of the methods described herein, any of the compositions described herein is administered to or through the round window membrane of the cochlea to a subject. In some embodiments of any of the methods described herein, the composition is administered using a medical device capable of creating multiple incisions in the membrane of a circular window. In some embodiments, the medical device includes a plurality of microneedles. In some embodiments, the medical device comprises a plurality of microneedles, generally including a first circular aspect, wherein each microneedle has a diameter of at least about 10 microns. In some embodiments, the medical device includes a base and/or reservoir capable of holding the composition. In some embodiments, the medical device includes a plurality of hollow microneedles individually containing a lumen through which the composition can be transported. In some embodiments, the medical device includes means for creating at least a partial vacuum.

This document also presents surgical options for treating vision loss (eg, retinitis pigmentosa). In some embodiments, the methods include the steps of: intraocular administration of a therapeutically effective amount of any of the compositions provided herein.

The invention will now be described in detail with reference to the following experimental examples. These examples are provided for illustrative purposes only and should not be interpreted as limiting unless otherwise noted. Thus, the invention should not be taken to be limited to the following examples, but rather to be taken to embrace any and all variations that will become apparent as a result of the ideas presented herein.

Without further description, it is believed that using the foregoing description and the following illustrative examples, one skilled in the art can prepare and use the compounds of this invention and practice the claimed methods. The following demonstrative examples specifically indicate various aspects of the present invention and should not be interpreted as limiting in any way the remainder of the description.

Examples

Example 1: Construction of viral vectors.

Recombinant AAV was produced by transfection using the adenoviral-free method used by Xiao et al. J. Virol. 73(5):3994-4003, 1999. AAV ITR cis-plasmids, AAV Rep and Cap trans-plasmids, and an auxiliary plasmid with an essential region from the adenovirus genome were co-transfected into 293 cells in a 1:1:2 ratio. The AAV-based vectors used herein express human CLRN1 or mouse CLRN1 in several dual vector strategies using the constructs described below. Each of AAV serotypes 1, 2, 3, 4, 5, 6, 7, 8, 9, rh8, rh10, rh39, rh43 and Apc80 are prepared to encapsulate three sets of CLRN1 constructs to test (i) the concatemerization-splicing strategy, (ii ) hybrid intronic-homologous recombination strategy

- 78 045887 splicing nations and (iii) exonic homologous recombination strategies, as summarized by Pryadkina et al., Meth. Clin. Devel. 2:15009, 2015.

Example 2: Creation and purification of viral particles.

Recombinant AAV-1 was produced using a triple transfection protocol and purified by two successive cesium chloride (CsCl) density gradients as described by Pryadkina et al., Mol. Ther. 2:15009, 2015. At the end of the second centrifugation, 11 500 µl fractions are removed from the CsCl density gradient tube and purified by dialysis in 1x PBS. Fractions were analyzed by dot blot to identify those containing rAAV genomes. The number of viral genomes (vg) of each preparation is determined by quantitative titration based on real-time PCR using primers and probe corresponding to the ITR region of the AAV vector genome (Bartoli et al., Gene. Ther. 13:20-28, 2006) .

Example 3: Composition of viral particles.

AAV, produced with a titer of 1e14 vg/ml, is obtained at dilutions of 3.2e13, 1.0e13, 3.2e12, 1.0e12 vg/ml in artificial perilymph. Artificial perilymph is prepared by combining the following reagents: NaCl, 120 mM; KCl, 3.5 mM; _CaCl2 , 1.5 mM; glucose, 5.5 mM; HEPES, 20 mM. Artificial perilymph is titrated with NaOH to adjust the pH to 7.5 (total Na+ concentration 130 mM) (Chen et al., J. Controlled Rel. 110:1-19, 2005).

Example 4. Description of the device.

The AAV-CLRN1 formulation is delivered to the cochlea using a custom microcatheter designed to consistently and safely penetrate the round window membrane (RFM). The microcatheter is shaped so that the surgeon performing the delivery procedure can enter the middle ear cavity through the external auditory canal and bring the tip of the microcatheter into contact with the MCO. The distal end of the microcatheter consists of at least one microneedle with a diameter of 10 to 1000 μm, which creates a perforation in the MCO sufficient to allow AAV-CLRN1 to enter the cochlear perilymph of the scala tympani at a rate of approximately 1 μl/min, but small enough to heal without surgical repair. The remainder of the microcatheter proximal to the microneedle(s) is loaded with an AAV-CLRN1/artificial perilymph formulation at a titer of approximately 1e13 vg/ml. The proximal end of the microcatheter is connected to a micromanipulator, which allows precise, small volume infusions of approximately 1 μL/min.

Example 5 Animal Model 1A: Surgical Method in Aged Mice.

AAV-CLRN1 produced in artificial perilymph was injected into the scala tympani of mice as described by Shu et al. (Human Gene Therapy, doi:10.1089/hum.2016.053, June 2016,). Six-week-old male mice are anesthetized with an intraperitoneal injection of xylazine (20 mg/kg) and ketamine (100 mg/kg). Body temperature is maintained at 37°C using an electric heating pad. An incision is made in the right postauricular region and the bulla tympani is exposed. The bulla is perforated with a surgical needle, and the small hole is widened to provide access to the cochlea. The bone of the lateral wall of the scala tympani cochlea is thinned using a drill so that the membranous lateral wall remains intact. The Nanoliter microinjection system in combination with a glass micropipette is used to deliver a total of approximately 300 nL of AAV-CLRN1 in artificial perilymph to the scala tympani at a rate of 2 nL/s. The glass micropipette is left for 5 minutes after injection. After a cochleostomy and injection, the hole in the eardrum is closed with dental cement, and the muscle and skin are sutured. Mice are allowed to awaken from anesthesia and their pain is controlled with 0.15 mg/kg buprenorphine hydrochloride for 3 days.

Example 6: Animal model 2: piston micropump for guinea pigs.

Surgical procedure.

AAV-CLRN1, prepared in artificial perilymph, was administered to guinea pigs to assess distribution and toxicity after intracochlear delivery using a reciprocating micropump, as described in Tandon et al., Lab Chip, DOI: 10.1039/c51c01396h, 2015. Each of the male guinea pigs gilts weighing approximately 350 g (n = 16) are anesthetized with a combination of sodium pentobarbital (Nembutal; 25 mg/kg, administered intraperitoneally), fentanyl (0.2 mg/kg, intramuscular) and haloperidol (10 mg/kg, intramuscular). Lidocaine with epinephrine is injected subcutaneously into the incision site as a local anesthetic. In the dorsal approach, a 5 mm diameter hole is made in the bulla and a cochleostomy is made approximately 0.5 mm distal to the round window membrane. The micropump cannula (described below) is inserted into the cochleostomy, threaded 3 mm apically into the cochlea, and adhered to the bulla using conventional cyanoacrylate glue. To measure the total action potential (SAP), a silver wire electrode with perfluoroalkoxyalkane insulation (uncoated diameter 203 μm) is inserted next to the round window niche and glued to the bulla.

Procedures for measuring distortion product frequency optoacoustic emission (DAEEF) and SPD are performed as previously described in Tandon et al., Biomed. Microdevices, 17:3-21, 2015. OAPR is measured before and after a cochleostomy procedure at representative frequencies: 32, 24, 16, 12, 8, 5, 6, 4 and 2.78 kHz to monitor any damage resulting from operations.

- 79 045887

AAV-CLRN1 with a maximum titer of 1e14 vg/ml is administered to a guinea pig using a micropump as described in Tandon et al., Lab Chip, DOI: 10.1039/c51c01396h, 2015. The micropump system has 4 selectable ports. These ports are connected to (i) a large liquid condenser used to store artificial perilymph; (ii) an outlet that connects to the cochlea; (iii) the outlet from the integrated reservoir AAV-CLRN1; (iv) the inlet to the integrated reservoir AAV-CLRN1. Each port is fluidly connected to a central pump chamber, and each port has separate access via a valve. The sequence of events for reciprocal delivery of AAV-CLRN1 is as follows: (i) the internal AAV-CLRN1 refresh loop is initiated, transferring AAV-CLRN1 from the AAV-CLRN1 reservoir to the main infusion line; (ii) AAV-CLRN1 is injected into the cochlea, and some artificial perilymph is drained from the artificial perilymph storage capacitor; (iii) the first two steps can be repeated several times for additional doses; (iv) after AAV-CLRN1 has been allowed to diffuse for some time, the volume of perilymph that is removed from the cochlea is equal to the volume introduced in steps (i)-(iii), replenishing the artificial perilymph storage capacitor. This process results in actual drug delivery with zero net volume of fluid added to the cochlea.

The liquid capacitors in the micropump are cylindrical chambers, the upper walls of which are a thin (25.4 μm) flexible polyimide membrane. The pump chamber has a diameter of 3.5 mm, the liquid storage condenser has a diameter of 14 mm, and all other capacitors have a diameter of 4 mm. The same membrane is deflected to block the flow at each valve. The valve chambers have a diameter of 3.1 mm. The serpentine channel, which includes the drug reservoir, has a square cross-section of 762 μm wide and 410 mm long with a total volume of 238 μL. All other microchannels in the pump are 400 µm wide and 254 µm high.

Urgent drug delivery in guinea pigs.

The micropump is loaded with AAV-CLRN1 and artificial perilymph, and the cannula is inserted into a cochleostomy made in the cochlear region between points with characteristic frequency sensitivity of 24 and 32 kHz, with an apical thread of 3 mm ending in the region of 12-16 kHz. Hearing tests for OAPE and SPD are performed before starting AAV-CLRN1/artificial perilymph infusion. The pump is then turned on and approximately 1 μL of artificial perilymph is injected every 5 min until a total of approximately 10 μL of artificial perilymph is delivered to the cochlea. After 20 minutes of waiting, about 10 μl of perilymph is removed from the cochlea. Delivery of AAV-CLRN1 then begins at a rate of approximately 1 μL every 5 min until a total of approximately 10 μL of fluid has been delivered.

Animals were sacrificed at 1 week, 1 month, 3 months and 6 months after treatment (n=4 per group) and their snails were removed. The extent of AAV transduction and CLRN1 expression along the organ of Corti is assessed by immunostaining with anti-CLRN1 antibodies. Antibodies against markers of hair cells (Myo7a) and supporting cells (Sox2) are used to quantify VVC, HVC, supporting cells, and stereocilia morphology. Annexin V staining is used to evaluate evidence of apoptosis in cochlear sensory epithelial cells.

Example 7: Animal Model 3: Sheep.

AAV-CLRN1 prepared in artificial perilymph was administered to young sheep to assess distribution and toxicity after delivery to the cochlea by trans-MKO infusion. Baseline acoustic brainstem evoked potentials (ASEP) and optoacoustic emission at distortion product frequency (DAEPF) are measured bilaterally in 3-month-old female sheep (n=40) to assess inner hair cell (IHC) and outer hair cell (OHC) function. before treatment. After measurements of initial ASVP and OAEAPI, 20 μl of AAV1-CLRN1 with titers of 1.0e14, 3.2e13, 1.0e13 and 3.2e12 vg/ml was injected into the left scala tympani of the sheep (n=10 per group). The right ear of each animal was left as an untreated control. Measurements of ASVP and OAEPPI are again carried out bilaterally 1, 5 and 10 days after the surgical procedure. 6 months after the procedure, additional bilateral measurements of ASVP and OAEAP were performed in all animals, after which the animals were sacrificed and their cochleae were removed.

In half of the sacrificed animals (n=5 from each dose group), immunostaining was performed to identify hair cell structures and to assess CLRN1 protein expression along the sensory epithelium of the cochlea. Antibodies against markers of hair cells (Myo7a), supporting cells (Sox2) and CLRN1 are used as previously described (Duncker et al. 2013, J. Neurosci. 33(22):9508-9519). At the basal, mid, and apical turns of the organ of Corti, the total number of hair cells and hair cells expressing CLRN1 were counted within 200 μm regions.

From the remaining half of the sacrificed animals (the remaining 5 animals from each dose group), cochlear tissue samples were collected from the same basal, mid, and apical regions as described above and analyzed for CLRN1 mRNA transcript.

Example 8: Human clinical example (pediatric treatment).

The patient is under general anesthesia. The surgeon approaches the eardrum from the

- 80 045887 external auditory canal, makes a small incision on the lower edge of the external auditory canal where it meets the eardrum, and lifts the eardrum like a flap to expose the middle ear space. A surgical laser is used to create a small hole (approximately 2 mm) at the base of the stapes. The surgeon then penetrates the round window membrane using a microcatheter filled with an AAV-CLRN1 solution prepared in artificial perilymph with a titer of 1e13 vg/ml. The microcatheter is connected to a micromanipulator, which injects approximately 20 μL of AAV-CLRN1 solution at a rate of approximately 1 μL/min. Once the AAV-CLRN1 infusion is complete, the surgeon removes the microcatheter and covers the holes in the base of the stapes and the MCO with a gel foam patch. The procedure ends with replacement of the eardrum flap.

Example 9 Non-invasive prenatal testing of maternal blood to detect the CLRN1 mutation.

Maternal blood samples (20-40 ml) are collected in tubes to collect extracellular DNA. At least 7 ml of plasma was isolated from each sample using a double centrifugation protocol at 2000 g for 20 min, then 3220 g for 30 min, with supernatant transfer after the first spin. cfDNA (cell-free DNA) is isolated from 7-20 ml plasma using the QIAGEN QIAmp® Circulating Nuclei Acid kit and eluted in 45 µl TE buffer. Pure maternal genomic DNA is isolated from the buffy coat obtained after the first centrifugation.

By combining thermodynamic modeling of assays to select probes with minimal probability of probe-probe interactions with amplification approaches described previously (Stiller et al., Genome Res. 19(10):1843-1848, 2009), multiplexing of 11,000 assays can be achieved. Maternal cfDNA and maternal genomic DNA samples were preamplified for 15 cycles using 11,000 target-specific assays, and the aliquot was transferred to a second 15-cycle PCR reaction using nested primers. Samples are prepared for sequencing by adding barcoded tags in a third 12-cycle round of PCR. The amplicons are then sequenced using an Illumina HiSeq sequencer. Genome sequence alignment is performed using commercially available software.

Example 10 Adenovirus (AAV) trans-splicing strategy.

At least two different nucleic acid vectors (eg, AAV-based vectors) can be used to restore an active CLRN1 gene (eg, full-length CLRN1 gene) in a cell after intermolecular concatamerization and trans-splicing. See, for example, Yan et al., Proc. Natl. Acad. Sci. U.S.A. 97:12; 6716-6721, 2000, are incorporated herein in their entirety.

In some examples, two different nucleic acid vectors will be used. The first nucleic acid vector may contain a promoter (e.g., any of the promoters described herein), a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located 3' of the promoter (e.g., any size portion of the CLRN1 protein described herein , and/or any of the N-terminal portions of the CLRN1 protein described herein), and a splice donor sequence located at the 3' end of the first coding sequence. The second nucleic acid vector may comprise a splice acceptor sequence, a second coding sequence that encodes the C-terminal portion of the CLRN1 protein (i.e., all of the portion of the CLRN1 protein that is not included in the N-terminal portion) located at the 3' end of the splice acceptor sequence ( for example, a portion of any size of the CLRN1 protein described herein and/or any of the C-terminal portions of the CLRN1 protein described herein), and a polyadenylation sequence at the 3' end of the second coding sequence (for example, any of the polyadenylation sequences described herein ). In some embodiments, each of the encoded portions is at least 30 amino acid residues in length (e.g., at least 50 amino acids, at least 75 amino acids, or at least 100 amino acids in length), the amino acid sequence of each of the encoded portions does not overlap with the sequence different encoded portion, and neither of the two different vectors encodes active CLRN1 protein (eg, full-length CLRN1 protein). When introduced into a mammalian cell (e.g., any of the mammalian cells described herein), splicing occurs between a splice donor sequence and a splice acceptor sequence, thereby generating a recombined nucleic acid that encodes an active CLRN1 protein (e.g., full-length CLRN1 protein).

In another example, three different nucleic acid vectors may be used. The first nucleic acid vector may include a portion of a promoter sequence (e.g., any of the promoter sequences described herein), a first CLRN1 gene coding sequence that encodes a first portion of a CLRN1 protein (e.g., any of the CLRN1 coding sequences described herein), located at the 3' end of the promoter, and a first splice donor sequence located at the 3' end of the first coding sequence. The second nucleic acid vector may comprise a first splice acceptor sequence, a second CLRN1 gene coding sequence that encodes a second portion of the CLRN1 protein located at the 3' end of the first splice acceptor sequence, and

- 81 045887 a second splice donor sequence located at the 3' end of the second coding sequence (eg, any of the splice donor sequences described herein). A feature of the second nucleic acid vector will be that self-splicing cannot occur (ie, splicing will not occur between the second splice donor sequence and the first splice acceptor sequence of the second nucleic acid vector). In some embodiments, the splice donor sequence of the first nucleic acid vector and the second splice donor sequence of the second nucleic acid vector are the same (eg, any of the splice donor sequences described herein or known in the art). In some embodiments, the first splice donor sequence of the first nucleic acid vector and the second splice donor sequence of the second nucleic acid vector are different (eg, any of the splice donor sequences described herein or known in the art). The third nucleic acid vector will comprise a second splice acceptor sequence, a third coding sequence of a CLRN1 gene that encodes a third portion of the CLRN1 protein located at the 3' end of the second splice acceptor sequence, and a polyadenylation sequence located at the 3' end of the third coding sequence (eg , any of the polyadenylation sequences described herein). In such methods where three nucleic acid vectors are used, the first splice donor sequence and the first splice acceptor sequence may be assembled together (recombine), and the second splice donor sequence and the second splice acceptor sequence may be assembled together (recombine), and portions of the CLRN1 protein encoded by the first, second, and third coding sequences do not overlap, and when introduced into a mammalian cell (e.g., any of the mammalian cells described herein), splicing occurs between the first splice donor sequence and the first splice acceptor sequence and between the second splice donor sequence and the second splice acceptor sequence to form a recombined nucleic acid that encodes an active CLRN1 protein (eg, full-length CLRN1 protein). Based on the strategies presented above, one skilled in the art will understand how to develop a strategy using four, five or six different nucleic acid vectors.

In any example of these methods, no amino acid sequence of the encoded portions overlaps with any other encoded portion, and no vector encodes an active CLRN1 protein (eg, full-length CLRN1 protein).

Each of the at least two different vectors contains a coding sequence that encodes a different portion of the CLRN1 protein, and each of the encoded portions may consist of at least 30 amino acids (e.g., from about 30 to about 1200 amino acids or any other subrange of this range, described in this document).

In some embodiments, each of the coding sequences may comprise at least one exon and at least one intron of SEQ ID NO: 9 (e.g., at least two exons and at least one intron, at least two exons and at least two introns, at least three exons and at least one intron, at least three exons and at least two introns, or at least three exons and at least three introns). In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, and each of the encoded portions may encode up to 80% of the amino acid sequence of SEQ ID NO: 1 (e.g., up to 10, 20, 30, up to 40, 50, 60 or up to 70% of SEQ ID NO: 1), so that each of the encoded parts does not overlap. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of the amino acid sequence of SEQ ID NO: 3 (e.g., up to 10, 20, 30, up to 40, 50, 60 or up to 70% SEQ ID NO: 3) provided that each of the encoded parts does not overlap with the other. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of the amino acid sequence of SEQ ID NO: 5 (e.g., up to 10, 20, 30, up to 40, 50, 60 or up to 70% SEQ ID NO: 5) provided that each of the encoded parts does not overlap with the other. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of the amino acid sequence of SEQ ID NO: 7 (e.g., up to 10, 20, 30, up to 40, 50, 60 or up to 70% SEQ ID NO: 7) provided that each of the encoded parts does not overlap with the other.

Each of the at least two nucleic acid vectors may further comprise an inverted terminal repeat (ITR) to facilitate head-to-tail recombination. The ITR will subsequently be removed by splicing. For example, the ITR may be a double-D palindromic ITR, as described in Yan et al., Proc. Natl. Acad. Sci. U.S.A., 97(12):6716-6721, 2000, included in its entirety

- 82 045887 this document, or the AAV serotype 2 ITR as described in Gosh et al., Mol. Ther. 16:124-130, 2008, and Gosh et al., Human Gene Ther. 22:77-83, 2011. Non-limiting examples of splice acceptor and/or donor sequences in the art. See, for example, Reich et al., Human Gene Ther. 14(1):37-44, 2003, and Lai et al. (2005), Nat. Biotechnol. 23(11):1435-1439, 2005, 2005. The splice donor and acceptor sequences can be any endogenous splice donor/acceptor sequence of a gene (eg, the CLRN1 gene).

For example, the splice donor sequence may be: 5'GTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGAAGACTCTTGCGTTTCT-3' (SEQ ID NO: 22), and the splice acceptor sequence may be 5'-GATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAG-3' (SeQ ID NO: 23) (see, for example, Trapani et al., EMBO Mol Med 6(2):194–211, 2014).

Methods for assessing splicing efficiency and splicing efficiency are known in the art (see, for example, Lai et al., Nat. Biotechnol. 23(11):1435-1439, 2005).

Example 11. Hybrid vector trans-splicing strategy using a highly recombinogenic region of the exogenous alkaline phosphatase (AP) gene.

At least two (e.g., two, three, four, five, or six) different nucleic acid vectors (e.g., AAV-based vectors) may also be used in any of the methods described herein to restore active CLRN1 (e.g., the full-length gene CLRN1) in the cell after intermolecular concatamerization mediated by the recombination marker gene and trans-splicing. This strategy is a hybrid strategy because it will involve homologous recombination and/or trans-splicing. See, for example, Gosh et al., Mol. Ther. 16:124-130, 2008; Gosh et al., Human Gene Ther. 22:77-83, 2011; and Duan et al., Mol. Ther. 4:383-391, 2001, each of which is incorporated herein in its entirety. In this context, the detectable marker gene may be a highly recombinogenic DNA sequence that allows recombination independent of the coding sequence. A non-limiting example of a detectable marker gene is the alkaline phosphatase (AP) gene. For example, the detectable marker gene may be the middle third of complementary human placental AR DNA, which is 872 bp in length. (See, for example, Gosh et al., 2008). At least two different nucleic acid vectors will contain a detectable marker gene (eg, any of the detectable marker genes described herein). Since the hybrid vector will be constructed from a trans-splicing vector as described in Example 10, an active CLRN1 gene (e.g., full-length CLRN1 gene) can be restored using ITR-mediated recombination and trans-splicing or mediated by a detectable marker gene (e.g., AP gene-mediated) recombination and trans-splicing. Following transsplicing, an active CLRN1 gene (eg, the full-length CLRN1 gene) will be restored to the genomic DNA of a mammalian cell (eg, any mammalian cell described herein).

In one example, two different nucleic acid vectors will be used. The first nucleic acid vector may contain a promoter (e.g., any of the promoters described herein), a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located 3' of the promoter (e.g., any size portion of the protein described herein CLRN1, and/or any of the N-terminal portions of the CLRN1 protein described herein), a splice donor sequence located at the 3' end of the first coding sequence, and a first detectable marker gene located at the 3' end of the splice donor sequence. The second nucleic acid vector may comprise a second detectable marker gene, a splice acceptor sequence located 3' of the second detectable marker gene, a second coding sequence that encodes the C-terminal portion of the CLRN1 protein located 3' of the splice acceptor sequence (e.g., part any size of the CLRN1 protein described herein and/or any of the C-terminal portions of the CLRN1 protein described herein), and a polyadenylation sequence at the 3' end of the second coding sequence (e.g., any of the polyadenylation sequences described herein). In some embodiments, each of the encoded portions is at least 30 amino acid residues in length (e.g., at least 50 amino acids, at least 75 amino acids, or at least 100 amino acids in length), the amino acid sequences of the encoded portions do not overlap, and none of the two different vectors does not encode active CLRN1 protein (eg, full-length CLRN1 protein). When introduced into a mammalian cell (e.g., any of the mammalian cells described herein), splicing occurs between a splice donor sequence and a splice acceptor sequence, thereby generating a recombined nucleic acid that encodes an active CLRN1 protein (e.g., full-length CLRN1 protein).

In another example, three different nucleic acid vectors may be used. The first nucleic acid vector may contain a portion of a promoter sequence (for example, any of

- 83 045887 promoter sequences described herein), the first coding sequence of the CLRN1 gene, which encodes the first part of the CLRN1 protein (for example, any of the CLRN1 coding sequences described herein) located at the 3' end of the promoter, the first donor sequence splicing located at the 3' end of the first coding sequence, and the first detectable marker gene. The second nucleic acid vector may comprise a second detectable marker gene, a first splice acceptor sequence located 3' of the second detectable marker gene, a second CLRN1 gene coding sequence that encodes a second portion of the CLRN1 protein located 3' of the first splice acceptor sequence, a second a splice donor sequence located at the 3' end of the second coding sequence (eg, any of the splice donor sequences described herein), and a third detectable marker gene. A feature of the second nucleic acid vector will be that self-splicing cannot occur (ie, splicing will not occur between the second splice donor sequence and the first splice acceptor sequence of the second nucleic acid vector). In some embodiments, the splice donor sequence of the first nucleic acid vector and the second splice donor sequence of the second nucleic acid vector are the same (eg, any of the splice donor sequences described herein or known in the art). In some embodiments, the first splice donor sequence of the first nucleic acid vector and the second splice donor sequence of the second nucleic acid vector are different (eg, any of the splice donor sequences described herein or known in the art). The third nucleic acid vector may comprise a fourth detectable marker gene, a second splice acceptor sequence located 3' of the fourth detectable marker gene, a third CLRN1 gene coding sequence that encodes a third portion of the CLRN1 protein located 3' of the second splice acceptor sequence, and a polyadenylation sequence located at the 3' end of the third coding sequence (eg, any of the polyadenylation sequences described herein). In such methods where three nucleic acid vectors are used, the first splice donor sequence and the first splice acceptor sequence may be assembled together (recombine), and the second splice donor sequence and the second splice acceptor sequence may be assembled together (recombine), and portions of the CLRN1 protein encoded by the first, second, and third coding sequences do not overlap with each other, and when introduced into a mammalian cell (e.g., any of the mammalian cells described herein), splicing occurs between the first splice donor sequence and the first splice acceptor sequence and between the second donor sequence splicing and a second splicing acceptor sequence to form a recombined nucleic acid that encodes an active CLRN1 protein (eg, full-length CLRN1 protein). As can be understood from the prior art, when three nucleic acid vectors are used, two of at least two different nucleic acid vectors may contain a detectable marker gene (for example, an AP marker gene) and one of at least two different nucleic acid vectors may contain the sequence a splice acceptor that is complementary to a splice donor sequence in the nucleic acid vector that contains the detectable marker gene. For example, in some embodiments, the first and second nucleic acid vectors may contain a detectable marker gene (e.g., an AP marker gene), and the third nucleic acid vector will contain a splice acceptor sequence that is complementary to a splice donor sequence in the second nucleic acid vector, and the third vector will the nucleic acid will not contain a detectable marker gene (eg, the AP marker gene). In other examples, the second and third nucleic acid vectors may contain a detectable marker gene (e.g., an AP marker gene), and the first nucleic acid vector will contain a splice donor sequence that is complementary to a splice acceptor sequence in the second nucleic acid vector, and the first nucleic acid vector will not will contain a detectable marker gene (eg, an AP marker gene).

Based on the strategies presented above, one skilled in the art will understand how to develop a strategy using four, five or six vectors.

CLRN1 coding sequences present in at least two nucleic acid vectors (eg, two, three, four, five or six) will not overlap. Each of the at least two different vectors may contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions consists of, for example, at least 30 amino acids (e.g., from about 30 to about 1600 amino acids or any of other subranges this range described in this document).

In some embodiments, the at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, each

- 84 045887 of the encoded portions encodes at least one exon and at least one intron from SEQ ID NO: 9 (for example, at least two exons and at least one intron, at least two exons and at least two introns , at least three exons, at least one intron, at least three exons and at least two introns, or at least three exons and at least three introns). In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of SEQ ID NO: 1 (e.g., up to 10, 20, 30, 40, 50 , 60, 70% SEQ ID NO: 1) provided that each of the encoded parts does not overlap with the other. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of SEQ ID NO: 3 (e.g., up to 10, 20, 30, 40, 50 , 60, 70% SEQ ID NO: 3) provided that each of the encoded parts does not overlap with the other. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of SEQ ID NO: 5 (e.g., up to 10, 20, 30, 40, 50 , 60, 70% SEQ ID NO: 5) provided that each of the encoded parts does not overlap with the other. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of SEQ ID NO: 7 (e.g., up to 10, 20, 30, 40, 50 , 60, 70% SEQ ID NO: 7) provided that each of the encoded parts does not overlap with the other.

As described in Example 10, each of the at least two nucleic acid vectors may further comprise an inverted terminal repeat (ITR) to facilitate head-to-tail recombination. The ITR will subsequently be removed by splicing. Examples of ITRs and splice acceptor sequences and/or splice donor sequences are known in the art and are described in Example 10.

Example 12. Hybrid vector trans-splicing strategy using the highly recombinogenic region of the exogenous gene (AK) of phage F1.

At least two (e.g., two, three, four, five, or six) different nucleic acid vectors (e.g., AAV-based vectors) may also be used in any of the methods described herein to restore active CLRN1 (e.g., the full-length gene CLRN1) in the cell after intermolecular concatamerization mediated by the recombination marker gene and trans-splicing. This strategy is a hybrid strategy because it will involve homologous recombination and/or trans-splicing. See, for example, Trapani et al., EMBO Mol. Med. 6(2):194-211, 2014, incorporated herein in its entirety. As used herein, the recombinogenic region (AK) of phage F1 will be used to enable coding sequence-independent recombination. The recombinogenic region of phage F1 may be 77 bp. recombinogenic region from the genome of phage F1, as described in Trapani et al. (2014). At least two different nucleic acid vectors will contain the F1 phage recombinogenic region. Since the fusion vector will be constructed based on a trans-splicing vector as described in Example 10, a nucleic acid encoding an active CLRN1 protein (eg, full-length CLRN1 protein) can be produced using phage F1 recombinogenic region-induced recombination and trans-splicing. Trans-splicing in a mammalian cell (eg, any of the mammalian cells described herein) produces a nucleic acid encoding an active CLRN1 protein (eg, full-length CLRN1 protein).

In one example, two different nucleic acid vectors will be used. The first nucleic acid vector may contain a promoter (e.g., any of the promoters described herein), a first coding sequence that encodes the N-terminal portion of the CLRN1 protein located 3' of the promoter (e.g., any size portion of the protein described herein CLRN1, and/or any of the N-terminal portions of the CLRN1 protein described herein), a splice donor sequence located at the 3' end of the first coding sequence, and a recombinogenic region of phage F1 located at the 3' splice donor sequence. The second nucleic acid vector may comprise a recombinogenic region of phage F1, a splice acceptor sequence located at the 3' end of the recombinogenic region of phage F1, a second coding sequence that encodes the C-terminal portion of the CLRN1 protein located at the 3' end of the splice acceptor sequence (e.g. , a portion of any size from the CLRN1 protein described herein and/or any of the C-terminal portions of the CLRN1 protein described herein), and a polyadenylation sequence at the 3' end of the second coding sequence (e.g., any of the polyadenylation sequences described herein document). In some embodiments, each of the encoded portions is at least 30 amino acid residues in length (e.g., at least 50 amino acids, at least 75 amino acids, or at least 100 amino acids in length), the amino acid sequence

- 85 045887 The scope of each of the encoded portions does not overlap, and neither of the two different vectors encodes active CLRN1 protein (eg, full-length CLRN1 protein). When introduced into a mammalian cell (e.g., any of the mammalian cells described herein), splicing occurs between a splice donor sequence and a splice acceptor sequence, thereby generating a recombined nucleic acid that encodes an active CLRN1 protein (e.g., full-length CLRN1 protein).

In another example, three different nucleic acid vectors will be used. The first nucleic acid vector may comprise a promoter sequence (e.g., any of the promoter sequences described herein), a first coding sequence that encodes a first portion of the CLRN1 protein (e.g., any of the CLRN1 coding sequences described herein), located at 5 ' promoter, the first splice donor sequence located at the 3' end of the first coding sequence, and the recombinogenic region of phage F1. The second nucleic acid vector may comprise a recombinogenic region of phage F1, a first splice acceptor sequence located at the 3' end of the recombinogenic region of phage F1, a second coding sequence that encodes a second portion of the CLRN1 protein located at the 3' end of the first splice acceptor sequence, a second a splice donor sequence located at the 3' end of the second coding sequence (eg, any of the splice donor sequences described herein), and a recombinogenic region of phage F1. A feature of the second nucleic acid vector will be that self-splicing cannot occur (ie, splicing will not occur between the second splice donor sequence and the first splice acceptor sequence of the second nucleic acid vector). In some embodiments, the splice donor sequence of the first nucleic acid vector and the second splice donor sequence of the second nucleic acid vector are the same (eg, any of the splice donor sequences described herein or known in the art). In some embodiments, the first splice donor sequence of the first nucleic acid vector and the second splice donor sequence of the second nucleic acid vector are different (eg, any of the splice donor sequences described herein or known in the art). The third nucleic acid vector may comprise a recombinogenic region of phage F1, a second splice acceptor sequence located at the 3' end of the recombinogenic region of phage F1, a third coding sequence that encodes a third portion of the CLRN1 protein located at the 3' end of the second splice acceptor sequence, and a sequence polyadenylation located at the 3' end of the third coding sequence (eg, any of the polyadenylation sequences described herein). In such methods where three nucleic acid vectors are used, the first splice donor sequence and the first splice acceptor sequence may be assembled together (recombine), and the second splice donor sequence and the second splice acceptor sequence may be assembled together (recombine), and portions of the CLRN1 protein encoded by the first, second, and third coding sequences do not overlap, and when introduced into a mammalian cell (e.g., any of the mammalian cells described herein), splicing occurs between the first splice donor sequence and the first splice acceptor sequence and between the second splice donor sequence and the second splice acceptor sequence to form a recombined nucleic acid that encodes an active CLRN1 protein (eg, full-length CLRN1 protein). As can be understood from the prior art, when three nucleic acid vectors are used, two of the different nucleic acid vectors may contain the F1 phage recombinogenic region, and one of the different nucleic acid vectors may contain a splice acceptor sequence that is complementary to a splice donor sequence in the nucleic acid vector. which contains the recombinogenic region of phage F1. For example, in some embodiments, the first and second nucleic acid vectors may contain a recombinogenic region of phage F1, and the third nucleic acid vector will contain a splice acceptor sequence that is complementary to a splice donor sequence in the second nucleic acid vector, and the third nucleic acid vector will not contain a recombinogenic phage F1 region (for example, AR marker gene). In other examples, the second and third nucleic acid vectors may contain a recombinogenic region of phage F1, and the first nucleic acid vector will contain a splice donor sequence that is complementary to a splice acceptor sequence in the second nucleic acid vector, and the first nucleic acid vector will not contain a recombinogenic region of phage F1 . Based on the strategies presented above, one skilled in the art will understand how to develop a strategy using four, five or six vectors.

The CLRN1 coding sequences present in each of at least two nucleic acid vectors (eg, two, three, four, five or six) will not overlap. Each of at least two different vectors contains a coding sequence that

- 86 045887 encodes different parts of the CLRN1 protein, each of the encoded parts consisting of at least 30 amino acids (eg, from about 30 to about 1600 amino acids, or any of the subranges of this range described herein).

In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes at least one exon and at least one intron of SEQ ID NO: 9 (e.g., at least two exons and at least one intron, at least two exons and at least two introns, at least three exons and at least one intron, at least three exons and at least two introns, or at least at least three exons and at least three introns). In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of SEQ ID NO: 1 (e.g., up to 10, 20, 30, 40, 50 , 60 or up to 70% SEQ ID NO: 1) provided that each of the encoded parts does not overlap. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of SEQ ID NO: 3 (e.g., up to 10, up to 20, up to 30, up to 40, up to 50, up to 60 or up to 70% SEQ ID NO: 3) provided that each of the encoded parts does not overlap. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of SEQ ID NO: 5 (e.g., up to 10, up to 20, up to 30, up to 40, up to 50, up to 60 or up to 70% SEQ ID NO: 5) provided that each of the encoded parts does not overlap. In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of SEQ ID NO: 7 (e.g., up to 10, up to 20, up to 30, up to 40, up to 50, up to 60 or up to 70% SEQ ID NO: 7) provided that each of the encoded parts does not overlap.

As described in Example 10, each of the at least two nucleic acid vectors may further comprise an inverted terminal repeat (ITR) to facilitate head-to-tail recombination. The ITR will subsequently be removed by splicing. Examples of ITRs and splice acceptor sequences and/or splice donor sequences are known in the art and are described in Example 10.

Example 13: Hybrid vector trans-splicing strategy using two CLRN1 isoforms.

At least two different nucleic acid vectors (eg, AAV-based vectors) can be used to restore an active CLRN1 gene (eg, full-length CLRN1 gene) in a cell after intermolecular concatamerization and trans-splicing. See, for example, Yan et al., Proc. Natl. Acad. Sci. U.S.A. 97:12; 6716-6721, 2000, are incorporated herein in their entirety.

In some examples, two different nucleic acid vectors will be used. The first nucleic acid vector may contain a promoter (e.g., any of the promoters described herein), a first coding sequence that encodes an N-terminal portion of the CLRN1 protein located 3' of the promoter (e.g., any size portion of the CLRN1 protein described herein , and/or any of the N-terminal portions of the CLRN1 protein described herein), and a splice donor sequence located at the 3' end of the first coding sequence.

The second nucleic acid vector may contain a splice acceptor sequence, a second coding sequence that encodes the C-terminal portion of the CLRN1 protein (i.e., all of the portion of the CLRN1 protein that is not included in the N-terminal portion) located at the 3' end of the acceptor sequence splicing (e.g., any size portion of a CLRN1 protein described herein and/or any of the C-terminal portions of a CLRN1 protein described herein), and a polyadenylation signal sequence at the 3' end of a second coding sequence (e.g., any of those described herein polyadenylation sequence document).

In some embodiments, each of the encoded portions is at least 30 amino acid residues in length (e.g., at least 50 amino acids, at least 75 amino acids, or at least 100 amino acids in length), the amino acid sequences of the two encoded portions do not overlap with each other , and neither of the two different vectors encodes active CLRN1 protein (e.g., full-length CLRN1 protein).

In some embodiments, at least two different vectors each contain a coding sequence that encodes a different portion of the first isoform of the CLRN1 protein (eg, SEQ ID NO: 3). In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of the amino acid sequence of SEQ ID NO: 3 (e.g., up to 10, 20, 30, up to 40, 50, 60 or up to 70% SEQ ID NO: 3) provided that each of the encoded parts does not overlap with the other.

- 87 045887

In some embodiments, one of the at least two different nucleic acid vectors further comprises a sequence that encodes a second isoform of the CLRN1 protein (eg, SEQ ID NO: 5). In some embodiments, at least two different vectors each contain a coding sequence that encodes different portions of the CLRN1 protein, wherein each of the encoded portions encodes up to 80% of the amino acid sequence of SEQ ID nO: 5 (e.g., up to 10, 20, 30, up to 40, 50, 60 or up to 70% SEQ ID NO: 5) provided that each of the encoded parts does not overlap with the other.

In some embodiments, the at least two different vectors each contain a coding sequence that encodes a different portion of the second isoform of the CLRN1 protein. In some embodiments, one of the at least two different nucleic acid vectors further comprises a sequence that encodes a first isoform of the CLRN1 protein.

When introduced into a mammalian cell (e.g., any of the mammalian cells described herein), splicing occurs between a splice donor sequence and a splice acceptor sequence, thereby generating a recombined nucleic acid that encodes an active CLRN1 protein (e.g., full-length CLRN1 protein).

Non-limiting examples of such vectors are shown in FIG. 1, 2, 4, 7-10 and 12-24.

Example 14 Expression of CLRN1 in HEK293FT cells.

HEK293FT cells were transfected with exemplary CLRN vectors. At 48 h posttransfection, HEK293FT cell lysates were prepared and CLRN1 protein expression was determined by Western blotting. As shown in FIG. 25-31, CLRN1 protein was detected in all samples tested. This result confirmed that the CLRN1 protein can be expressed using the exemplary CLRN1 vectors described herein.

In fig. Figure 32 shows that HEK293FT cells transfected with the CLRN1-6eGFP vector expressed high levels of GFP as early as 72 hours after transfection. At 24 h posttransfection, several HEK293FT cells expressed GFP after transfection with the CLRN1-e6GFP vector at MOIs of 8.41E+04 and 2.53E+05. At 72 h posttransfection, most HEK293FT cells transfected with the CLRN1-e6GFP vector at an MOI of 2.53E+05 expressed GFP, whereas only some HEK293FT cells transfected with the CLRN1-e6GFP vector at an MOI of 8.41E+04 expressed GFP. As shown in FIG. 33, CLRN1 was expressed at high levels in HEK293FT cells transfected with CLRN-0 vector, CLRN-3 vector, and CLRN-13 vector.

Example 15. Mouse P2 cochlear explants expressing CLRN1.

P2 cochlear explants from WT mice were infected 16 h postinoculation and collected for RNA and immunofluorescence at 72 h postinfection. As shown in FIG. 34, CLRN1 is efficiently expressed in cochlear explants. As shown in FIG. 35, outer hair cells (OHCs) and inner hair cells (IHCs) of P2 cochlear explants express Myo7a when transfected with the vector CLRN-0 (1.3E10 vg/cochlea), CLRN-3 (9.9E09 vg/cochlea) and CLRN-13 (1.0 E10 vg/cochlea). Transfection with either vector did not disrupt the structural integrity of the snail NVC or VVC. Thus, in FIG. 35 shows the lack of toxicity of CLRN1 constructs with viable and organized outer hair cells (OHCs), inner hair cells (IHCs), and stereociliary bundles. As shown in FIG. 36, expression of eGFP with CLRN1-3UTR appears to determine transduction over the CAG promoter alone. Cochlear explants infected with 1E09 AAV/Anc80.CAG.eGFP expressed Myo7a in inner hair cells. Snail explants infected with 1E09 AAV/Anc80.CAG.eGFP.CLRN-3′UTR expressed My07a in both NVC and VVC. Higher transduction and coexpression of CLRN1 was observed in NVCs of snail explants infected with AAV/Anc80.CAG.eGFP.CLRN-3′UTR. GFP expression in cochlear explants infected with AAV/Anc80.CAG.eGFP.CLRN-3′UTR was restricted to NVC.

Other embodiments

It should be understood that while the invention has been described in connection with its detailed description, the foregoing description is intended to be illustrative and does not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, this description, including definitions, will control. Section headings and any descriptions of materials, methods, and examples are illustrative only and are not intended to be limiting.

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List of sequences

SEQ ID NO: 1 - Isoform D of human full-length wild-type CLRN1 protein:

MPSQQKKIIFCMAGVFSFACALGVVTALGTPLWIKATVLCKTGALLVNASGQEL DKFMGEMQYGLFHGEGVRQCGLGARPFRFSFFPDLLKAIPVSIHVNVILFSAILIVLTMV GTAFFMYNAFGKPFETLHGPLGLYLLSFISVALWLPATRHQAQGSCGCLVMILFASEVKI HHLSEKIANYKEGTYVYKTQSE KYTTSFWVIFFCFFVHFLNGLLIRLAGFQFPFAKSKDA ETTNVAADLMY

SEQ ID NO: 2 - Wild-type human CLRN1 isoform D cDNA:

atgccaagc caacagaaga aaatcatttt ttgcatggcc ggagtgttca gttttgcatg tgccctcgga gttgtgacag ccttggggac accgttgtgg atcaaagcca ctgtcctctg caaaacggga gctctgctcg tcaatgcctc agggcaggag ctggacaagt ttatgggtga aatgca gtac gggcttttcc acggagaggg tgtgaggcag tgtgggttgg gagcaaggcc ctttcggttc tcattttttc cagatttgct caaagcaatc ccagtgagca tccacgtcaa tgtcattctc ttctctgcca tccttattgt gttaaccatg gtggggacag ccttcttcat gtacaatgct tt tggaaaac cttttgaaac tctgcatggt cccctagggc tgtacctttt gagcttcatt tcagttgccc tttggctgcc agctaccagg caccaggctc aaggctcctg tggctgtctt gtcatgatat tgtttgcctc tgaagtgaaa atccatcacc tctcagaaaa aattgcaaat tataaagaag ggacttatgt ctacaaaacg caaagtgaaa aatataccac ctcattctgg gtcattttct tttgcttttt tgttcatttt ctgaatgggc tcctaatacg acttgctgga tttcagttcc ct tttgcaaa atctaaagac gcagaaacaa ctaatgtagc tgcagatcta atgtactga

SEQ ID NO: 3 - Isoform A of human full-length wild-type CLRN1 protein:

MPSQQKKIIFCMAGVFSFACALGVVTALGTPLWIKATVLCKTGALLVNASGQEL DKFMGEMQYGLFHGEGVRQCGLGARPFRFSFFPDLLKAIPVSIHVNVILFSAILIVLTMV GTAFFMYNAFGKPFETLHGPLGLYLLSFISGSCGCLVMILFASEVKIHHLSEKIANYKEGT YVYKTQSEKYTTSFWVIFFCFF VHFLNGLLIRLAGFQFPFAKS KDAETTNVAADLMY SEQ ID NO: 4 - wild-type human CLRN1 isoform A cDNA:

atgccaagc caacagaaga aaatcatttt ttgcatggcc ggagtgttca gttttgcatg tgccctcgga gttgtgacag ccttggggac accgttgtgg atcaaagcca ctgtcctctg caaaacggga gctctgctcg tcaatgcctc agggcaggag ctggacaagt ttatgggtga aatgca gtac gggcttttcc acggagaggg tgtgaggcag tgtgggttgg gagcaaggcc ctttcggttc tcattttttc tcattttttc cagatttgct caaagcaatc ccagtgagca tccacgtcaa tgtcattctc ttctctgcca tccttattgt gttaaccatg gtggggacag ccttcttcat gtacaatgct tt tggaaaac cttttgaaac tctgcatggt cccctagggc tgtacctttt gagcttcatt tcaggctcct gtggctgtct tgtcatgata ttgtttgcct ctgaagtgaa aatccatcac ctctcagaaa aaattgcaaa ttataaagaa gggacttatg tctacaaaac gcaaagtgaa aaatatacca cctcattctg ggtcattttc ttttgctttt ttgttcattt tctgaatggg ctcctaatac gacttgctgg atttcagttc ccttttgcaa aatctaaaga cgcagaaaca actaatgtag ctg cagatct aatgtactga

SEQ ID NO: 5 - Isoform C of wild-type human full-length CLRN1 protein:

MQALQQQPVFPDLLKAIPVSIHVNVILFSAILIVLTMVGTAFFMYNAFGKPFETLH GPLGLYLLSFISGSCGCLVMILFASEVKIHHLSEKIANYKEGTYVY KTQSEKYTTSFWLTKGHS

SEQ ID NO: 6 - Wild-type human CLRN1 isoform C cDNA:

atgcaggc cctgcagcag caaccagttt ttccagattt gctcaaagca atcccagtga gcatccacgt caatgtcatt ctcttctctg ccatccttat tgtgttaacc atggtgggga cagccttctt catgtacaat gcttttggaa aaccttttga aactctgcat ggtcccctag ggctgtacct tttgag cttc atttcaggct cctgtggctg tcttgtcatg atattgtttg cctctgaagt gaaaatccat cacctctcag aaaaaattgc aaattataaa gaagggactt atgtctacaa aacgcaaagt gaaaaatata ccacctcatt ctggctgact aaaggccaca gctga

SEQ ID NO: 7 - Isoform E of human full-length wild-type CLRN1 protein:

MPSQQKKIIFCMAGVFSFACALGVVTALGTPLWIKATVLCKTGALLVNASGQEL DKFMGEMQYGLFHGEGVRQCGLGARPFRFSCYFLDPFMGLPTGVPHLLSLPCSTSCRRE HTSERVQEPAGCFSAVRSKLHAGPAAATSFSRFAQSNPSEHPRQCHS LLCHPYCVNHGGDSLLHVQCFWKTF

SEQ ID NO: 8 - wild type human CLRN 1 isoform E cDNA:

atgccaagc caacagaaga aaatcatttt ttgcatggcc ggagtgttca gttttgcatg tgccctcgga gttgtgacag ccttggggac accgttgtgg atcaaagcca ctgtcctctg caaaacggga gctctgctcg tcaatgcctc agggcaggag ctggacaagt ttatgggtga aatgca gtac gggcttttcc acggagaggg tgtgaggcag tgtgggttgg gagcaaggcc ctttcggttc tcatgctatt ttcttgaccc cttcatgga ctcccaacag gggtacccca tttactcagc ctgccctgct caacctcttg caggagggag cacacgagtg aacgagtgca ggaaccagct ggctgcttta gtgctgtgag gagtaaactc catgcaggcc ctgcagcagc aaccagtttt tccagatttg ctcaaagcaa tcccagtgag catccacgtc aatgtcattc tcttctctgc catccttatt

- 89 045887 gtgttaacca tggtggggac agccttcttc atgtacaatg cttttggaaa accttttga

SEQ ID NO: 9 - Genomic sequence of wild type human CLRN1:

aggagatact tgaaggcagt ttgaaagact tgttttacag attcttagtc caaagatttc 61 caattaggga gaagaagcag cagaaaagga gaaaagccaa gtatgagtga tgatgaggcc 121 ttcatctact gacatttaac ctggcgagaa ccgtcgatgg tgaagttgcc ttttcagctg 1 81 ggagctgtcc gttcagcttc cgtaataaat gcagtcaaag aggcagtccc ttcccattgc 241 tcacaaaggt cttgtttttg aacctcgccc tcacagaagc cgtttctcat catgccaagc 301 caacagaaga aaatcatttt ttgcatggcc ggagtgttca gttttg catg tgccctcgga 361 gttgtgacag ccttggggac accgttgtgg atcaaagcca ctgtcctctg caaaacggga 421 gctctgctcg tcaatgcctc agggcaggag ctggacaagt ttatgggtga aatgcagtac 481 gggcttttcc acggagaggg tgtgaggcag tgtgggttgg gagcaaggcc ctttcggttc 541 tcatgtaagt agcaattgca tttgagttat ttaatgcttt aggcagactc ttcccagtg t 601 tgcgaggaat tatatttgag aattttgccg tgtttactgc aggacttttt aaatcggtgt 661 gaaccatatg aaaaacctat gactctgagc aatttcttct tcctagtttt tattatttta 721 tacttgcttt ttattataat atagagttaa ttcattgtta cataattaag gt ttttggaa 781 atattggcaa ttaagatgct taagtattaa tatttatgta aaaaattatg gagtcttttt 841 aaaaaagtaa acttggggaa ataggaaagc tgtaaagaat gatctttatg ctttttgttc 901 tttataaaaa gaaccaaggt catgggctcc gtatttaacc aggttgccac ctttctcatg 961 attttgtttc ctgctcccca ctccctccca ttattcctgc taagaccttt cctgctgcta 1021 a atattcagt tttcattttt aactaatttg gaatcatttg gctatagaaa tttaaaatga 1081 tctgctgtgc taactgggaa agaaatggat gcctatttag tatagaacat tttaaactga 1141 ttgacctgca aatcatgtag agaatatgag agagattttc ttgttgtgat ttttgt gaaa 1201 tggaagtgta atccacagta tttataacct gtttatctta agaagagaat ttttaaaaat 1261 taccatgtga ataggcaact cattaaatga aaattaatag gaagtcattt gttatatctc 1321 ttacaacaca cattcagaag ttattattat ttcagaaggg ctggtttgga acaaccttat 1381 gaagacacag tcagtaaatt actgcataaa tcactcttca ggaaaggagg ttaccaactg 1441 aagcatttaa aatgaattat tattttgccc aggttttttt tttctttcta gtataggtag 1501 aaggctaaat taattgaatt tattattaac atatgcagtg cctaattaaa tttcagtgct 1561 ggtctattta tatttctgca acattcctta tatcttctta gcagtcattg gacaccaacc 1621 ttcagctcac ataggttact a agtgatatg aattttcata gggctccaga aaatttccaa 1681 gaattggttg ttagcttttt aattgatgaa gtggatacca gttcttttca ctgaatggct 1741 tttattcatt aaggtaatgg ggctgttaga gttgcttagt tttcctgggg aaggggaagg 1801 aagaaaacaa agcagaatgt catgtgatat gcaactgtat taaaaaaccg aaaaggaaaa 1861 aagttgagag agatgattta accgtgagtc accggcagcc aaagcgtgag taaagcttct 1921 cacagatgaa tttagacaaa agcggagaag gtactggtga attttctgga gcctttacat 1981 tttctacagt gaaatggaga taaactttac tcatgccata ggacatgttt caaaacaata 2041 ataagatgt t ttctgaacac ttactacata ctaagcactt tatatgcttt gtctcattta 2101 atccttacac agccacattc ttctggggtt tagcgaatga tttttgtggt tgtgtcctat 2161 gcttgtcctg tctaaggatg aagttgttct aattgggtgc ccctcctttt gctttctgtg 2221 aggacttgca gaactggtgg ggtttaaaca gtaccctcac ttatctcaca gaatttcatt 2281 agctcccaga tacccctgac attctccc cc tagcctagtg aagaaaatct tccatttact 2341 tgttcattct gcagtgacag ctccatcaat atacaataga ctatacatat taagtgtact 2401 gtatatacta tacatgttaa aaatctcatt cattttggtg aggcccagct aagaatactt 2461 acagtagagc tttttttttt ttccta agca taaaagtatc tttttcaatg cagcatgaga 2521 cagagttggg aaaaccaaaa taaatagatc caatggactc cccaaagagg ataatattca 2581 tttaaataaa cacccctctc agtgttaaaa ctttctaatc aacatgcctt tgggacacat 2641 tgcaccctca aagtttacac tcccattgca acgcagcttt gtggttcacg ttttttccat 2701 tcagaatgtc attaccctgt caatgatgtt tcatcaacg t ttgcttggat gagaatcctc 2761 tgatattctt cctgatagaa atgtataagc cctgttcata taaatgaata aaagatctaa 2821 ccttactttc tcagtagtgg cttccttgga gcaaaaagca gggacctcca gagagctcag 2881 gtggatgact cttttctgtt tcttcca gag ctcaacttac aattagtgca caattcattt 2941 cccagaatgt cttctttctt attgtgcctt tagaaagtta ttaagcaaac atttgaattc 3001

- 90 045887 acagaatctt accagtgtaa gaggaatgga aaaggtaact tatcaaggta acaatcactt 3061 cgtggccagt tttttcggct cactgcaact acccctcctg ggttcaagcg attctcctgc 3121 ctcagcctcc caagtagctg ggactacagg cgtgcaccac catgcccagc taattttttt 3181 tttgtatttt tagtaaagac agggtttcac catgtgggcc aggctggtct catggcaagt 3241 tttctttgtg ttgtcatgtt attatcaatt aataggaatt tatatttcag ttctgttagg 3301 tggataaaca ctattttgca tacctaaat g tttcatttat atcagcactg gccaataaaa 3361 atatactata agcaggccgg gtgcagtggc tcacgcctgt aatcccaact tttgggaggc 3421 caacactttg ggaggacaca gggtcaggag atcgagacca tcctggctaa cctggtgaaa 3481 tcccgtctct actaaaaata caaaaaatta gccgggcgtg gcgggggcgc ctgtagtccc 3541 agctacttgg gaggctgagg caggagaatg gcacgaacc c gggaggtgga gcttgcagtg 3601 agccgagatc tcgccactgc actccagcct tggtgacaga gcaagactct gtctcaaaaa 3661 aaaaaaaaaa aaaaaaaaaa aaaaaatata tatatatata tatatattac aagccacaag 3721 ccacatatgt acttttaaat gt cctagtag ccatattaga aaacaaaagt aaaaaggaat 3781 agatgaaatt aattttaatg atttttttaa acccaagata tccaaaatat tatcatttta 3841 acatataatt aaaaatttat tgagatgttt tacattgttt ttttttttct tgacgctgtc 3901 ttggaaatct agagtgtatt ttacatttac attacatcta attcagtcta gccacatttc 3961 acatgctcat ttttttgtgt gtggttttat ggagcaga ga gtttaatagg caagaaagaa 4021 aagagaaggc agaagaaaat ggctcccctg tacagagacg cgggggtggg gcgctccaaa 4081 gccaaaagag gaggtcccta agtatggtag acaccagcca ggaatatatg cagtgtctgg 4141 aggaggggat gtctgatttg catagggtca catgctcatt tttatggcta ctgtattggt 4201 cagtacagat ttagatgggg atttgctctg aacaagttgg tgattgatgg tgttcatatt 4261 ttaattgaat ttttcctggg ttctgctgta cacttgtatg tgtgttagtt tcatgtgcaa 4321 tgcttgtgtc acttttaaaa cccagatata tggcataaca tgagaatgaa aaatggacca 4381 gaaaaatagt ttggcaatgt agtcatgttt gttcctatta aatg ttccct attgaccact 4441 ctatctcttt taattataac aagaatctgc cctgccagca tgcccagtta cgctgggaaa 4501 acttctgcct catttactct ggctgattct catccactta tgggtcagtg gttcattttc 4561 tagaggtcac cagcattcat acctagcata caatttcatt cattataatg aaggaatgtt 4621 ttcccttcaa agagacacaa ctagtgggct taatttttct tgatatgtca cctgtaaaat 4681 tttaatgatg atgtttaaac tctaaatgta gccatcaaga caaaaactgc aaattttgag 4741 cctcagtgtg tgtgggtggg tttctgtttc ggtaatttga aacattgcag aatatcatca 4801 aaatatgata cccaagaatc atatggtatc aatcattcct agatatactg atctattcat 4861 t gccaagata gttcaatgag ctggcaaaaa catatggaat tattttctta aaatgtgaaa 4921 aataaaattt aaccaatcat gtatcacagc ttgcaacttt agtcatactt tgaaaagcat 4981 tttaatttgg acctcatgat tgaaaattta taaaaagctg aacagaaatt agttcacttc 5041 atattttaga aaagcagagt ttctttacta aatgaggcat ttgacccaaa ttggagagaa 5101 aatgttgaaa ctacttctgt gagcaagcag gtggcttctc aaacacatgt tgggatgaaa 5161 tggttgggcc tcagggtctc agtgcctgtc actgagagtt ggcactctct atctccatgg 5221 tctcctccaa gtgtgactct tgtctcttgc tgacctgacc tgccccaagt gactcactgg 5281 tcatgacc ct gcacaccttg cgtctctcct atcaccctgc cgatggcaga gctacaaagg 5341 tctttgatgt agctctgtct gatatcctgt gtttccccct atggtctgtg tggaagcagg 5401 tatgggggtg tgtaaagggg aagcctatga agttcatctg caaagactac ctggttaggg 5461 gaggagagga agaagctata tgcaccattt caccagcaag catgggctct tctgcctttt 5521 agcttagggg tcctgttgtc tagtctcact cacctattaa aacagtccag caaatagagg 5581 ttttgtttac ctcccattaa aaaaaaagca attaatggaa tagaagataa taatgtatga 5641 gaagcactat tgtgaaagaa aaaccttcaa cttctctcag ccaaataatt gcttcctcct 5701 ctgtccttcc cagacct tga tgtttgctct attatttcaa aacaactata ttataaatat 5761 ttgagaatgt gtatttccct gcaaggagat cttaatcccc aagaaggcag gagctgtgta 5821 ttattcatcc cagtgctcct tcaaaccagg gcctcagaca gtgcatggcc caaagaggta 5881 cttaataaac gttt ggtaaa ctgacactat tgaaattaag caacctggat ttgaggtggg 5941 tctctgccac tcacaagaga ttacgctttg agaaaattcc atcacttcat tgattttcag 6001 ttcttgcatc tgtatatggg agacgatact aggtgatttc tgacatctct caccgtttaa 6061 atgctctgtg atctatacaa cgaggggctc gctgttctag acaagttcct tccagcttta 6121 cagttgcata acccttctaa tcttagtcac atgatgactc cactgacaga

- 91 045887 tttttggcca 6181 ccatcattag acatgctgag ttacgtgtgc ctttgctctg atcctcaaaa ctcatgattt 6241 ttaaagtttt ctgaaatatc taccatttat caggatccag atggatttca tgaccaaagt 6301 ggatgtttct tttctctccc attacaatct tttacttttt gtgtgggaaa ttgcatgtta 6361 aagaaaggga aattgaagaa tgggatgctt tggaattctg gcaagatgga ttagtgggtt 6421 ccagaaagta ggggcagcca caaataccga aataaatgag atcgtattat tgagaaagca 6481 caaatggaag aaggt caaaa gcaagaagaa gctgacatcc tgcttcctcc aatttttgct 6541 ttctctgttt ttccaagaaa ctcctcttcc aagccttgct gaaaaactcc actttcctaa 6601 atctaacttc ttaaactgat aatggcaaga agttaggaat gaccaatatg tttaacactc 6661 caagagtatt tgttttgttt tgttttgaga ctgggtctca ctctgtcgtc cagcctggag 6721 tgcagtggtg t gatcacagc tcactgcagc cttgacctct cctgcccaag gaatcctccc 6781 acctcagcct cctgagtaga agggaccaca ggcatgtgcc actacacctg gctaactttt 6841 aaaaaatttt ttttagaga tggggttgcc caggcaggtc tcaaactgct gggctcaagc 6901 a atcctcctg cattggcctc ccaaagtgct ggaattatgg gcataagcca ctacgcctga 6961 cctctccaag ggcattcttt acccagaaga ggaacttggc agaacttatc ctccaattgg 7021 tgaggaatat ggagaaaatg actttaagca aaggaacttc tggttctgcc tacctaatcc 7081 agaaaaagaa gttttatttc tcccttcccc tagtaactat cttcccatat tcacataaaa 7141 aagtacagaa tcaacattgt tcaagaatta taattttact t gtaagcaca tgtgcacacg 7201 cacacccata taccttcctt ccctttaaat catcccacac cctaatagta gtaaaatcat 7261 tgacccgagc atacctggga gaggaagagg agtctgacag gggcaggttc taagtggcac 7321 tcctggaact taaccctggt gtatatgaac tttacct att gaaggatgac tcctcaactg 7381 ttctcacaat ttgctgctct gctttctttt ctaatttctg aaggtgactc atcttcccca 7441 aggactttca gacttctcag aagaaaaaaa tattgggtgg gtctctgcca ctggcaaaag 7501 attagacttt gagaatcata aaagtatatc agtatatact cattaatatt gaattactat 7561 aattaatatt atgatattga tataatgata gaatgatatt gataaaagca atattcaata 7 621 atgaatatta tttcagctgc ccacttattg ggtgcctcat aggtgccagg cattttgtat 7681 gtattatcta caacccttac atgggacata ttatgatgct gtttctcttg aagaaatatg 7741 gaaactggaa acagagaggt caccacaatt ttccaaagtc acatagctaa taggtagcag 7 801 acttgggatt caaattcata tgcatatggt aaatcatgct cttcctctgc tacattttgc 7861 ccccttagaa tatgaaaaag ggatacaaag agatgaagaa aatatgtaag attatccttc 7921 aatttcacta tcttttttaa agtttttttt attatacttt aaattctgaa atacatgtgc 7981 agaacatgca ggtttgttac ataggtatac acgtgccatg atggtttgtt gcacccatca 8041 acctgtcatc tacattaggt atttttccta atgctatccc tcccctagtc ccccacccac 8101 cgacaagccc cggtgtgtga tattcccctc cctgtgtcca tgtgttctca ttgttcaact 8161 cccacttatg agtgagaaca tgcgg tgttt ggttttctgt tcctgcgtca gtttgctgag 8221 aatgatggtt tccagcttca ttcatgttcc tgcaaaaggc atgaactcat tttatggctg 8281 cataccattc tatggtatac atgtgccaca ttttcttaat ctagtctatc attgatgggc 8341 atttggctta gttccaagtc cttgctattg tgaacagtgc tgcaataaac atatgtgggc 8401 atatgtcttt atagtagaat gatttataat cctttgggta tagaccagt aatgggattg 84 61 ctgggtcaaa tggcatttct ggttctaggt ccttcaggaa ttgccacact gtcttccaca 8521 atagctgaac tagtttacac tcccaccaac agtgtaaaag cgttcctatt tctccacatc 8581 ctctccaaca tctgttgctt cctgactttt taatgattgc cattctaatt ggag tgagat 8641 ggtatctcag tgtggttttg attagcattt ctttaatgac aagtgatgat gagctttttt 8701 tcatgtttgt tggccgtata aatgtcttct tttgagaagt gtccgttcat atcctttgcc 8761 cactttttaa cggggttttt tcttgtaaat ttgtttaact tccttgtaga ttctggatat 8821 tagtcctttg tcagatgggt agattgcaaa aattttcttc cattctgcag gttg cccgtt 8881 cactctgata atagtttctt ttgctgcgca gaagtttttt tagtttaatt agatcccatt 8941 tgtcaatttt ggcttttgtt gccattgctt ttggtgttta gtcatgaagt ctttgcccac 9001 gcctatgtcc tgaatggtaa tgcctaggtt t tcttctagg atttttatgg ttttaggtct 9061 tatgtttaaa tctttaatcc atcttgagtt aatttttgta taaggtataa ggaaggggtc 9121 cagtttagtt ttctgcatat ggctagccag ttttcccaac accatttatt aaatagggaa 9181 tcctttcccc gttgcttgtt tttgtcaggt ttgtcaaaga gcagatggtt gtagatgtgt 9241 ggcattattt ctgaggcctc tgttctgttt cattggtctc tgtatctgtt ttgatacaag 93 01 taccatgctg ttttggttac tgtagacttg tagtataatt tgaagtcagg tagcgtaata 9361 cctccagttt tgttcttttt gcttaggatt gtcttgacta

- 92 045887 ttcaggctct tttttggttc 9421 catatgaaat ttaaagtagt tttttctaat tctgtgaaga aagtcaatgg tagcttgatg 9481 ggaaaagcat tgaatctata agttactttg ggcagtatgg ccattttcat gatattaatt 9541 cttcctatcc gt gagcatgg aatgtttttc catttgtttg tgtcctttct tatttccttg 9601 agcagtagtt tgtagttctc cttgaagagg tccatcacat cccttgtaag ttgtattcct 9661 aggtattttg ttctctttgt agcaattgtg aatggaagtt cactcataag tttgctct ct 9721 gtttgtctgt tattggtgta taggaatgct tgtgattttt gcacattgat tttgtatcct 9781 gagactttgc cgaagttgct tatcagctta aggagatttt gggctgagac gacagggttt 9841 tctaaatata caatcatctc atctgcaaac agagacaatt tgacttcctc tcttcctatt 9901 tgaatacgct ttatttcttt ctcttgcctg tttgccctgg ccagaacttc caatactgtg 9961 ttgaatagga gtg ttcacca cctattttaa gaatagtatt gaagcctcac aaaagctggt 10021 tctcatgtaa ccatctgaga atatttggcc ttatgacttg aattcattca ttgccttttt 10081 atttcacatt ttagtgatcc tgatgtctaa atcttaatct ttgatccttg caaggtaaaa 10141 tagccaagtc aagcctgttt aataatattg gttgaggaag tcacatgctt atgatcaatc 10201 tttgggttat gtaattatat taccttaatg ttggcagttt aggtgtaagg cagagatatc 10261 tgatcacatg tgtggttagc taatttaaga tcactgccaa ctaaaatctt catggtatga 10321 tcttcaaagt tagctacttt gaccacagca atgatttcac cacagcaatt aacaaaatgg 10381 cagactcttt cctgaggtgg catga acagt tttaaaacaa agtcaaggac caaaagaaaa 10441 gcaggcacat ggcatttgat tcatttcaaa aactagtatt gtattaagag ccaaggggat 10501 agaattgtag catcaattaa aatcttgttt gaaaaaaaat aaaaacaaac gtccattttt 10561 atctctca aa tatattaggg ttttcataaa gttataggtg tatttttaaa aaaacaaaac 10621 tcatatacat tagactgaaa aatttgcctg tcatctcatc atgcagctaa atgcaattgt 10681 ctatggcgag atacactctt attagaggta tgatagcact aactaatagc aaactttgta 10741 cctggtagtc taatttatgc agggttcata tttcgctccc tctcagcatg ctgtaactgt 10801 ggcaaagcca ttctcaggag ttattacccc aacataatca tacccctgtg gattaggagc 10861 agttaaatgg gtcctgttat cagagacaca tatgtgccac agccgctgtc atccctaagc 10921 caccgtgggt gattaagact cactgatggg actacctctg aataggcttg agtgaggtgg 10981 atacacttca gctgagagaa at tcaggtaa ggggctgaga aaatcagatt ttgaatggtt 11041 ttatcatacc atcaggtctc cttttaagtg ctggggtcat ggatttcatt caacctgacc 11101 acatagcctt tggaagcttg gctcaatacc tgagtgtgag attatgggtg atattaaagg 11161 agatgaatgc attgagctga tgtcagagaa tgtcttttac tggattttca taatgactgg 11221 ctgcagatgg gctgagggga aagtcagatc aaga gcattt ctgtaagaag aaagaaatct 11281 tccctcttat tctctttcaa gaaaatgaat agctgagcac caagaggcca aatacttttt 11341 taaaaaacac atccttttat gtagagaagg acaggttgag acgaaaaaca ggacctctga 11401 aactgtcttt atagctttaa tctaggaaga aattgcggca ccattgctga catcattatc 11461 agaggctgcc ttagttctga gagcttcaca gatggccttt tctgcatttt acatctggcc 11521 agatgaaggc aaaaaggttg atgaaaccaa aactattaga tcagtggtcc ataactctgg 11581 ctgcacttta gaatcatctg gggagtcctt aaaactactg atcctgaggc tccatcccag 11641 accaattgaa tcaggatctc tgggggtggg acctgagcat tggaatgct t taaaagttcc 11701 tcagggactc taatgtgcag ccaaggctga gaatgactga ggtggatggt ggccaagaca 11761 ggtgaggcca agagttagaa gcccttactg ttagggaagg cagaagccac aagggagg 11821 ggagggggaa ggagcagtat ttagcatttc ttccacaca g ttggggggtt ttctgatcaa 11881 aattaggctg ggatctttcg cttccatttt catgaaggtc ttatgctttg tccacagcca 11941 cctggcctca gggcaatgag caatctgatt gatgaatttt cagtaagaaa ctgagcacac 12001 ttggctctca gccccagtgg cttcccctgt ttccaaatct gcccaccagt tacaggagcc 12061 tgctcaccaa ctggttgggt taaagaagtc ggctctgtcc ttggcaggga ggcct tcagc 12121 tgtctggccc tgtctgtgac tgcgtgggtg aagctgccta atttggggaa cttgatggaa 12181 gatctaagct atgttctcta acagttttat cagaaataaa gttaactttt gacctccatc 12241 tgcctgtctc ctgtggaagg gctct gctcc ttccaaagag actctcaggg gttctcctta 12301 gaggtgtgtt atcagtccaa agatcatttt agaccagcca ttacagagga tgtccaagaa 12361 attgcacaag ggaaatagaa gtaagaatga gagcaatata tcagatagta aggaaagtat 12421 gtgactggtt tcaaataagt aattaaccat aaatccaaag ttcctgcatt agttatagca 12481 atagtcatcc acctggtcag gaaaaaaaaa gtaaaagact gagctgcaag

- 93 045887 atagaaagtt 12541 tgcctgaatt ccacgtactt caaggactac tatggaggat tccttggtcc caatgcagag 12601 acatgtactc tgaccaccca tgggccaaat ccctcttacc caccctcagt gattcctcct 12661 gggacctcac tacattgagt tcttacatt c cccactcttt tcgggggaaa tataaccctt 12721 ctgctcttct catgatgtta aaaatattta gacaattact taaaatttac aacaatcttc 12781 cacataaatg atctcactta tgtttcttgt gagctctgtg atttatttct attatcatct 12841 atgctgatag ttaaggaaac t gagatatcg agaccaacat gcatagtaaa tggcaaaacc 12901 agatgaattt taaactttcc taactccaaa agccacatcc tgcccaaccc gccatgctgc 12961 cgctcagtta atgcctggct gtttgtctcc ccattggccc ctctacccat tgtgctttga 13021 tggcacactg tattccaact gcctgagact cctggttaat gccattacgt acagacttag 13081 gttgaattta ctaggatttt taagatt tgt aggataagag atatgactgt tagactggaa 13141 tcagcaatag ataaaaggtt aacaaagttt cagaataaaa tataatagaa aaccccagca 13201 gatagaagta aaatgaatgg taagacaact gaaatgaaag ccatacattt agaaatatca 13261 aataaaacac agattaatgg cagacaata a aggaacatac ttagcagtta gtaaaaacac 13321 tttttacctt attcttatta ccctccagta accttttttt tttttttttt tgagacaaag 13381 tctcgctgtg tcgtccaggc tggagggtag tgatgtgatc tcggctcact gcaacttctg 13441 cctcttgggc tgaagagatt ctcctgcccc agcctcctga gtagctggga ctataggggc 13501 ccatcactgc acctggctaa tttttgtatt tttagtagag acggggtttc accatgttgg 13561 ccaggctggt cttgaactcc tggcctcagg tgatccaccc gcctcagcct cccaaagtgc 13621 tgagattaca agcgtgagcc accaagcccg gctgtaacct attgaaaata acattacttg 13681 acatgtgaga caaattattt gtaagttaaa gagtttatgt gccttcaatg ctcccaccct 13741 tccctcccct aaaaagatta ttgagtgccc atgatgtgcc taagccttct ggtagactct 13801 gagaatgtga agagagttag aggatacttg ttcaacaacc cagaatctag cagaagtgtt 13861 ttgaaatgac cagccacttg ggagagctat gctagcatat cattcaggat gggctgggtc 13921 atgttttaat aacaagtaag tttgaacttt ataggtttga aa caaaaaag atgtgtttct 13981 tgctcacagt tcatattttt tggagattgg ctggagcttc attccaggat actgccacca 14041 tctggaatgt tgacagttac cgtaacagag aaagagttgt ggaggctgtc acactggcaa 14101 ttaaattcgc tgacctggaa ctgacacat g ccacctccac ttatatttta ttggccaagg 14161 cttgttacac agccacatct aacttcagag aggtcaagat gagcaaatcc taccacgagc 14221 tatagatgga tgagtagcac tcattattat cacaattatt ttatttgtta taaaaactcc 14281 aagaaggaga ggtactctat gtgaggaata ggcataggaa aatcagaggg aagttcttaa 14341 agatgagcta gatttcacta gatggcattg aagaaacatt ccaagtaaat gaacagcat a 14401 agcaaatgca tgaagaactt attgtggtcc tagtacagac gatgcgtgag agtgtggagg 14461 agggaaaagg taagactgga gaggaaggca ggaaccagaa caggacagac tgtgttcact 14521 gtcaggcagt taagtctatc ttgtaggcaa catgaagcct ttta aggaag gcaagcagct 14581 atgtgacagg acagaagatg gattggaaga aaatcaaaag agaagtgggg accagtcata 14641 aggctcctcc aatatttggg gatccaaacc aaagcactgg cagagaaata gaaaggaagg 14701 gaaatatttc caaaatattc aaaacagaaa ccaagagaac ttgatgacag aagatgaacc 14761 caggtttcta ctgaatggac agttgttaca ttctctgaga taaggaatac agaaggaaaa 14821 agttgagagg gaatatgaaa ttatttttaa tcatgtttaa tttgatcact tgtggaacat 14881 caaccagaga tgtccatcag ttacaccaat ttgtaggttt tgagagaggc ctgaggtaga 14941 ggcagagaag tgggaatcag cagattagcg gcagtagttg gaaccata ac tgaagatgag 15001 atttcccagg gaggggagtt gaacaggaag gtagacaaag gctgagtgca gtggctcata 15061 cctgtaatcc cagcactttg ggaggctgca gtgggtagat cacaaacaag atcaggagtt 15121 caagaccagc ctggccaaca tggtgaaacc ccgtctctac taaaaaaaca caaaaattag 15181 ccgggcgtgg tggcacacac ttgtaatccc agcctcagga ggctgaggca ggagaattgc 1 5241 ttgaacccgg gaggcagagg ttgcagtgag ccaagatcgt gccattgcac tccagcctgg 15301 gcgacagagc gagactccgt ccccaccgac cccctaaaaa agaaagtaga caaagatgtg 15361 tcctagaaaa cactaatatg aatgggtaga gaggggagac ttgtca agga gatcgagggg 15421 agagtcagtg aggtgaaacc ttagaggata gaccttcacc aaggaagtaa cagtcaacag 15481 gcctaaatgc cacagagatg tcaaatgaga gacactggaa atggttcttt gaatattaca 15541 gccagaacat cacaggagac catttccaaa gcagtcttga tgaagtggtg

- 94 045887 gggaagggag 15601 gtccctgaag gagctaagga gggactggga gatcatgacc cagataag tgttgcaggt 15661 ataaaaggga aagactgaga tcaggaaata gccacaggat ccctaaggcc aggcttcggg 15721 tggggtggtg tgtgtgtgtg t gtgtgtgtg tgtgtgtgtg tataaaatgg gaagaccttg 15781 agtataattc tgtactaaga agatagagca gtagagagga aaaggctgaa gacagatggg 15841 agggtaaata gtgaattaga aaggtctgtg caaagatgag aaaggatgag tctgaaagca 15901 cagg gagaag ggccagcctt ggacaggaga aaacatttct ttcactaaga ataaagggaa 15961 ggttgggtat acaccacaaa gaaggtgtag atgggtggca atggagttct gtcaagttga 16021 gggcattcca tgatagcctc acctttctct gtgaaatgag agagtttagt ttacaagata 16081 tttctgagca cttcataagc caggttcata gactgaaaga agtggaggtg gagtgtgata 16141 ggtccttaag aatagg ggaa gtttggaata tctgacaagg gacagagagg aaaaaactag 16201 aaaaggcttt gcagaatgtg ggcccacaga tcagaggcta aggggtcccc atttgtgcag 16261 gagagtaagg gcagggaggc aaggctcaca gcccaaaata tagagcccct caccaaatga 16321 ctgca ggagg gcagctttcc tatgagagca tccctatcac tgttttcact ccgagtcatt 16381 aacttacgac ttactcagct ctgtttcgta atagcagact cgagtaatga gggtatgaca 16441 gcctctctct gcatgccaag gtatgcagcg tggatttcct ttttcgcttt ctctctcctg 16501 tggcttaggt gccttctgtt ctgctaccag gatagagaac ccagtgacta gtttcttcta 16561 gctctctttt tctgactagg tatcttgtca gaaatttctg cttaccagac ttcatggaga 16621 gggaatcaag ctttgaatca gggttgaaaa agtagagctt aatatatata ttacaaaatg 16681 ccactcacgt tcttgaggtt accttgtatc tataccacaa ctagcattct tttagaaagc 16741 accattacc g aagtaatccc tttcctggga attcacccaa aaaggttatt cccacttatc 16801 ccccatctcc aaaataaaaa agaaaaatgt gtgtgcttag agatgttcct ggaagcatga 16861 gctgtaatac tgaaccaata gaagacgaac taacagattg cagggcatcc gtttggcaaa 16921 aaacttatgc agttatctaa atgatagtta tgaagacaat atgtataaca cattatattc 16981 tgagtgaaaa gaacagaagg tgatttcaaa actgcattgg gataata gta atataggaaa 17041 tagtgagatg aacaaagatt tcaaaggaac aaaaataaag aaaaattttg ctttttatat 17101 tggtaggcgt atgggtgaaa ttccaatttt aattttaatt tcatagttat aaaattgttc 17161 ataaaaaaag gtcccccata gacagtt ggg ctttgggaca aactaacaga aacagagtag 17221 gaagaaaatt catcttcctt caatcccctt tctctgctta aaacaaaaca aaaaagagct 17281 ttgtcatgtt caggtgtgca acgaattctt tttccaaatc tggaacttta catctgctat 17341 taaacaggag tcagtttcca tgtaacatgt tgacaatccc ccaagtgtgt tggaataatt 17401 ttttttaatg aggagatttg aaattccatt tcaattgcca acctg cctct ttcaacttct 17461 aaaaacaaag taaaacaaaa caaaaacaca ctgggtccta tcaccccctc ttgctactac 17521 tattttatct ccattgccct gaattctttc caaacttctt tccacccagc tttgatttgt 17581 tttcagtcgg gtttattgag g cataattta cgtacagtaa aattcatcct tcttagattt 17641 agaggtctat gcattttgac taatgcatat tggcttataa tgactaccac aacaaagata 17701 tagaacacac ccatcactcc cgggttctcc ctgtcccttt tttggtccat ctcctctcct 17761 acccccaacc ccttggcaac cactgatctg ttttctgtcc ttatcatttt gctttttcca 17821 ggatgttgta tataaggaat catgcagcat gcagcctctc gagtctgact tcttcca gtt 17881 agcacagtta tttaagatct atccgagtta ttgtgagtag cagcatcttt tttattgctg 17941 actagtattt catcacatgg atgggccaca acttgtttat ctgttcacct gtcaatggat 18001 actaagttgt ttccagtttt tggcaaatat gaataaagta aacatt tgca tacagatttt 18061 tgtgtggaca catgttttca attctcttag gtaaatactg agcaatggga ttgctgggtt 18121 atatgttaag tctatgttca gttttctaag ttctgaaaca attggatatc tatatgcaaa 18181 aatacaaaat taaccttgac tcaaacttgt accatacaca aaaaataacc tgaaagagat 18241 cacaggtgta aatgtaaacc tagaactaaa aacttcaagg agagaaacat agcagaaaat 18 301 atttgtgacc ttgcattagg caaagacttc ttagatttga catttgaaac atgatacata 18361 aaaaatcttg ataaattgga gttcataaaa ataagaacta ctcttcaaaa gacactgata 18421 agagaatgaa aatacaagcc acagacagag aaaatatttg tgaatttctt atctgataaa 18481 gggtttgtat ccagcatgca taaagacttt tcaaaactca ataataaaca atccaataag 18541 aaatgcacaa aagatacaaa cacatcatcg aaaatgacct atgaaaggca aataagccca 18601 caaaaaaatt ctcaacatca ttagacactt gggaaatgca aattaaaaca acactgagat 18661

- 95 045887 aaactacata tctattaaat ggctaccact ttaaaaacct gtcaagtgcc agccagaatg 18721 tggaacaagt aggactctct tacattgcta gtgggaaggt gaatggtaca gccactttgg 18781 aaaacactcc gcagcttctt atagttacac ataggacctg gggg tagagg atggattgac 18841 tgtaaagggg caaaacttcc tggtaggggt ggggaaagtt tttagaaggg tgaaattgtt 18901 ctatatcttg attattgtgg tggttacaca actgtctgca tttgtcaaaa ctcacagaac 18961 tgtacactaa aaaggtatat ttttatg ctc tgctaatttt actttaatct taaaaatagg 19021 aaggaaaaaa taaaatcaat gccactgtgc gactttgggc aagttacttc acttctctgt 19081 gccttggtct tttgaaatct atacattaag gataaaataa taccttcctc atactgttag 19141 aattaaatgt gctaatttat gttttatata tataaagtac ttggccgggt gtggtgactc 19201 acacctgtaa tcccagcact gtgggaggcc gaggtg ggca gatcacttga ggacaggat 19261 tcaagactag cctggtcaac atggtgaaac cctgtctcta ctaaaaatac aaaaattagc 19321 tgggcttggt ggtgcgtgct tgtaatccca gctacttgag tggctgaggt gggaggatca 19381 cttgaactcc agaggtggag gctg cagtgg gctccaccca ctgcctgggt gacagagcta 19441 gactccatct cgaagaaaaa ataagtactt gaaacatagc aaatgtttta taattattgg 19501 cttttttttc ttattgttat tacttgcatt attgctgttt gaagaagttt ggtgataatg 19561 gagagaaaag ggcaattagg ggtctgggat ggtttaagta tgaggagacc gagacacatt 19621 gactcagagt gaagaaatca aagataagag aatgaaagaa agg gagggta attctgaacg 19681 cacagacaaa gttatgttac taacgtggca tcggctgtgt gttgtaataa ataactccct 19741 ttcacttgtc aatagctaat caaatacttt ctggagacca gaagtgactt gctggatcaa 19801 tgacaactcc tccacagatc aaaatgtt ca aatccttttt ctgtgttgta atcctaaatc 19861 taaaagaaca gagagaccaa gcaaatctac ctcccaacat cattaaagtg acaactctca 19921 gtatttattt gaatggtctg ctctcagctt caaccaagga aaagtcaaat tagtgttggt 19981 cagaaaacag aagggtgtta cgagagttct ggctggtcat tacagacttg gggatttttg 20041 attaaaagaa gaagaagaag aagaaacctg ataaagtgta aatatagcaa gcagggat t tttaggaca ggctaaacct 20281 agccacccta tcagagatga tgaagtagcc atctttttaa caggtgggga gatgaatgga 20341 atcagggttt gtttgtttgt ttgtttaata actgctagta aaaaccaagt caatagctga 20401 ctgagtgtaa gggaggctcc agaaggcagg ttattgtagt atagatgtga ctcgacttat 20461 gatgatgtta cttcccgata aacccgtcat aagttgaaat atcgttaaat tgaaaat gct 20521 tttaatacac cgaatctacc gaacatcata gcttagctca gcctacgtta aatgtgctca 20581 ggacgcacat tgcctacagc tgagccaaat cacctggcaa cacaggacac tgtagagtat 20641 cggttgctgg cccttgtgat gctgtgactg actgggagct gcgcttagt g cctctaccca 20701 gcattgagag tttcttatcg cttattacta gcctgggaaa agaccaaaat tcaaaactca 20761 aagtgcggtt tctaccgaat gcttataact ttcagaccat catgatgttg aaaaatcgaa 20821 ccatcgtagg ttgggatcca tcctataaga cgagctacac tgccggaagt gtaagactgc 20881 tatgctgccg gaagatgggg catagtggac aactgcaagt cctgacaaca ggaggtcagc 20941 atctgcgacc t ttaacatcc acattgacac taccacagtc ttccaaacag agctgatgat 21001 atagtttgga tgtcgtccct gcccaaatct catgtcgaat cgtaatcccc agtgttggag 21061 gtggggcctg gtgggaggtg attgggtcat gggggcagag ttcttatgaa tggtttagca 211 21 cggtcccccc ttggtactgt atagtgagtg agttctcatg cgatctggtt gtttaaaagt 21181 gtgtggcacc tcccctctct ctctttctcc tactctggcc atgtgaagtg ttggctcccg 21241 ctttgccttc caccatgatt gttaaattcc cagaggtctc cctagaagct aatgctgcca 21301 cgtacagcct ggagaactgt gagccaatta aacctcatct ctttttaaat tacccagtct 21361 caggccgggc gcggtgactg acacctgtaa tctcagcact ttgggaggct caggcaggaa 21421 gatgatttga ggtcaggagt tcgagaccag cctggccaac atggtgaaac cccatctcta 21481 ctgaaaatat aaaaattagc caggcatggt ggcgggtgcc tgtaatccca gctacttggg 21541 aggctgaggc agg agaatcg cttgaacctg ggagtcagag gttgcagaga gccaaaatgg 21601 agccactgta ctccagcctg ggcaatggag tgagaccctg tctcaaaaaa tatatatata 21661 ttacccagac tcaggtattt ctttacctga gactatgaga gaatggacta atatagctga 21721 agaattttat tttattttta

- 96 045887 aaaaactttt acgtttgggg gtacctgtaa aagtctgtta 21781 cataggtaaa ctcctgtcat gaggatttgt tgtacagatt ctttcctgct cctccccctc 21841 ctcccaccct ccatcctcaa gaagatccca gtgtctgttg tttcct tctt tgtgttcgta 21901 agttctcatc atgtagctcc cacgtataag tgagaacatg cagtatttgg ttttctgtcc 21961 ctgtgttagt ttgctaagga tgatagcctc caactccatc tatcttcctg caaaagacat 22021 gatctcattc atttttattg ctgcatagta ttccatggtg tatatgtacc acattttctt 22081 tatccagtct gtcattgatg ggcatttagg ttgattctgt gtcttcagaa ttgtgaatag 22141 tgctgcaacg aacattcgtg tgcttgtgtc tttatagtag aatgatttct attcttctgg 22201 tagtaatggg attgctgggt caaatggtcg ttctgctttt agctctttgc agaatcacca 22261 tactgctttc cacagtggtt gaactaattt acactcccac taacagtgta taagtgttcc 22321 cttttctctg caaccttgcc agcctctgtt atcttttgac tttttaataa aaaccattct 22381 aattagtgtg atggtatttc attgttgttt tgatttgcat ttctctaatg atcagtgatg 22441 ttgagctttt tttcatgttc gttggctgca ggtacatctt cttttgaaaa gtgtctgctc 22501 atgtcctttg cccacttttt aatggggttg tttttctctt gtaaatttaa gttcctcata 22561 gatgctgggt attagacctt tgtcagatgt atagcttgca aatattttct cccattctgt 22621 aggttgtctg cttactcttt tgattgtttc ttttaccatg cagaagctcc taagtttaat 22681 tagatcccat ttgtcaattt ttgcttttgt tgcaattgct tttggtgtct ttgtcat gaa 22741 atctttgcca ggtcctatgt ccagaatgat attgcctagg ttgtcttcta gggttttttat 22801 agttttgggt tttacattta aatctttaat ccatcttgag ttgatttttg tgttttggtgt 22861 aaggaagggg tccagtttca atattctgca t atggctagc cagttatccc agcattattt 22921 attgagtaag gagtatctcc tccgttgctt gtttttccca ggtttgttga agatcagatg 22981 gttgtaggtg tgtggcctta ttttggggct ctctatcctg ttcatttggt ctatgtgcct 23041 gtttttgtac cagtaccatt ctgttttggt tactgtagcc ctatagcata tttcaaagtt 23101 gggtaacatg atgcctccag ctttattctt tttgcttaga attaccttgg ccattgggc 23 161 tctttttggt accatatgaa gtttaaaata gttttttttc tagttatgtg aagaatgtcg 23221 ttggtaattt gataggaata acatgtaatg atattgattc ttcctatcca tgagcatggg 23281 atgtttttcc atttgtttgt gtcttctctg atttcttcaa g cagtgtttt gtaactcata 23341 ttgtagagat tattcacctc cttgcttagc tgtattccta ggtattgtat tctttctgta 23401 gtaattgtga atgggattgc ttttctgatt tggccctcag cttggtattg ttggtgtata 23461 ggaatgctag tgattttttg tatcctgaga ctttgctgaa gttatttatc agctgaagga 23521 gcttttgggc tgagactagg gggtttttta gatatagaat catgttctct gcaaacagat 23581 ttagtttga c ttcctctctt cctacttgga tgccctttat ttctttctct tgcctgattt 23641 ccctggccag gacttccagt accatgttga ataggcgtgg tgagagaggg cattcttgtc 23701 ttgtgccagt tttcagggag aatgcttcca ccttttgccc attcagtacg atgtt tgtgg 23761 tggtttgtca tatatggcta ttattatttt gaggtgtgtt cctttaatac ctagtttatt 23821 gacagttttt aacatgaagc agtgtttaat tttattaaaa gtcttttctg cctctgttga 23881 gatagtcatg tggcttttgt ctttagttct gtttatgtga tgaatcacat ttgttgattt 23941 ccttatgttg gaccaacctt gcatcccagg gatgaagcct acttgattgt ggtggtttag 24001 ctttttgata tactact gga ttcagtttgc aagtattttg ttgaggattt ttgcattgat 24061 gttcatcacg gatatcggcc tgaagtttct ttttttgttg tgtctctgtc aggttttggt 24121 atcagaatga tgctggcctc ctagaatgag ttggggagga gttcctcctc ctcaatt ttt 24181 ttggaatagg ttctgtagga atggtaccag ctcttcttta tacatctggt agagtttggc 24241 tgtgaagcca tcaggtcctg ggatttttta gttggtaggg tatttattac tgattcccta 24301 aatagaccga taatgatttt agaagtggag tcggtttttt cctggtccag tcttgggaag 24361 gtgtatgtat ccaggaattt atttagctct tctaggtttt ctagtttgtg tgcatatggg 24421 tgttcatagt agtttctgat ggttg ttttt atttccgtgg gatcagtggt aacattctct 24481 tcatcatttc tttttttttt tttttttttt ttttttgaga cggagtctcg ctctgtcgcc 24541 caggctggag tgcagtggcg cgatctcggc tcactgcaag ctccgcctcc cgggttcac g 24601 ccattctcct gcctcagcct cccgagtagc tgggactaca ggcgcccgct accacgtccg 24661 gctaattttt tgtattttta gtagagacgg ggtttcaccg tgttagccag gatggtctcg 24721 atctcctgac ctcgtgatcc gcccgcctcg gcctcccaaa gtgctgggat tacaggcgtg 24781 agccaccgcg cccggcccat ttctaattgt gtttatttga atcctctctc ttctcttctt 24841 tattaggcta gctagtggcc tatctatctt attaatttt t tcaaaaaacc agctcctgga 24901 tttcttgatc ttttgaatgg tttttcatgt atcaatcctt cagttcagct ctgattttgg 24961 ttatttcttg tcttgtgcta gctttggggt tgacttgttc

- 97 045887 ttgcttctct aattctttca 25021 gttctgatgt tagtttgtta gtttgagatc taactttttg atgtggacat ttagtgctat 25081 aaatttaact cttaacactg ccttagctgt gtcccagaga gtctggtatg ttgtatcttt 25141 g ttctcatta gtttgaaaaa acttcttgat ttctgtctta atttaattat ttatccaaag 25201 tcattcagga acatgttgtt taatttccat gtaattgcat ggttttgagc gattttctta 25261 gtcttgactt ctatttttat tgtaccgtgg tctgagggtg tttgatatga ctttggttct 25321 tttgcatttg ctgaggattg ttttatgtcc aattatgtgg ttgattttag agtatgtgcc 25381 atgtggtgat gagaagaatg tatattctgt tggttttggg tacagagttc tgtagaggtc 25441 tattagatcc atttggtcca atgttgagtt cagatcctga atatctttgc taatttcctg 25501 cctccatgat ctaatactgt cagtaaagca ctgaagtctc ctactactat tgtgtgggag 25561 t ctatgtctc tttataggtc tctaagaact tgctttatga atctgggtgc ttctgtgttg 25621 gatgcatata tatttaggat agttagatct tcttgttgaa ttgaaccctt taccattatg 25681 taacgccctt ctttgtcttt tttttttcttt gttggtttga agtct tcttt gtctgaaatt 25741 aggattgcaa cccctgcttt tttctgtttt ctgtttgctt ggtagatttt cctccatccc 25801 tttattttgg acctatgggt gtccttacat attttatctt tatctatcca tccagccatc 25861 cagccatcca ttcatccgta tcatttttaa ccaataagga cttttaaaag cgcaaccaca 25921 acaccattaa cataaccaat aaaatctata acaatgataa aatatcatct aatactcagt 25981 ccatgtccaa ttttccctcg ctatct caaa atcgtcttct tagaaatggt ctgttcaaat 26041 gagatcacat ggacagagga aggcgaacct cacactgtgg ggactgttgt ggggtggggg 26101 gaggggggag ggatagcatt gggagatata cctaatgcta gatgacaagt tagtgggtgc 26161 agcgcaccag catgg cacat gtatatgtat gtaactaacc tgcacaatgt gcacatgtac 26221 cctaaaactt aaagtataat aataaaaaat aaaaataaaa aaataaaaag tgaaaaaaga 26281 aaaaaaaaaa aaaaagaaat ggtctgttca aatcacaaac cagattcaga aacaatagcc 26341 atacattaca ttttattaat atgtctctta aatttctttt aatctattac agtctttgga 26401 atttttatgt cttc gtttat ccttccaatt attaaaaaaa aagtattttt gtattcattg 26461 aatagacaat gcttgcagaa aagtaaaaaa aaaaaaattt agtacaaaaa ggtacatagt 26521 gagctgttcc ttagtctccc ttcccagaag caatgttacc acttttgtac aaatagtctc 26581 tgcctagaca cacatgccag tccctaaggt ggctgtaaca aggtggttaa gagtgagaac 26641 atgaattcaa attcctatta tgccactcac taagtataaa tcttggtcat ggtacatgcc 26701 tctgtgcctc agtttttaat aatggtacct acctcatagg gctgttgaga gaattaaatc 26761 agataagtgc ttaaataact attaatattt attattattc acattccctt ttggcttttt 26821 tcccaaatag cagagtggtg cacatatgtc ttcatt tatt tggcttgttt tttcacctca 26881 catcacattt tgatgaataa ttccatacat gttgttatag atttgcttca ttctttgtaa 26941 tcattgacta atattccatt gtatgaatat gctactgcta aacatgtacg ttatttccaa 27001 cctcttatta tcaagaaatg ctgcaat gaa tatccttgta atactttagt ggattcatgt 27061 gcaaaaatat tcataggata aaatcctgaa agttaaattg ctgagctaaa gggtatgtgc 27121 attttaatgc tttatagatt gcccagctgc ctcaaaggag gttataacaa tttacactcc 27181 caagaaaaat gcacaagggt ccccatttcc ccatacccta gctaacacag gatattgcta 27241 aatgctttca tctttgtaaa catgatgtat tgaaaatggt atctcaa agt tttaatgtgc 27301 atttttctga ttgtgagaag ataaaggaaa tgtagtacaa ctaaacatca gcagtcaaat 27361 gacctggcca tgactcctga gtgaggacac tggtaaacac catcaggatc caaacacctc 27421 tgtatttacg aagaggatgc tccctattgg atagcacta a gcttatttca tgtatgtaca 27481 tatgtagtta gttaattaca tccagcggtg gcaaagggct tgttctgacc caatgaaact 27541 ttctctcctg gcccccttcc agcatgtggt caggagtaga gtgttgtggc catgaggcat 27601 gcatttgtac agatgactac ttactcctcc ttgaaacatt tttttccatt tgcttccctg 27661 ctgtctcact catgggtctg ctcctaattc acaaatcact cttttcccag tct tcttggt 27721 tgggttttct cctcttctgt gcttgtagac atgggggagc cccagggctt ctctcttgaa 27781 ctacagcttc tccctgggtt catctccttg ggatgtctgt tccaatgggt ttaaatacta 27841 gggctaggac tagggagagg tcattgaggc acttagcaca ta aagtttaa ggaaacattc 27901 tttatcaggc ccatgcaagt gcaggactgg ccctggaggg tgactaccac cttacctttt 27961 ccaccctagg caccttgttt gccttaccct agccccagtc ctctttaaca ccccagtctt 28021 ctccctggac ctccagaaac ataaatccta tttgacattt ctacttggag gttttaaggt 28081 aactcaaacg taaaatatct aagacagaac tcttgcatca cttcccatcc tggggcccaa 2 8141 gcctgtctct tctactagtc tatctcagtt aacagcatca

- 98 045887 ccatttattc agttgctcag 28201 gacaaaaaat ttgaagtaat ccttgactct tctttttttt tttttgagac ggattctcac 28261 tctgttgccc aggctggagt gcagtggtgg gaccttggct cactgcaacc tctgcctcct 2832 1 gggttcaagc aattctcctg cctcagtctt ctgacctcgt gatccactcg cctcggcctc 28381 ccaaagtgct gggattacag gcgtgagcca ccgcacccgg cctggattct tttttttttt 28441 tttaaacaag tcctatcttc catctccaaa atgtatccca aatctgaca a cctctcccac 28501 cgtaggccag cccccatctc tcccctctga aaatagcctc ccttagatct ctggacattt 28561 gttcttcccc acccccttgt gatcactatt cagcattcag aatgatcttt taatattatg 28621 aaggagactg tgttcctctc ctacttaaaa ttctctagtg gcttcctaat aaatttagaa 28681 taaaaagcca actcctcgcc atggtcacca ggccaggatc cagtgggtac aacaatctgt 28741 tcccag caca ataatcccac ttctgcctcc ccaccattca ccaggctcca ctgcactggc 28801 tcattcctgc ctcagttgtg cttcttttcc ctggaaagtt ctttctgtag atctttaaag 28861 ggtgatttcc ttctcaacat tcaggtgtca gctcgtttca ctttcctgac catgcccatc 28921 cactcagaga tcactcaaaa tcccattacc ctattttatt tctccatcat atgtatcact 28981 atctgaaact atcttgttgt tgatgcaggc tattttcttg accccttcat gggactccca 29041 acaggggtac cccatttact cagcctgccc tgctcaacct cttgcaggag ggagcacacg 29101 agtgaacgag tgcaggaacc agctggctgc tttagtgctg tgaggagtaa actccatgca 29161 ggccctgcag cagcaaccag gtaggggtgc ctgcaacccc agggccccag agggtgtgtt 29221 acaatgctct cgtagctctg ccatctgtgg acagcagtgt gttgtcagct cagtgggccc 29281 tttgcttcat catgtagggt ggctgccctc tgcctgtgag ggcaaagggc cagggtgaca 2934 1 gtctttttgg gtacccacaa tttgtgcatc ctgaattctt gtttggtgcc caagaagaat 29401 ggggtcacac agatgaactg aaggatggtg aatgcagaga attagcaatg aaagtggctc 29461 tcagcagaga gagaagctga aaagggaatg ggaagggcag gtcactctcc cctgaagtca 29521 agtcacatct ctccaatgtc cagccaccat ctctgaagtc aagtttcctc tctctgatgt 29581 ccagccactt ctcctctcta ctggctga gt ctggggtatt tataggcaga ggataggtgg 29641 tggggcaggc catacataat tttggaaaag gcaacattct attggtaaaa agacattatt 29701 cataaagaac caattgggaa agagcgggca cacagggatg gaagttctca ctttgggctg 29761 caggtttcag gcttttcagc tcaaaagtga ggtttttcca gggacctgcc ccgtctgcct 29821 aaaatttcta cacttctgtc attgataccg ctggataaca gctctcctat aaagttcagg 29881 ggcttaaaac aaaaatttac taattcaccc ggacagttct tgatagggtc tctcctaact 29941 gttgcagtta catagcaact gggttggagt catcttttct gggcttgaca tccaggacag 30001 cttcttccct tgtgtgtctg gtgcctcagt g ctcctccag gcagcctttc tctccagaag 30061 agtagcctgg acttcttggc aactcaagct tccaaaagaa aaaaaagcag agactgctgg 30121 ttctcttatc aaacaggcct ggaactggca caatgtactt ctgctgccat attcaggagg 30181 tcaaagcaat cgaaggccaa tcca agttca aaggcattgg agaaaaatga gaagtgtcac 30241 ttaaatgaga agtgacacat gcgtaaaagg gggaaaagca ttgattgtgg ccatttttgg 30301 agataagcta tcacgtttat ttgtttgttt gctttctaat ggtctgtctt ctcccattag 30361 gttataagct ctgtgagaca acaggaatct tgtccatctt gttttatggc tctacttcca 30421 acacctagaa taatgcctgg cacatagtag gtgctcagtg aataacttaa gcacttgata 30481 catgtttggg gaactaaaat gaacagaatt aaacttcccc agattggtcc tgccagattt 30541 gctgatgcca agcatgctga tgcctcacca gatgaaagaa gccctaaaat gtagggtttc 30601 gctttctctg caaacaagaa aaacttgccc t gaacacaaa atctagaaat agatttggcg 30661 tgttttctac attgaaatat ttcccgtagt accagaaatt attttcccac agctttgtgc 30721 tacattaaaa tattgaagtt gactgaaaat atctccattc tttaatcttg gtgtagacta 30781 gaaacaattt ttttgtaaca aagtaaatat gaaaacttcc taatatttga actccccaga 30841 tatccccaga tatctccaaa cttaaaatat cattgcaagt taagataaat ttttttaa at 30901 gactaccgag aaaggtcatt aaaggcttgg ttattaaaat gtacagattt gggttataaa 30961 gccagaactt atttgtttaa atcattacat atgaccaagc acagaaaata aattacctca 31021 aatctcctct ttgctaattt ttactggtaa actctataaa atgatcctat ctttaa acct 31081 ttttgtaaac cccttataag ttagtaagtg agaatgtatt catcagaagg attttagtga 31141 tgtttgaaat taaaaaagag agatttgatt tttaaaatta tacttgcaga ctactgctaa 31201 tgaaacttct tctaacccta gttttgtctt atcttcagtt tttccagatt tgctcaaagc 31261 aatcccagtg agcatccacg

- 99 045887 tcaatgtcat tctcttctct gccatcctta ttgtgttaac 31321 catggtgggg acagccttct tcatgtacaa tgcttttgga aaaccttttg aaactctgca 31381 tggtccccta gggctgtacc ttttgagctt catttcaggt aagtacaaaa ttct acctct 31441 gaagacaaat gtgcttttca atatgtcaaa aagaccgtct acctaaatat aaagttataa 31501 tcttaacata tatacatgga tgcacactgt agtattatac ataataacaa aaagtgtgga 31561 aataccacac ttgctcaaca gtagggaatt caataaatac tttatgg aca tctatatgaa 31621 taactgtgat gctgacatta aattatattt ttgaagatgt aatcaagagg ataaacgctt 31681 gtctcaaaaa gttacatggg aaaagcagta tgtaaactta tataaacatt gtgaacctaa 31741 tttgattata tatataaaat atagggaata tacatataaa atacatatat gtatatatgg 31801 gggctatata tatatatata tgaaagagat agatagatag atagatagat agatagatag 31861 acagacaga c agacaataca gactccaatc tgttggtcgt ggttgtctct gacccatgac 31921 actatggggg acttttattt ttgctcatac ttttcaatat ttcttagtgt tcaataatgt 31981 gctattattt atacataata ataaaaataa ataaatggca tcaaaaaaga gtaaagggcc 32041 ag tgttccgc ccacatatga gcagccatat tcaagcctgt agacactttg tgtagcctaa 32101 tgctaggtgt atctgggcaa ggataaactc taaagccaga aattagttca tcaataaaca 32161 tgtgctactc aatagctagg gctgatggaa aagaatataa aacccagtct gtgccaaatg 32221 gtgcttacta tctgcaagtg ggagaaggag aaagacgaga aaatgaaaaa tgtgtgtata 3 2281 atttatatgt agctgttctg taggagatct ctgacttcac cccattctaa ctttgcaaaa 32341 agatccaaca ctttgtcaga ttcctgggag gcaagtaatt ttattgatgg tttcatggag 32401 ggatacagaa cgataacaac tcacacaaag caaacaatgt aatgaa aatc tctattcgac 32461 tgtttctttt tctcctgaag ttgccctttg gctgccagct accaggcacc aggctcaagg 32521 tactttcttg ctcttgacac tactcccttc tctcatacaa ttcaacccca accacaaacg 32581 tgtatagatc tctctctcta taaaacaaag gcctgtagtt aacaggaggt cacttgcagt 32641 gtagcctctg ttcattgtta cttgtgcaca ctgcttaggg tctcacccca tccacattct 32701 gctaatcaca ttattcaccc atccaatgta gatctctcca gtggagattc tgctaatatt 32761 ttctttagat ttgtcacaag tatataatac agttttaaat tgtacagatg attatcctat 32821 aacagaagag tctaagcctt ttacatcttt gtatctctaa cgaaagcatt cagcatgaag 32881 ctctg tacac agcagacaat tcaatatgaa tttgctgact tgaaacagca agcctagaaa 32941 ggagatgtta acttggtcac ttagacagaa caggtttcag caatcagaat tcagatgaca 33001 tggaactggt agaacaggcg ctttgaagca ataggacatg agccagtgag gagagggatg 33061 gaatatcata aacaaaggcc aagggctttg caatcagagc tgaagagcca agagcacagg 33121 ctcagggtgt gggcagact g aatgagaaag tgattcaatc acatgtgaaa gtccagatga 33181 gaagagagag ttgggattac ttctgctcac caaacatcca aaaccaaaca ggtggatccg 33241 ggtggtgtgc tgttttactg atgaccatta cacagaattt taacagaagg aatgtaaagc 33301 agt ggttctc aaactggagt tccgatga gcagcgtctg catcatctgg aaacctgata 33361 aagcagcaaa ttctcaggcc ctaccccaga cccactgaat cagaaacttg ggggtctggg 33421 ggaagatggc catctgtatt ttaacaatct cccttcagga gattctgagg ctggctcaag 33481 tttgaactac aggtagttgg ttcaacaggt gttggtggac tgacaaacaa aaagagactc 33541 cgaggtaact ccaagatggt aatgtcagaa a gcagctacc acccctaggg cttgggggaa 33601 ccaacaaaag agtttggcat tgccagaacc tagaatcttg aggagaggcc ccagagcatt 33661 gtgtctcaga ccttgaggac ttggcactgg gacaccatga ggggtttctg ggtgtgggaa 33721 agggctggaa actccccagt tg ctgccacc agggagaact acaagtgaag tggaaggtgt 33781 gggcctttct cccttttctt ttctcgtctt ctctctcccc ctggtgctca tgtttgacag 33841 aaaacagctg aaaaggcaga actagtttgg ggagtcttga cctggcatca taaagcagag 33901 aaaagcaaag ctggagtgaa ggtgagacac aacagctcat tagcagcaac agccgtctag 33961 cgctccagct tctgaatgaa attctgaaga acagcg cact tggaagacaa attatttgac 34021 agttctgaca gacgaccaaa ctaacagcat ttgaaaagca agatgactca gagaatacag 34081 aatttaatcc aaatcccaga tcctatctct gcctttggcc aggcctaatg caaggagaac 34141 ctgagcacac aaatatatgc aggaatgatc a ggacctgtg cctgcattct attctgtctc 34201 acccaccttc aaatttgttg taaaaacatg ggctcaataa aggtttgtga atcagggaag 34261 gaagagaagg ggagaaagga agggaaggag ccagctccag atctgtgtct tgcagaggat 34321 aaaggccagt gtttttagat cacccagtgt ttttctaagc

- 100 045887 ccccaatact tattttgaaa 34381 tatcaaaatg ttcaataact aaaaaaaaaa ccgttacaac aataaaacat gtttgaggt 34441 cagatggact ggcagtttgt gacctctggg gataaacagg tcactttgga atcacagact 34501 t cctcattcc ccttaaatct catatggtac ccagaagccc ttggaacttt ggaaggtgtt 34561 tattcacagt tgtaatgtcc atgcagaccc tggctctaag acccaattgt gtaagggtag 34621 gtttgtagcc cttatcccaa acattctaag tgtgagccaa tgcgtcacac actcagaggc 3 4681 cagagactgt attggggtcc tttatttcac gtacgagtca cattccatta agagacccca 34741 gaagtcagct ctcttccact gactggttct cttcccttgt ttctcttgcc aatgtgtgct 34801 gcccaggtgg cagtgctcac tgtcagcaga gaagaaaaat gctttcctcc ttggacctct 34861 tttctctttt tctcctccct actcacattc aggttcccta agcttccccg ctccttgtgc 34921 tgaagtcatt ctatggtcat ttcttcaact gtctacttcc ctgctggatg ggcacccaag 34981 acttggcatc ctggggcatg tagaaagggg aaagggaagg gaagggaaaa gaagtcctcc 35041 caattgtcta tctggacctt tccacactgc cccagtact gctatgggca tct ccttatg 35101 tctcccgatg tggtgcatgc cagaccctgc aggtagaaaa ggaaagaaag caacccattg 35161 gaccaggcca gcaaaggctt cagtcacaca gctggctcat acttatggct tcatattctg 35221 ttgcctcttg aaccagacat ttcttccact ctcataacct ccagtttagc tcgtattcct 35281 cagcattctc catgtaatat tgttgcatga aacccatgca agtcagccaa tttgctcttt 35341 ctcatcttgt catttataaa tt gatgctga gaagtctttt tcccaaggtt tttagtaata 35401 ccttcatcat cccccatagt tcattttggg cagtgattcg cttctttgac tgtacattag 35461 aatcatctga agaactttct aaaactactg atctcaggtc tcacacaaca ctaattaaat 35521 tatagtctct ggtgg ggtag ggcttgggca ctgctatttt accttaagct ctctggagtc 35581 attctaattt gtagccagtg ctaagggttg caatataagt gaatatattt cacgtatttg 35641 tcaaacattg actgagtgcc cattatgtgc cagccattat aataggcact ggtgatccca 35701 cagtgaatca ggcacacaat gctgtcttca cggagcttgt tgtctagtgg gagagtcaaa 35761 caaaagtgta tatcaataat taagtga tta cagattgcaa taattacaat aagggtgata 35821 aacaggttgc tataatatac aatagtattg cctttcacca gacatttctt aaagaggtaa 35881 atcatctatc agacaccttt taaaaatctc atctaatttc aaaagtgtac ataaataatt 35941 aagtgattac agttt gcaat aattacaatg agggtgataa acaagttgct atgaaagaga 36001 aagatagcag agatctggct ttgagatggt ggtcagggaa gactgctcca atagctgagt 36061 tctaaagcta agaaggaact gagaaccttc acagaacgtc ccaagtagaa gagaaagcac 36121 actgaagact ctagggaaag aggtctgctt gttgtaggaa ccgaaagaag gccaatgtgg 36181 ctaggtgctg ggtagtgagg ggaaatggca caaggaaaaa atga ggttag agagatcagt 36241 tgataccagt taatgttgga ccctaaacat taaccatggt aagtctttta gaattgattc 36301 taattgcaat gaaaaccttt tgaaagattt taaaaagata tctgatagct gatttacctc 36361 tctaagaaat gtctggtgaa agacaatacc atca cattgg agatggaaaa agatgaatgg 36421 attctaaaaa cattctgaaa gtacattcaa aatgtttttc aggtagctta tgcaactaat a catgaatct 36661 ggagttcagt gaagaggtct agaagaaaga tgtatatttg ggcattattc ggatatagat 36721 attatgtaaa gcaataaaat tggatgagat cacctaggga gagaatgcac atagataaaa 36781 actgacctag gaccacttca tgtctaaaac accaaaagca atgtcaacaa aagccaaaat 36841 tgacaaatgg gatctaatta aactaaagag cttctgcaca gcaaaagaat cagagtgaac 36901 aggcaaccca caaaatggaa gaaaattttc acaacctact catctgacaa agggctaata 36961 tccagaatct acagtgaact caaacaaatt tacaagaaaa aaacaaacaa ccccatcaaa 37021 aagtgggtga aggacatgaa cagacacttc tcaaaagaag acatttatgc agccaaaaaa 37081 cacatgaaaa aatgctcacc atcactggcc atcagagaaa tgcaaatcaa aaccacaatg 37141 agataccatc tcacaccagt tcaaatggca atcattaaaa agtcaggaaa caacaggtgc 37201 tggagaggat ctggagaaat aggaacactt ttacactgtt ggtgggacta taaactagtt 37261 caaccattgg ggaagtcatt gtggcgattc ctcagggatc tagaactaga aataccattt 37321 gacccagcca tcccattact gggtatatac ccaaaggact ataaatcatg ctgctataaa 37381 gacacatgca catgtatgtt tattgcggca ctattcacaa tagcaaagac ttggaaccaa 37441 cctaaatgtc

- 101 045887 caacaatgat agactggatt aagaaaatgt ggcacatata caccatggaa 37501 tactatgcag ccataaaaaa tgatgagttc atgtcctttg tagggacatg gatgaagctg 37561 gaaaccatca tcctcagcaa actatcgcaa ggacaaaaaa ccaa acaccg catgttctca 37621 cccataggtg ggaattgaac gatgagaaca catggacacg ggaaggggaa catcacacac 37681 tggggactgt tgtggggtgg gaagaggggg gagggatagc attaggagat atacctaatg 37741 ctaaatgacg agttattggg tgcagcacac cagcatggca catgtata ca tatgtaccta 37801 acctgcacat tgagcacacg taccctaaaa cttaaagtat aataataata aaataaaata 37861 aaataaaaaa acaaaaattg atgtaggacc aattcctgaa gaacactgac agttaatttt 37921 ttggtttagg aggaggagaa gccagcaaac gacactgagt agcaatatcc aaagaaaaag 37981 aggaaaaagg aaaactggga gattatgagt gtcccagagg gaat gtttca agattaccat 38041 cagcagtgag ctttgtgtaa aggtggcctc ctgtaataga ggtgcgggca ggagaaggca 38101 gaatagggaa aagggggtga aaaagcttcc ctcaagattt ataatacagt ggaagagaga 38161 gacagagaga gagaaagaga aagagaga gagaact taa ggaggtagag gaagagagag 38221 aaccaaaaaa gagggagctg agtatagaag caattagatt catagttttt agttgcggca 38281 gtgatatttg agtggggggcc ttttatatatat tccattctag gtgtttccca gttgatggga 38341 gagggtctta cctagatctg catgtaaaag ggagtaggcc agctggcaga cttgacatgg 38401 atcagtggta gaacatccta gcagttctgt gaatactctc tgagaatgac atgaa aggta 38461 ttggttcagg ccttttggag gtgataaaaa ccaccaaaat gtggacttat tgcaaattgt 38521 atttgttacc atttgcaatg attataatta ttctcttata tataggcttt cttacatata 38581 gcttctctta cacatagcgt catgagttat gccttctctt acata tagtg tctgctatga 38641 gttatgccaa gcagggcaaa caaaattgct gcctttcttt aaaaagagga cgctcctagt 38701 atgggcctaa ttaattatga taattacagc tatggcatgg aacataagca cattcatata 38761 cacaaagaca ataaaataaa gaacagttca aaaacagaac agttacatta tatatcagtt 38821 tcagtatgaa taataccctg gactctgaaa tatgtctggg gcacattatt ctgtaattgg 38881 tggtgaaa aa aaatctgcat cttatctcta cgccaatcct tatgaaggag ctgtttttca 38941 ggagttcgag aaagagacac agggatgtcc agtcatcaaa gccgcagagc ctgaggaaga 39001 ataaaggatt tgtggcagga aaacccagta atgaatgtat tctgctagtt tctcag cata 39061 gaacttagaa aagaggccac agaaggaaaa gagaagtaat gttagacagc tgatgttggc 39121 aatgggcaaa gaatttcatt ctcatatgca gggcagtggc taaaggggca gtgttgtgag 39181 gaatcacatt ccaggtcatt catgtccagg gtgtggtagg aggactgtgt ttcatttatt 39241 ttgtacatgg cccagctatg accttgtgca aggaaatgct taatcatttt ctatcacagt 3930 1 tgcaaagaga ttcttatcct actcagaatg tacgtcttct cttctgtttc atttacagtc 39361 acaacccaag tccttgcttt gacctccaaa gcaccacttg atgtatccac ttcagaaaca 39421 cacacagaca gctcacctct ttctatccct taccttcctc ccctcttcac tca aaccacc 39481 tacttccttt gcattcactc ttccttcagc ctgaaataat cttcctccaa atatctacct 39541 tctcactccc tcacttctct caagatacac ttaaatgtta tattccctat gaggcctccc 39601 ctggccatcc ctccccagcc ttcctatccc ccctctctgc tttattttat tctccttaat 39661 atatatcaca ctctgataaa ccattgaatg tacttatcaa gttattgcct ctctctccct 39721 ttccattgtc tccatc actg agagctctgt gaagaaaagg atttgtacct gtttcattta 39781 gtgctgtacc cccagttccc acaacagcgc aacaggcact caataaatag ttgttgaata 39841 agtgaataaa acagaagtag ctgcatattt tctggtaaca aatgatattc ttctgaaaat 39901 gt catatttt cagacatatt tccgaaaata aattcaaatt agataaacat tgtattttta 39961 gaccatttct tctttgcatt aatcatcctt ctcaataata taacatttgt aaaacttagg 40021 ttagatatgg gctcttcaac tttccattac agaagataaa gtgaaaaggc tagacccaat 40081 ggtgttattc cttcatctac atctatcctt tggaaacaca tgaccaaatt gcttgccatc 40141 acaatctcaa aatctaccct ttggtattaa ctcacttcac ttgtccctct gtcccttttt 40201 agatggtagc catcggtctc tggagcagtg tagagtcaga acaacttcta tttggggaag 40261 aaatcattgc tggtgacctt actttcaatt actaactttc tagtgacatt tacataattt 40321 tagagaaaat taacacctac acttg taaag ttgtggcttt cccacaccta tttatcatct 40381 ctcaatattc cttgaaaagg aaattatcaa tttatcattc tatattggca atgaaatgcc 40441 cctaatatct gtcacctata agacaattga agatgatgtg ttgaaagctt tctgaaaatg 40501 ctgatcatta ctttaaatgg aattgaaatt ccagtttatt atttccaaaa atatgatctt 40561 actgatcata ggataacatt

- 102 045887 tcataacatt tcagagattt cttccccttc gaggagccaa 40621 acccatagga cctctggact cccacagatc ctggcaggga gttcccactc ataaaagcac 40681 aggtgccctc agagtcattc agggatgaag aagcaaccct cattggccat gtcctacgtt 4 0741 ccccatatag taaggactgg aggagaccag tgctcaattc tgcagtctca gacagctgtc 40801 agaggagagt catgaatgtg cagtgtctag cacattacaa acgtttgtta attgactgat 40861 cattcatggt gtgacagccc tataactcag ctatcctatt cagtcagaaa ttaactcag t 40921 aatcaaagtc attaaaagga agaaaaaaaa aacctacagt acgacaga tggtggggaa 40981 atcagacaga tgaaaggaaa aatggctgta ggtcattgag taagacactg ggcagcaaaa 41041 cctgggcctt gtgcctggtt atactccaca ttatagctcc agcaaggttt ggcaggattt 41101 ccacagtcct ggcttattct aacctttctt gggagcagga gcagtgttgg t cagatagac 41161 agacacataa ggaatctgtc caactggcac cgtgtgaatt tgggctcttg gtgtacatgg 41221 ataactggga aaaagaggag agagacatgt aggactgatc ctaccgtttg tgaagtcttg 41281 ggcaagagta tgaatgaaaa cccacttctc ttcccctgcc t ggctccact gcacacagta 41341 aagagcctca agcataggtg tgtggacatt gcaccatgta tccaagctct gaccatgcct 41401 cttgaaacag ctattcctca gccaccctct gaccatggga ggaatgaccc aggagaaatg 41461 accacatagg tcttgaaaat gggctcaggg ctatttacga agtcaattcc ggggtcccag 41521 gagtatggac taaaatgtga gtcaggcatg ccagatgggt atgttctatt gacttcaagg 41581 att cctcatg ctgtgggaag gaacctctcc agaagagaga cagagcagaa ccctctaaat 41641 gtggggcaca aagcaggagc ccctcttgct ggattcaaag ggtcatactg gaagagtgta 41701 ggttgagtct tattctcaca tcactcatat cacttacaca cttcttttat agccttagca 41 761 gccatgccac aaagagaaac tcttcatgca tatcttttgg tccataagtc ataaatagtt 41821 atccttgatc ccatgtcttt tttagagcca tggacagaga gaagcaaaaa tataccaagt 41881 tcacactgag ttgtctccct tcatatctct tagcagtcac tgaaaggtta tgagactcag 41941 gctgggtttc tatcctctgt ccctgaaacg acaacgttga cctcgtgatc aaccctagaa 42001 tccagag caa gatctcagac tgtcctctct actaccagac agcacacttt gttttggggg 42061 ctgtgtgctt gaaatattag ctatggcaaa aggctttgag tcttatgaca ccccaagtaa 42121 cttttacttt aggaatttga aatacagcct tgctgtaatg ctgtctcctt aaca aagcag 42181 tacctttgaa atatttaaca acttgaaaag gaaaccgagc ttgaattttc ctttcaggtg 42241 ctcaggaaat aatgtttcac ttctgtctga aattcaccat ctcctcagac aaagaaggct 42301 cttatggtaa aaggaatggc attttctcca caattttcga ataaaagata aagagaaaac 42361 agcactgcag cctttttgtt aggatctaac aataaagaaa taatacggtt ttgccagggg 42421 agagctctgg tttta agctc agaatacaaa aataggctga caaaatttta caaaggaata 42481 ttctcagcta ccactctgag gatggtagaa agtgaaattt caagaaaatt atattatttg 42541 attatttgat gatgattaag ctgattggcc agtcctatgt gaaattctaa agtagaagaa 42601 atgtgatgt t gtcttttctg ctcacctctc ccctcattcc tacccccaaa tctctgcctc 42661 taccccaaac ccagcctgac ctttgggaaa ggaatggggg ctgtcacttg caccgtagct 42721 cctcctgcct gcagtactct ccccccacag tccagcctcc ctctgctcag ctaacttttc 42781 ctatagctcc ttctggctac ttctaaggaa ccttccataa tgctgcccac cctctcagta 42841 acagcccctc tactatccct tgattacatg cactgtaatt ggttagtaat tgattttatg 42901 tcctctgcca aattatactc catgagagca aaaatcatga gtattatctt taatgtttaa 42961 atctccacaa ctatccccca tataagtcta gagaataaat gaatgagtga attaatgaat 43021 agaaactcaa gccattatgt tgccactcct a ggatatttg gattaacttt aactgaagag 43081 taaaaagcat ttacctgtcc taaaggagac ataaaattag tgggagagta tttggagaaa 43141 aaaaagacac tgtaatacat tcttttgtgt tgcctaccct gatgtagtca ggtgtccctg 43201 atatggggtg ggctgaggat ttgaaataaa atacctaatt tgacattgta agtggaggaa 43261 tcaggatttg aaaccaaatt ggtttgacct aa atcaagct attatgataa ggacttgcaa 43321 gaaaaaagga atccataaaa accatatgaa tagctaccaa ttagtaagca tttatatgtg 43381 tcaattacaa agccaaatgc aaatcatgct ttatttatat tagccacctt ttatagatga 43441 agaaattgag acctgaatat taaaattg cc tacttttaca tagtaagtaa aggaatcagg 43501 gtttgaaccc aaattggttt cacctaaggt agaaaaccat cccagcaagt ctcctattaa 43561 ctggaaccct attgtggtgg cctgagatat aacagtagct gtggaagcgc tgtagagtcc 43621 tggccatcct atgtgctcct gatctggtcc ctcctgccac ctgcttctgc tccctgtgcc 43681

- 103 045887 atccacccat ctggaagtct cccagtgtcc atcttcgggg gagacactca ccagagtttc 43741 cagcttccag ccagtatgga gtgcccctgt cccacagcaa tctcaccgaa atcacagcta 43801 catctgttaa aattaggcta ccaatgagtg atagatgagg gggaaaaata ataatagtgt 43861 actaaacaaa acaaatgttt atttttctca cacataaaaa tctagaggtt gaagtccagg 43921 gctggtccag aggctccaag gatctgggat ttagactccc tctttcttgt ttttccacag 43981 catatggctt ccatttctgg ggccacat tg gtccaaaatg tatgctgggg ctccagccat 44041 tgcatccata tttcagccac aggaaggagg aagtggggaa gaaaggacag gcccctaata 44101 cctgtatagt tcaagaagac tatcccgccc atacttccca accaccctta gttgaacaat 44161 gctgtcttaa ttcaagacac tcacatgtct agccaaaaat ctgaattctg ttacaaacaa 44221 ggagaataga gatgtgcgcc acctcaatac ctcatccata gctacc tttt cctttgtgca 44281 gctgtggcca agtgaaagct gaaggagctg tggtaaccct tctgaaggga ggctggggcc 44341 tttcacaaga ggctgcatga ttgacattta tcctgcatgg cctgtgaagt acagagaaat 44401 attttctctt gaagccacat catagcagtg gctgct ttgt agcctgattc caccattatg 44461 cctttaaagt gcctagcaat tcagccttca catcatgcaa agaggaatat ctcccagtct 44521 ttgtaagatc agcttaattc taaccacctc cttacctccc actgcactcc tacacgcaca 44581 cacaaatctt cttcactcag agcagaacca taacccaagc cctaccacct agagactgaa 44641 gaatcaggct catgattaca aatatgcaat aattttttgt gtggataatg tca atgggga 44701 tgatggtaag agaattcctt ggtttacaca ttgaccctct tccctgtccc ttacaatcag 44761 gaaatatttg tcccaacacc ttgtttcttc tgttgcaggc tcctgtggct gtcttgtcat 44821 gatattgttt gcctctgaag tgaaaatcca tcacc tctca gaaaaaattg caaattataa 44881 agaagggact tatgtctaca aaacgcaaag tgaaaaatat accacctcat tctgggtcat 44941 tttcttttgc ttttttgttc attttctgaa tgggctccta atacgacttg ctggatttca 45001 gttccctttt gcaaaatcta aagacgcaga aacaactaat gtagctgcag atctaatgta 45061 ctgaaaggca aacctttcta taattttaca agggagtaga ctt gctttgg tcacttttag 45121 atgtggttaa ttttgcatat ccttttagtc tgcatatatt aaagcatcag gacccttcgt 45181 gacaatgttt acaaattacg tactaaggat acaggctgga aagtaaggga agcagaagga 45241 aggctttgaa aagttgtttt atctgg tggg aaattgcttg acccaggtag tcaaaggcag 45301 ttgactagaa tcgacaaatt gttactccat atatatatat gtgtgtgtgt gtgtgtgtgt 45361 gtgtgtgtaa gatgtcttcc tatcaaaaag atatcaaagg cacatggaat atattttaat 45421 aaaaacaaat aatatctcta atatatccac acatttgttg ccagatttca gaaaactgag 45481 ctgcaatcgc tttcctaaaa cagtagtgta ttaaatgaac atctataaaa tgtatcaaca 4 5541 cacattttaa aaaatttgtt taaagtatac tcttaggcca ggcgtggtga ctcacacctg 45601 taattccagc acttcaggag gccaaggtgg gaagatcatt tgagttcagg agttcgagtt 45661 acagcctggg caataaagtg agaccctgtc actaacaaaa ttaa aaaata aaataaatat 45721 aaaatatagg ctttaaaaaa gcatagtctt attaaccatg tctgttggtc aaaatctgca 45781 aactctaaaa gaagaaaaga agaaaaaacc aagcttaggg tatttttcct cccgtgcctg 45841 agtcccaatt acattcacga cagtactttc aatgaacata attgttagga ccactgagga 45901 atcatgaaaa atgatctctg cttagtacat ttgatgcaaa atgacttatt aggggctgtt 45961 tttctagcta tagtgtctcg agtactaata tgcaattatg aaaattatat taaatctggg 46021 attatgacgg tatcactgta tcatcttggt cttgttctgg ctgtcaccaa gcatgaccca 46081 ggtcaacttt ttttttcccc tgaattaccc atcaaattga tctgcagctg actaaaggcc 4614 1 acagctgagc ctggaactga cccttccttc atcctcaacc tgctgtcctc cagaaagcac 46201 caaggaaaaa gcagagaatg acagcaaaca gatcactagg cctctgacca caggtgctga 46261 gtactcagca gccctcatat aataggtttg aaagtactcc ttaaaataaa acactgtttc 46321 cctttggaac tatttacaag gatgaaacaa ccgtatacct gagaaataac ttgctctggt 46381 gtcaattcgc tattcgccag cagacatcag aacacaccga gtttccagat gctggttttt 46441 ccccttaaat caggaaatac acctggacaa tttctagaag actacaattc agtctagcca 46501 caaaggggat tttttttttt tggtaacagg ctagagcccg gttctgtaag tctttagctg 46561 aaatggt cca gtacaaaagc actggaaatg agtgggctag gaggacaagg accgtctcct 46621 gcgtgaggag ttggttggag gtccccaagg ccaggtaccc cctgcactct tattggattc 46681 ctctctgtct tcttggagtt ttgaaaaact ccttcgaaca ccaggctttt ttcttttagaa 46741 aacaagtctc caatcgttct ctgttccgta gaaagagaaa gaaaacctgg agcagctgct 46801 gaaaaatcta atga ggaact aagaggcaaa cccacca

SEQ ID NO: 10 - Mouse CLRN1 Protein Isoform 1:

MPSQQKKIIFCMAGVLSFLCALGVVTAVGTPLWVKATILCKTGALLVNASGKEL DKFMGEMQYGLFHGEGVRQCGLGARPFRFSSRSMKERYSLYEDKGETAVFPDLVQAIP VSIHINIILFSMILVVLTMVGTAFFMYNAFGKPFETLHGPLGLYLVSFISGSCGCLVMILFA SEVKVHRLSEKIANFKEGTYAYRT QNENYTTSFWVVFICFFVHF LNGLLIRLAGFQFPFTKSKETETTNVASDLMY

SEQ ID NO: 11 - Canine CLRN1 Protein:

MPNQQKKVVFCTAGVLSFVCALGVVTALGTPLWIKATFLCKTGALLVNASGQE LDKFMGEMQYGLFHGEGIRQCGLGARPFRFSLFPDLLKVIPVSIHVNVILFSTILVVLTMV GTAFFMYNAFGKPFETLHGPLGLYLLSFISGCGCLVMILFASEVKIHHLSEKIANYKEGT YAYKTQSEKYTTSFWVV FICFLVHLLNGLLIRLAGFQFPFAKS KDTETTNVAADLMY

- 104 045887

SEQ ID NO: 12 - 5'-UTR:

AGGAGATACTTGAAGGCAGTTTGAAAGACTTGTTTTACAGATTCTTAGTCCA AAGATTTCCAATTAGGGAGAAGAAGCAGCAGAAAAGGAGAAAAGCCAAGTATGAG TGATGATGAGGCCTTCATCTACTGACATTTAACCTGGCGAGAACCGTCGATGGTGAA GTTGCCTTTTCAGCTGGGAGCTGTCCGTTCAGCTTCCGTAATAAATGCAGTCAAAGA GGCAGTCCCTTCCCATTGCTCACAAAGG TCTTGTTTTTGAACCTCGCCCTCACAGAA GCCGTTTCTCATC

SEQ ID NO: 13 - 5'-ITR:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCT

SEQ ID NO: 14 - 3'-ITR:

AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTC ACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTC AGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

SEQ ID NO: 15 - 3'-UTR:

AAGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTT TAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCC TTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAA GCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGT AGTCAAAGGCAGTTGACTAG AATCGACAAATTGTTACTCCATATATATATATGTGTG TGTGTGTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATATCAAAGGCA CATGGAATATATTTTTAATAAAAACAAAATAATATCTCTAATATATCCACACATTTGTT GCCAGATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATTAAAT GAACATCTATAAAATGTATCAACACACATTTTTAAAAAATTTGTTTAAAAG TATACTCT TAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTG GGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGCCTGGGCAATAAAGTGAGACC CTGTCACTAACAAAATTAAAAAATAAAATAAATATAAAATATAGGCTTTAAAAAAG CATAGTCTTATTAACCATGTCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGAAAA GAAGAAAAAACCAAGCTTAGGGTA TTTTTCCTCCCGTGCCTGAGTCCCAATTACATT CACGACAGTACTTTCAATGAACATAATTGTTAGGACCACTGAGGAATCATGAAAAA TGATCTCTGCTTAGTACATTTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAGCT ATAGTGTCTCGAGTACTAATATGCAATTATGAAAATTATATTAAATCTGGGATTATG ACGGTATCACTGTATCATCTTGGTCTTGTTCTGGCTGTCACCAAG CATGACCCAGGT CAACTTTTTTTTCCCCTGAATTACCCATCAAATTGATCTGCAGCTGACTAAAGGCCA CAGCTGAGCCTGGAACTGACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAAGC ACCAAGGAAAAAGCAGAGAATGACAGCAAACAGATCACTAGGCCTCTGACCACAG GTGCTGAGTACTCAGCAGCCCTCATATAATAGGTTTGAAAGTACTCCTTAAAATAAA ACACTGTTTCCCTTTGGAACTAT TTACAAGGATGAAACAACCGTATACCTGAGAAAT AACTTGCTCTGGTGTCAATTCGCTATTCGCCAGCAGACATCAGAACACACCGAGTTT CCAGATGCTGGTTTTTCCCCTTAAAATCAGGAAATACACCTGGACAATTTCTAGAAGA CTACAATTCAGTCTAGCCACAAAGGGGATTTTTTTTTTTTGGTAACAGGCTAGAGCC CGGTTCTGTAAGTCTTTAGCTGAAATGGTCCAGTACA AAAGCACTGGAAATGAGTG GGCTAGGAGGACAAGGACCGTCTCCTGCGTGAGGAGTTGGTTGGAGGTCCCCAAGG CCAGGTACCCCCTGCACTCTTATTGGATTCCTCTCTGTCTTCTTGGAGTTTTGAAAAA CTCCTTCGAACACCAGGCTTTTTTCTTTAGAAAACAAGTCTCCAATCGTTCTCTGTTC CGTAGAAAGAGAAAGAAAACCTGGAGCAGCTGCTGAAAAATCTAATGAGGA ACTA AGAGGCAAACCCACCA

- 105 045887

SEQ ID NO: 16 - Chimeric intron:

GGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGCCTCGCGCCG CCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCC CTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCTTTTCTGTG GCTGCGTGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGGGAGCGGC TCGGGGGGTGCGTG CGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCCCGCGCTG CCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGGGGCTTTGTGCGCTCCGCGTGTG CGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCTGCGAGGG GAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGGTGTGGGC GCGGCGGTCGGGCTGTAACCCCCCCCTGCAC CCCCCTCCCCGAGTTGCTGAGCACGG CCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCCGTGCCGG GCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGCCGCCTCGGGCCGG GGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTGTCGAGGC GCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGC GCAGGGACT TCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGCACCCCCTC TAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGGGCGGGGAG GGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCCAGCCTCGGGGCTGTC CGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGCAGGGCGGGGTTCGGCTTCTGG CGTGTGA CCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTCTTCTTTTTCC TACAG

SEQ ID NO: 17 - CMV Enhancer:

GACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTT CATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGC TGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTA ACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGACTATTTACGGTAAACTGCC CACTTGGCAGTACATCAAG TGTATCATATGCCAAGTACGCCCCCTATTGACGTCAAT GACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCT ACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATG

SEQ ID NO: 18 - CBA promoter:

TCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCTCCCCCCCCTCCCCA CCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGG GGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCG AGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTT TATGGCGAGGCGGCGGC CGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCG

SEQ ID NO: 19 - tGFP:

MESDESGLPAMEIECRITGTLNGVEFELVGGGEGTPEQGRMTNKMKSTKGALTF SPYLLSHVMGYGFYHFGTYPSGYENPFLHAINNGGYTNTRIEKYEDGGVLHVSFSYRYE AGRVIGDFKVMGTGFPEDSVIFTDKIIRSNATVEHLHPMGDNDLDGSFTRTFSLRGGYY SSVVDSHMHFKSAIHPSILQNGGPMFAFRRVEEDHS NTELGIVEYQHAFKTPDADAGEE

SEQ ID NO: 20 - Poly-A Bovine Growth Hormone:

CTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCT TGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCAT CGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGTGGGGTGGGGCAGGACAGC AAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTAT GG

SEQ ID NO: 21 - Soluble Neuropilin-1 Polyadenylation Signal: AAATAAAATACGAAATG

SEQ ID NO: 22 - Splice donor sequence:

GTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCT

TGTCGAGACAGAGAAGACTCTTGCGTTTCT

SEQ ID NO: 23 - Splice acceptor sequence:

GATAGGCACCTATTGGTCTTACTG ACATCCACTTTGCCTTTCTCTCCACAG

SEQ ID NO: 24 - 3'-ITR:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCC CGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAG AGGGAGTGGCCAACTCCATCACTAGGGGTTCCT

SEQ ID NO: 25 - ITR:

TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAA

GCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCA

GAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCT

- 106 045887

SEQ ID NO: 26 - sh-chimeric intron:

GGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGCCTCGCGCCG CCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCC CTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTTGTTTCTTTTCTGTG GCTGCGTGAAAGCCTTGAGGGGCTCCGGGAGCTAGAGCCTCTGCTAACCATGTTCAT GCCTTCTTCTTTTTC CTACAG

SEQ ID NO: 27 - 3'-UTR 600A:

AAGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTT TAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCC TTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAA GCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGT AGTCAAAGGCAGTTGACTAG AATCGACAAATTGTTACTCCATATATATATATGTGTG TGTGTGTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATATCAAAGGCA CATGGAATATATTTTTAATAAAAACAAAATAATATCTCTAATATATCCACACATTTGTT GCCAGATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATTAAAT GAACATCTATAAAATGTATCAACACACATTTTTAAAAAATTTGTTTAAAAG TATACTCT TAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTG GGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAG

SEQ ID NO: 28 - 3'-UTR 600B:

GAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGCCTGGGCAATAAAGTGAG ACCCTGTCACTAACAAAATTAAAAAATAAAATAAATATAAAATATAGGCTTTAAAA AAGCATAGTCTTATTAACCATGTCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGA AAAGAAGAAAAAACCAACGTTAGGGTATTTTTCCTCCCGTGCCTGAGTCCCAATTAC ATTCACGACAGTACTTTCAATGAACATAATTGTT AGGACCACTGAGGAATCATGAAA AATGATCTCTGCTTAGTACATTTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAG CTATAGTGTCTCGAGTACTAATATGCAATTATGAAAATTATATTAAATCTGGGATTA TGACGGTATCACTGTATCATCTTGGTCTTGTTCTGGCTGTCACCAAGCATGACCCAG GTCAACTTTTTTTTTTCCCCTGAATTACCCATCAAATTGATCTGCAGCTGACT AAAGGC CACAGCTGAGCCTGGAACTGACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAA GCACCAAGGAAAAAGCAGAGAATGACAGCAAACA

SEQ ID NO: 29 - 3'-UTR 600C:

AGGCCTCTGACCACAGGTGCTGAGTACTCAGCAGCCCTCATATAATAGGTTT GAAAGTACTCCTTAAAATAAAACACTGTTTCCCTTTGGAACTATTTACAAGGATGAA ACAACCGTATACCTGAGAAATAACTTGCTCTGGTGTCAATTCGCTATTCGCCAGCAG ACATCAGAACACACCGAGTTTCCAGATGCTGGTTTTTCCCCTTAAAATCAGGAAATAC ACCTGGACAATTTCTAGAAGACTACA ATTCAGTCTAGCCACAAAGGGGATTTTTTTT TTTTGGTAACAGGCTAGAGCCCGGTTCTGTAAGTCTTTAGCTGAAATGGTCCAGTAC AAAAGCACTGGAAATGAGTGGGCTAGGAGGACAAGGACCGTCTCCTGCGTGAGGA GTTGGTTGGAGGTCCCCAAGGCCAGGTACCCCCTGCACTCTTATTGGATTCCTCTCT GTCTTCTTGGAGTTTTGAAAAACTCCTTCGAACACCAGGCTTTTT TCTTTAGAAAACA

AGTCTCCAATCGTTCTCTGTTCCGTAGAAAGAGAAAGAAAACCTGGAGCAGCTGCT GAAAATCTAATGAGGAACTAAGAGGCAAACCCACCA

SEQ ID NO: 30 - FP:

KRKRRG

SEQ ID NO: 31 - T2A

EGRGSLLTCGDVEENPGP

SEQ ID NO: 32 - eGFP:

MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLP VPWPTLVTTLTYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEV KFEGDTLVNRIELKGIDFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIE DGSVQLADHYQQNTPIGDG PVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGITL GMDELYK

SEQ ID NO: 33 - Mus:

EQKLISEEDLEQKLISEEDLEQKLISEEDL

SEQ ID NO: 34 - HA:

YPYDVPDYA

SEQ ID NO: 35 - 3xFLAG Tag:

DYKDHDGDYKDHDIDYKDDDDK

- 107 045887

SEQ ID NO: 36-3'-UTR 1357

AAGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTT TAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCC TTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAA GCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGT AGTCAAAGGCAGTTGACTAG AATCGACAAATTGTTACTCCATATATATATATGTGTG TGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATATCAAAGGCACATGGAATATAT TTTAATAAAAACAAAATAATATCTCTAATATATCCACACATTTGTTGCCAGATTTCAG AAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATTAAATGAACATCTATAA AATGTATCAACACACATTTTTAAAAAATTTGTTTTAAAGTATACTCT TAGGCCAGGCGT GGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTGGGAAGATCATTT GAGTTCAGGAGTTCGAGTTACAGTCTGGGCAATAAAGTGAGACCCTGTCACTAACA AAATTAAAAAATAAAATAAATAAAATATAGGCTTTAAAAAAGCATAGTCTTATT AACCATGTCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGAAAAGAAGAAAAAAC CAACGTTAGGGTATTTTTC CTCCCGTGCCTGAGTCCCAATTACATTCACGACAGTACT TTCAATGAACATAATTGTTAGGACCACTGAGGAATCATGAAAAATGATCTCTGCTTA GTACATTTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAGCTATAGTGTCTCGA GTACTAATATGCAATTATGAAAATTATATTAAATCTGGGATTATGACGGTATCACTG TATCATCTTGGTCTTGTTCTGGCTGTCACCAAGCATGACCCA GGTCAACTTTTTTTTT CCCCTGAATTACCCATCAAATTGATCTGCAGCTGACTAAAGGCCACAGCTGAGCCTG GAACTGACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAAGCACCAAGGAAAAA GCAGAGAATGACAGCAAACAGATCACTAGGCCTCTGACCACAGGTGCTGAGTACTC

AGCAGCCCTCATATAATAGGTTTGAAAGTACTCCTTAAAATAAAACACTGTTTCCCT TTGGAACTATTTACAAGGATGAAACAACCGTATACCTGAGAAAATAACTTGCTCTGGT GTCAATTCGCTATTCGCCAGCAGACATCAGAACACACCGAGTTTCCAGATGCT

SEQ ID NO: 37 - 3'-UTR 1406:

AAGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTT TAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCC TTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAA GCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGT AGTCAAAGGCAGTTGACTAG AATCGACAAATTGTTACTCCATATATATATATATGTG TGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATATCAAAGGCACATGGAATATAT TTTAATAAAAACAAATAATATCTCTAATATATCCACACATTTGTTGCCAGATTTCAG AAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATTAAATGAACATCTATAA AATGTATCAACACACATTTTTAAAAAATTTGTTTTAAAGTATACTCT TAGGCCAGGCGT GGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTGGGAAGATCATTT GAGTTCAGGAGTTCGAGTTACAGCCTGGGCAATAAAGTGAGACCCTGTCACTAACA AAATTAAAAAATAAAATAAATAAAAATATAGGCTTTAAAAAAGCATAGTCTTATT AACCATGTCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGAAAAGAAGAAAAAAC CAACGTTAGGGTATTTTTC CTCCCGTGCCTGAGTCCCAATTACATTCACGACAGTACT TTCAATGAACATAATTGTTAGGACCACTGAGGAATCATGAAAAATGATCTCTGCTTA GTACATTTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAGCTATAGTGTCTCGA GTACTAATATGCAATTATGAAAATTATATTAAATCTGGGATTATGACGGTATCACTG TATCATCTTGGTCTTGTTCTGGCTGTCACCAAGCATGACCCA GGTCAACTTTTTTTTT CCCCTGAATTACCCATCAAATTGATCTGCAGCTGACTAAAGGCCACAGCTGAGCCTG GAACTGACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAAGCACCAAGGAAAAA GCAGAGAATGACAGCAAACAGATCACTAGGCCTCTGACCACAGGTGCTGAGTACTC AGCAGCCCTCATATAATAGGTTTGAAAGTACTCCTTAAAATAAAACACTGTTTCCCT TTGGAACT ATTTACAAGGATGAAACAACCGTATACCTGAGAAATAACTTGCTCTGGT GTCAATTCGCTATTCGCCAGCAGACATCAGAACACACCGAGTTTCCAGATGCTGGTT TTTCCCCTTAAATCAGGAAATACACCTGGACAATTTCTAGAAGAC

SEQ ID NO: 38 - Anti-CLRN1 Antibody Epitope:

EKIANYKEGTYVYKTQSEKY

- 108 045887

SEQ ID NO: 39 - CLRN-0:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCCCTCTCCAGCCTC GGGGCTGTCCGCG GGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCT CTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGA CAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTTT GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACTAAGAGCTCAAGGCAAACCTTCTCTATAATTTTACAAGGGAGTAGA CTTGCTTTGGTCACTTTTAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATAT TAAAGCATCAGGACCCTT CGTGACAATGTTTACAAAATTACGTACTAAGGATACAGGC

- 109 045887

TGGAAAGTAAGGGAAGCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAA ATTGCTTGACCCAGGTAGTCAAAGGCAGTTGACTAGAATCGACAAATTGTTACTCCA TATATATATATGTGTGTGTGTGTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAA AAGATATCAAAGGCACATGGAATATATTTTAATAAAAACAAATAATATCTCTAATAT ATCCACACATTTGTTGCCA GATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAAC AGTAGTGTATTAAATGAACATCTATAAAATGTATCAACACACATTTTTAAAAAATTTG TTTAAAGTATACTCTTAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTC AGGAGGCCAAGGTGGGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGCCTGGGC AATAAAGTGAGACCCTGTCACTAACAAAATTAAAAAATAAAATAA ATATAAAATAT AGGCTTTAAAAAAGCATAGTCTTATTAACCATGTCTGTTGGTCAAAATCTGCAAACT CTAAAGAAGAAAAGAAGAAAAAACCAACGTTAGGGTATTTTTCCTCCCGTGCCTG AGTCCCAATTACATTCACGACAGTACTTTCAATGAACATAATTGTTAGGACCACTGA GGAATCATGAAAAATGATCTCTGCTTAGTACATTTGATGCAAAATGACTTATTAGGG GCTGTTTTTCTAGCTATA GTGTCTCGAGTACTAATATGCAATTATGAAAATTATATTA AATCTGGGATTATGACGGTATCACTGTATCATCTTGGTCTTGTTCTGGCTGTCACCAA GCATGACCCAGGTCAACTTTTTTTTTTCCCCTGAATTACCCATCAAATTGATCTGCAGC TGACTAAAGGCCACAGCTGAGCCTGGAACTGACCCTTCCTTCATCCTCAACCTGCTG TCCTCCAGAAAGCACCAAGGAAAAAGCA GAGAATGACAGCAAACAGATCACTAGG CCTCTGACCACAGGTGCTGAGTACTCAGCAGCCCTCATATAATAGGTTTGAAAGTAC TCCTTAAAATAAAACACTGTTTCCCTTTGGAACTATTTACAAGGATGAAACAACCGT ATACCTGAGAATAACTTGCTCTGGTGTCAATTCGCTATTCGCCAGCAGACATCAGA ACACACCGAGTTTCCAGATGCTGGTTTTTCCCCTAAATCAGGAAATACACCTGGA C AATTTCTAGAAGACTACAATTCAGTCTAGCCACAAAGGGGATTTTTTTTTTTGGTA ACAGGCTAGAGCCCGGTTCTGTAAGTCTTTAGCTGAAATGGTCCAGTACAAAAGCA CTGGAAATGAGTGGGCTAGGAGGACAAGGACCGTCTCCTGCGTGAGGAGTTGGTTG GAGGTCCCCAAGGCCAGGTACCCCCTGCACTCTTATTGGATTCCTCTCTGTCTTCTTG GAGTTTTGA AAAACTCCTTCGAACACCAGGCTTTTTTCTTTAGAAAACAAGTCTCCA ATCGTTCTCTGTTCCGTAGAAAGAGAAAGAAAACCTGGAGCAGCTGCTGAAAAATC TAATGAGGAACTAAGAGGCAAACCCACCACTGTGCCTTCTAGTTGCCAGCCATCTGT TGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTT TCCTAATAAAATGAGGAAATTGCATCGCAT TGTCTGAGTAGGTGTCATTCTATTCTG GGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGC ATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCTCGGAC CGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTC ACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGC GGCCTC AGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

SEQ ID NO: 40 - CLRN-1:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT

- 110 045887

ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCT ATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCGCCAGGCGG GGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCGTGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGCGTGGGGAGCGCCGGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGGGGCTTTGTGCGCTCC GCGTGTGCGCG AGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGGG GGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCGCGCAGGAAGGAAATG G GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCA GAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCTTC TTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGAGC GAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGCAGCGGAGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGT GGAAGAGAACCCCGGACCTATGCAGGCTCTGCAGCAGCAGCCAGTGTTCCCCGATC TGCTGAAAGCCATTCCTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCT CATTGTCCTCACTATGGTTGGAACGGCCTTTTTTATGTATAATGCCTTTGGGAAGCCG TTTGAAACCCTGCACGGACCCCTGGGACTCTATCTCCTGAGCTTCATCTCCGGCTCTT GCGGCTGCCTCG TGATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTCTG AGAAAATTGCTAATTACAAAGAAGGGACATACGTTTACAAAACGCAGAGCGAAAA GTATACGACCAGCTTCTGGCTGACCAAGGGCCACTCTTAAGAGCTCGCTGATCAGCC TCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCT TGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCAT CGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGC AAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTAT GGAAGCTTGAAT TCAGCTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGATGGAG TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTC GCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTG CCTGCAGG

- 111 045887

SEQ ID NO: 41 - CLRN-2eGFP:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT

- 112 045887

GCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCT CGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCC CTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTG TG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTG AACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACA AGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGCAGCGGAGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGT GGAAGAGAACCCCGGACCTATGCAGGCTCTGCAGCAGCAG CCAGTGTTCCCCGATC TGCTGAAAGCCATTCCTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCT CATTGTCCTCACTATGGTTGGAACGGCCTTTTTTATGTATAATGCCTTTGGGAAGCCG TTTGAAACCCTGCACGGACCCCTGGGACTCTATCTCCTGAGCTTCATCTCCGGCTCTT GCGGCTGCCTCGTGATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTC TG AGAAAATTGCTAATTACAAAGAAGGGACATACGTTTACAAAACGCAGAGCGAAAA GTATACGACCAGCTTCTGGCTGACCAAGGGCCACTCTGGATCAGGCGAAGGCAGGG GATCTCTGCTGACCTGCGGAGATGTCGAAGAGAATCCTGGACCAatggtgagcaagggcgagg agctgttcaccggggtggtgcccatcctggtcgagctggacggcgacgtaaacggcca caagttcagcgtgtccggcgagggcgaggg cgatgccacctacggcaagctgaccctgaagttcatctgcaccaccggcaagctgcccgtgccctggcccaccctcgtgaccaccctgac ctacggcgtgcagtgcttcagccgctaccccgaccacatgaagcagcacgacttcttcaagtccgccatgcccgaaggctacgtcca gga gcgcaccatcttcttcaaggacgacggcaactacaagacccgcgccgaggtgaagttcgagggcgacaccctggtgaaccgcatcgagc tgaagggcatcgacttcaaggaggacggcaacatcctggggcacaagctggagtacaactacaacagccacaacgtctatatcatggccg acaagcagaagaacggcatcaaggtgaacttcaagatccgcca caacatcgaggacggcagcgtgcagctcgccgaccactaccagca gaacacccccatcggcgacggccccgtgctgctgcccgacaaccactacctgagcacccagtccgccctgagcaaagaccccaacgag aagcgcgatcacatggtcctgctggagttcgtgaccgccgccgggatcactctcggcatggacgagctgtacaagTAAGAG CTC GCTGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCC CGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGA GGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGTGGGGTGGG GCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCG GTGGGCTCTATG GAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCTAGGAACCCCT AGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCG ACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAG CGCGCAGCTGCCTGCAGG

- 113 045887

SEQ ID NO: 42 - CLRN-3:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTC

- 114 045887

GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTAGGAGATACT TGAAGGCAGTTTGAAAGACTTGTTTTACAGATTCTTAGTCCAAAGATTTCCAATTAG GGAGAAGAAGCAGCAGAAAAGGAGAAAAGCCAAGTATGAGTGATGATGAGGCCTT CATCTACTGACATTTAACCTGGCGAGAACCGTCGATGGTGAAGTTGCCTTTTCAGCT GGGAGCTGTCCGTTCAGCTTCCGTAATAAATGCAGTCAAAGAGGCAGTCCCTTCCCA TTGCTCACAAAGGTCTTGTTTTTGAACCTCGCCCTCACAGAAGCCGTTTCTCATCGCC ACCATGCCTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTC GCCTGTGCTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACA GTGCTGTGCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAA GTTCATGGGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTG GCCTGGGAGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCC CCGTGTCCATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAA TGGTCGGAACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGC ATGGACCTCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGG TCATGATTCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCC AACTACAAAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAG CTTTTGGGTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGA CTGGCCGGCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGT GGCCGCCGATCTGATGTACTAAGAGCTCAAGGCAAACCTTTCTATAATTTTACAAGG GAGTAGACTTGCTTTGGTCACTTTTAGATGTGGTTAATTTTGCATATCCTTTTAGTCT GCATATATTAAAGCATCAGGACCCTTCGTGACAATGTTTACAAATTACGTACTAAGG ATACAGGCTGGAAAGTAAGGGAAGCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCT GGTGGGAAATTGCTTGACCCAGGTAGTCAAAGGCAGTTGACTAGAATCGACAAATT GTTACTCCATATATATATATGTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAAAAG ATATCAAAGGCACATGGAATATATTTTAATAAAAACAAATAATATCTCTAATATATC CACACATTTGTTGCCAGATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGT AGTGTATTAAATGAACATCTATAAAATGTATCAACACACATTTTAAAAAATTTGTTT AAAGTATACTCTTAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGG AGGCCAAGGTGGGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGTCTGGGCAAT AAAGTGAGACCCTGTCACTAACAAAATTAAAAAATAAAATAAATATAAAATATAGG CTTTAAAAAAGCATAGTCTTATTAACCATGTCTGTTGGTCAAAATCTGCAAACTCTA AAAGAAGAAAAGAAGAAAAAACCAACGTTAGGGTATTTTTCCTCCCGTGCCTGAGT CCCAATTACATTCACGACAGTACTTTCAATGAACATAATTGTTAGGACCACTGAGGA ATCATGAAAAATGATCTCTGCTTAGTACATTTGATGCAAAATGACTTATTAGGGGCT _{GTTTTTCTAGCTATAGTGTCTCGAGTACTAATATGCAATTATGAAAATTATATTAAAT} CTGGGATTATGACGGTATCACTGTATCATCTTGGTCTTGTTCTGGCTGTCACCAAGCA TGACCCAGGTCAACTTTTTTTTTCCCCTGAATTACCCATCAAATTGATCTGCAGCTGA CTAAAGGCCACAGCTGAGCCTGGAACTGACCCTTCCTTCATCCTCAACCTGCTGTCC TCCAGAAAGCACCAAGGAAAAAGCAGAGAATGACAGCAAACAGATCACTAGGCCT CTGACCACAGGTGCTGAGTACTCAGCAGCCCTCATATAATAGGTTTGAAAGTACTCC TTAAAATAAAACACTGTTTCCCTTTGGAACTATTTACAAGGATGAAACAACCGTATA CCTGAGAAATAACTTGCTCTGGTGTCAATTCGCTATTCGCCAGCAGACATCAGAACA CACCGAGTTTCCAGATGCTCTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCT CCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAA TGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGT GGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGAT GCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCTAGGAAC CCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCG GGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAG CGAGCGCGCAGCTGCCTGCAGG

- 115 045887

SEQ ID NO: 43 - CLRN-4:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC

- 116 045887

AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGA CCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCT CTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACT GCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGCAGCGGAGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGT GGAAGAGAACCCCGGACCTATGCAGGCTCTGCAGCAGCAGCCAGTGTTCCCCGATC TGCTGAAAGCCATTCCTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCT CATTGTCCTCACTATGGTTGG AACGGCCTTTTTTATGTATAATGCCTTTGGGAAGCCG TTTGAAACCCTGCACGGACCCCTGGGACTCTATCTCCTGAGCTTCATCTCCGGCTCTT GCGGCTGCCTCGTGATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTCTG AGAAAATTGCTAATTACAAAGAAGGGACATACGTTTACAAAACGCAGAGCGAAAA GTATACGACCAGCTTCTGGCTGACCAAGGGCCACTCTTAAGAG CTCAAGGCAAACC TTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTTTAGATGTGGTTAATT TTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCCTTCGTGACAATGTTT ACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAAGCAGAAGGAAGGCT TTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGTAGTCAAAGGCAGTT GACTAGAATCGA CAAATTGTTACTCCATATATATATATATGTGTGTGTGTGTAAG ATGTCTTCCTATCAAAAAGATATCAAAGGCACATGGAATATATTTTAATAAAAACAA ATAATATCTCTAATATATCCACACATTTGTTGCCAGATTTCAGAAAACTGAGCTGCA ATCGCTTTCCTAAAACAGTAGTGTATTAAATGAACATCTATAAAATGTATCAACACA CATTTTAAAAAATTTGTTTAAAAGTATACTCTTAGGCCAGGCGTG GTGACTCACACCT GTAATTCCAGCACTTCAGGAGGCCAAGGTGGGAAGATCATTTGAGTTCAGGAGTTC GAGTTACAGCCTGGGCAATAAAGTGAGACCCTGTCACTAACAAAATTAAAAAATAA AATAAATATAAAATATAGGCTTTAAAAAAGCATAGTCTTATTAACCATGTCTGTTGG TCAAAATCTGCAAACTCTAAAAGAAGAAAAGAAGAAAAAACCAACGTTAGGGTATT TTTCCTCCCGTGCCTG AGTCCCAAATTACATTCACGACAGTACTTTCAATGAACATAAT

TGTTAGGACCACTGAGGAATCATGAAAAATGATCTCTGCTTAGTACATTTGATGCAA AATGACTTATTAGGGGCTGTTTTTCTAGCTATAGTGTCTCGAGTACTAATATGCAATT ATGAAAATTATATTAAATCTGGGATTATGACGGTATCACTGTATCATCTTGGTCTTGT TCTGGCTGTCACCAAGCATGACCCAGGTCAACTTTTTTTTTTCCCCTGAATTACCCATC AAATTGATC TGCAGCTGACTAAAGGCCACAGCTGAGCCTGGAACTGACCCTTCCTTC ATCCTCAACCTGCTGTCCTCCAGAAAGCACCAAGGAAAAAGCAGAGAATGACAGCA AACAGATCACTAGGCCTCTGACCACAGGTGCTGAGTACTCAGCAGCCCTCATATAAT AGGTTTGAAAGTACTCCTTAAAATAAAACACTGTTTCCCTTTGGAACTATTTACAAG GATGAAACAACCGTATACCTGAGAATAACTTGCT CTGGTGTCAATTCGCTATTCGC CAGCAGACATCAGAACACACCGAGTTTCCAGATGCTGGTTTTTCCCCTAAATCAGG AAATACACCTGGACAATTTCTAGAAGACAGGCCTCTGTGCCTTCTAGTTGCCAGCCA TCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTG TCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTC ATTCTA TTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAG CAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCT CGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCT CGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCG GCCTCAGTGAGCG AGCGAGCGCGCAGCTGCCTGCAGGG

- 117 045887

SEQ ID NO: 44 - CLRN-6eGFP:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT

- 118 045887

GCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCT CGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCC CTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCatggtg agcaagggcgaggagctgttcaccggggtggtgcccatcc tggtcgagctggacggcgacgtaaacggccacaagttcagcgtgtccg gcgaggcgagggcgatgccacctacggcaagctgaccctgaagttcatctgcaccaccggcaagctgcccgtgccctggcccaccctc gtgaccaccctgacctacggcgtgcagtgcttcagccgctaccccgaccacatgaagcagcacgacttct tcaagtccgccatgcccgaa ggctacgtccaggagcgcaccatcttcttcaaggacgacggcaactacaagacccgcgccgaggtgaagttcgaggcgacaccctggt gaaccgcatcgagctgaagggcatcgacttcaaggaggacggcaacatcctggggcacaagctggagtacaactacaacagccacaac gtctatatcatggccgacaagc agaagaacggcatcaaggtgaacttcaagatccgccacaacatcgaggacggcagcgtgcagctcgc cgaccactaccagcagaacacccccatcggcgacggccccgtgctgctgcccgacaaccactacctgagcacccagtccgccctgagc aaagaccccaacgagaagcgcgatcacatggtcctgctggagttcgtgaccgccgccgggat cactctcggcatggacgagctgtacaa gTAATAAGAGCTCAAGGCAAACCTTCTTAATTTTACAAGGGAGTAGACTTGCTTT GGTCACTTTTAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCA TCAGGACCCTTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAA GTAAGGGAAGCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAA TTGCT TGACCCAGGTAGTCAAAGGCAGTTGACTAGAATCGACAAATTGTTACTCCATATATA TATATGTGTGTGTGTGTGTGTGTGTGTGTGTAAGATGTCTTTCCTATCAAAAAGAT ATCAAAGGCACATGGAATATATTTAATAAAAACAAATAATATCTCTAATATATCCA CACATTTGTTGCCAGATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAG TGTATTAAATGAACATCTATA AAATGTATCAACACACATTTTAAAATTTGTTTAA AGTATACTCTTAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAG GCCAAGGTGGGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGCCTGGGCAATAA AGTGAGACCCTGTCACTAACAAAATTAAAAAATAAAATAAATATAAAATATAGGCT TTAAAAAAGCATAGTCTTATTAACCATGTCTGTTGGTCAAAATCTGC AAACTCTAAA AGAAGAAAAGAAGAAAAAACCAACGTTAGGGTATTTTTCCTCCCGTGCCTGAGTCC CAATTACATTCACGACAGTACTTTCAATGAACATAATTGTTAGGACCACTGAGGAAT CATGAAAAATGATCTCTGCTTAGTACATTTGATGCAAAATGACTTATTAGGGGCTGT TTTTCTAGCTATAGTGTCTCGAGTACTAATATGCAATTATGAAAATTATATTAAATCT GGGATTATGACGG TATCACTGTATCATCTTGGTCTTGTTCTGGCTGTCACCAAGCAT GACCCAGGTCAACTTTTTTTTTTCCCCTGAATTACCCATCAAATTGATCTGCAGCTGAC TAAAGGCCACAGCTGAGCCTGGAACTGACCCTTCCTTCATCCTCAACCTGCTGTCCT

CCAGAAAGCACCAAGGAAAAAGCAGAGAATGACAGCAAACAGATCACTAGGCCTC TGACCACAGGTGCTGAGTACTCAGCAGCCCTCATATAATAGGTTTGAAAGTACTCCT TAAAATAAAACACTGTTTCCCTTTGGAACTATTTACAAGGATGAAACAACCGTATAC CTGAGAAATAACTTGCTCTGGTGTCAATTCGCTATTCGCCAGCAGACATCAGAACAC ACCGAGTTTCCAGATGCTGGTTTTTC CCCTTAAATCAGGAATACACCTGGACAATT TCTAGAAGACTACAATTCAGTCTAGCCACAAAGGGGATTTTTTTTTTTGGTAACAG GCTAGAGCCCGGTTCTGTAAGTCTTTAGCTGAAATGGTCCAGTACAAAAGCACTGGA AATGAGTGGGCTAGGAGGACAAGGACCGTCTCCTGCGTGAGGAGTTGGTTGGAGGT CCCCAAGGCCAGGTACCCCCTGCACTCTTATTGGAT TCCTCTCTGTCTTCTTGGAGTT TTGAAAAACTCCTTCGAACACCAGGCTTTTTTCTTTAGAAAACAAGTCTCCAATCGT TCTCTGTTCCGTAGAAAGAGAAAGAAAACCTGGAGCAGCTGCTGAAAAATCTAATG AGGAACTAAGAGGCAAACCCACCACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTT GCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTG TCCTTTCCTA ATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGG TGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCT GGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCT AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTG AGGCCGGGCGACC AAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTG AGCGAGCGAGCGCGCAGCTGCCTGCAGG

- 119 045887

SEQ ID NO: 45 - CLRN-7eGFP:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCCCTCTCCAGCCTC GGGGCTGTCCGCG GGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCatggtg agcaagggcgaggagctgttcaccggggtggtgcccatcctggtcgagctggacggcgacgtaaacgg ccacaagttcagcgtgtccg gcgagggcgagggcgatgccacctacggcaagctgaccctgaagttcatctgcaccaccggcaagctgcccgtgccctggcccaccctc gtgaccaccctgacctacggcgtgcagtgcttcagccgctaccccgaccacatgaagcagcacgacttcttcaagtccgccatgcccgaa ggctacg tccaggagcgcaccatcttcttcaaggacgacggcaactacaagacccgcgccgaggtgaagttcgaggcgacaccctggt gaaccgcatcgagctgaagggcatcgacttcaaggaggacggcaacatcctggggcacaagctggagtacaactacaacagccacaac gtctatatcatggccgacaagcagaagaacggcatcaaggtgaacttcaagatccgcca caacatcgaggacggcagcgtgcagctcgc cgaccactaccagcagaacacccccatcggcgacggccccgtgctgctgcccgacaaccactacctgagcacccagtccgccctgagc aaagaccccaacgagaagcgcgatcacatggtcctgctggagttcgtgaccgccgccgggatcactctcggcatggacgagctgtacaa gTAAG AGCTCAAGGCAAACCTTCTTAATTTTACAAGGGAGTAGACTTGCTTTGGT CACTTTTAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCA GGACCCTTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTA AGGGAAGCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGA CCCAGGTAGTCAAAGGCAGTTGACTAG AATCGACAAATTGTTACTCCATATATATAT ATGTGTGTGTGTGTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATATC AAAGGCACATGGAATATATTTAATAAAAACAAAATAATATCTCTAATATATCCACAC ATTTGTTGCCAGATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGT ATTAAATGAACATCTATAAAATGTATCAACACACATTTTTAAAAAATTTGTTTAAAA GT ATACTCTTAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCC AAGGTGGGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGCTGTGCCTTCTAGTTG CCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACT CCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGT CATTCTATTCTGG GGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAG ACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTG ACGTGCCTCGGACCGCTAGGAACCCCTAGTGATATGGAGTTGGCCACTCCCTCTCTGCG CGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTG CCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCA GCTGCCTGCAGG

- 120 045887

SEQ ID NO: 46 - CLRN-8:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCCCTCTCCAGCCTC GGGGCTGTCCGCG GGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCT CTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGA CAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC

- 121 045887

TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAG TTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGCAGCGGAGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGT GGAAGAGAACCCCGGACCTATGCAGGCTCTGCAGCAGCAGCCAGTGTTCCCCGATC TGCTGAAAGCCATTCCTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCT CATTGTCCTCACTATGGTTGGAACGGCCT TTTTTATGTATAATGCCTTTGGGAAGCCG TTTGAAACCCTGCACGGACCCCTGGGACTCTATCTCCTGAGCTTCATCTCCGGCTCTT GCGGCTGCCTCGTGATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTCTG AGAAAATTGCTAATTACAAAGAAGGGACATACGTTTACAAAACGCAGAGCGAAAA GTATACGACCAGCTTCTGGCTGACCAAGGGCCACTCTTAAGAGCTCGAAG ATCATTT GAGTTCAGGAGTTCGAGTTACAGCCTGGGCAATAAAGTGAGACCCTGTCACTAACA AAATTAAAAAATAAAATAAATATAAAATATAGGCTTTAAAAAAGCATAGTCTTATT AACCATGTCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGAAAAGAAGAAAAAAC CAACGTTAGGGTATTTTTCCTCCCGTGCCTGAGTCCCAATTACATTCACGACAGTACT TTCAATGAACATAATTGTTAGGA CCACTGAGGAATCATGAAAAATGATCTCTGCTTA GTACATTTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAGCTATAGTGTCTCGA GTACTAATATGCAATTATGAAAATTATATTAAATCTGGGATTATGACGGTATCACTG TATCATCTTGGTCTTGTTCTGGCTGTCACCAAGCATGACCCAGGTCAACTTTTTTTTT CCCCTGAATTACCCATCAAATTGATCTGCAGCTGACTAAAGGCCACAGCT GAGCCTG GAACTGACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAAGCACCAAGGAAAAA GCAGAGAATGACAGCAAACACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCC CTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAA AATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGG GTGGGGCA GGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGG ATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCTAGGA ACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGC CGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCG AGCGAGCGCGCAGCTGCCTGCCAGG

SEQ ID NO: 47 - CLRN-9:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT

- 122 045887

ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGGCCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGG CGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGC TTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCGTGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCG GGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGCGGGCGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGG AGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGC CGTCCCCTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTT CGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATC CACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACG TCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGCAGCGGAGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGT GGAAGAGAACCCCGGACCTATGCAGGCTCTGCAG CAGCAGCCAGTGTTCCCCGATC TGCTGAAAGCCATTCCTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCT

- 123 045887

CATTGTCCTCACTATGGTTGGAACGGCCTTTTTTATGTATAATGCCTTTGGGAAGCCG TTTGAAACCCTGCACGGACCCCTGGGACTCTATCTCCTGAGCTTCATCTCCGGCTCTT GCGGCTGCCTCGTGATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTCTG AGAAAATTGCTAATTACAAAGAAGGGACATACGTTTACAAAACGCAGAGCGAAAA GTATACGACCAGCTTCTGG CTGACCAAGGGCCACTCTTAAGAGCTCAGGCCTCTGAC CACAGGTGCTGAGTACTCAGCAGCCCTCATATAATAGGTTTGAAAGTACTCCTTAAA ATAAAACACTGTTTCCCTTTGGAACTATTTACAAGGATGAAACAACCGTATACCTGA GAAATAACTTGCTCTGGTGTCAATTCGCTATTCGCCAGCAGACATCAGAACACACCG AGTTTCCAGATGCTGGTTTTTCCCCTAAATCAGGAAATACACC TGGACAATTTCTA GAAGACTACAATTCAGTCTAGCCACAAAGGGGATTTTTTTTTTTGGTAACAGGCTA GAGCCCGGTTCTGTAAGTCTTTAGCTGAAATGGTCCAGTACAAAAGCACTGGAAAT GAGTGGGCTAGGAGGACAAGGACCGTCTCCTGCGTGAGGAGTTGGTTGGAGGTCCC CAAGGCCAGGTACCCCCTGCACTCTTATTGGATTCCTCTCTGTCTTCTTGGAGTTTT G AAAAACTCCTTCGAACACCAGGCTTTTTTCTTTAGAAAACAAGTCTCCAATCGTTCT CTGTTCCGTAGAAAGAGAAAGAAAACCTGGAGCAGCTGCTGAAAAATCTAATGAGG AACTAAGAGGCAAACCCACCACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCC CCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATA AAATGAGAAATTGCATCG CATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGG GGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGG GATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCTAGG AACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGG CCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGC GGCCTCAGTGAGC GAGCGAGCGCGCAGCTGCCTGCAGG

SEQ ID NO: 48 - CLRN-10:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG

- 124 045887

GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCGTGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGCGTGGGGAGCGCCGGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGGGGCTTTGTGCGCTCC GCGTGTGCG CGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCATG GGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAA TGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAG CAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCT TCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGA GCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGATCCTATCCCTATGATGTGCCAGACTATGCTAAGCGGAAGA GA AGAGGCGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGTGGAAGAGAACCCCG GACCTATGCAGGCTCTGCAGCAGCAGCCAGTGTTCCCCGATCTGCTGAAAGCCATTC CTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCCTCATTGTCCTCACTAT GGTTGGAACGGCCTTTTTTATGTATAATGCCTTTGGGAAGCCGTTTGAAACCCTGCA CGGACCCCTG ACTCTATCTCCTGAGCTTCATCTCCGGCTCTTGCGGCTGCCTCGTG ATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTCTGAGAAAATTGCTAAT TACAAAGAAGGGACATACGTTTACAAAACGCAGAGCGAAAAGTATACGACCAGCTT CTGGCTGACCAAGGGCCACTCTGGATCCGACTACAAAGACCATGACGGTGATTATA AAGATCATGACATCGATTACAAGGATGACGATGACAAG TAAGAGCTCGCTGATCAG CCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTC

CTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGC ATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGTGGGGTGGGGCAGGACAG CAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCT ATGGAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGATGG AGTTGGCCACTCCCTCTCTGC GCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGG TCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGC TGCCTGCAGG

- 125 045887

SEQ ID NO: 49 - CLRN-10myc:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCCCTCTCCAGCCTC GGGGCTGTCCGCG GGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC

- 126 045887

TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGC AGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTA TCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAA CCACAAACGTGGCCGCC GATCTGATGTACGGATCCGAGCAGAAACTCATCTCTGAAGAAGATCTGGAACAAAA GTTGATTTCAGAAGAAGATCTGGAACAGAAGCTCATCTCTGAGGAAGATCTGAAGC GGAAGAGAAGAGGCGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGTGGAAGA GAACCCCGGACCTATGCAGGCTCTGCAGCAGCAGCCAGTGTTCCCCGATCTGCTGAA AGC CATTCCTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCCTCATTGTC CTCACTATGGTTGGAACGGCCTTTTTTATGTATAATGCCTTTGGGAAGCCGTTTGAA ACCCTGCACGGACCCCTGGGACTCTATCTCCTGAGCTTCATCTCCGGCTCTTGCGGCT GCCTCGTGATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTCTGAGAAAA TTGCTAATTACAAAGAAGGGAC ATACGTTTACAAAACGCAGAGCGAAAAGTATACG ACCAGCTTCTGGCTGACCAAGGGCCACTCTGGATCCGACTACAAAGACCATGACGG TGATTATAAAGATCATGACATCGATTACAAGGATGACGATGACAAGTAAGAGCTCG CTGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCC GTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTA ATAAAATGAG GAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGG CAGGACAGCAAGGGGGAGGATTGGAAGACAATAGCAGGCATGCTGGGGATGCGG TGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCTAGGAACCCCTA GTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGA CCAAAGGTCGCCC GACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGC GCGCAGCTGCCTGCAGG

SEQ ID NO: 50 - CLRN-10NF:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC

- 127 045887

ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGG GGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCG TTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCGTGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGCGTGGGGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGGGGCTT TGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCC GCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGGGGCGAAGCGTG CGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACC AGC CAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGA AGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGATCCTATCCCTATGATGTGCC AGACTATGCTAAGGGCGAAGGC AGAGGCAGCCTGCTTACATGTGGCGACGTGGAAGAGAACCCCGGACCTATGCAGGC

TCTGCAGCAGCAGCCAGTGTTCCCCGATCTGCTGAAAGCCATTCCTGTCAGCATCCA TGTCAACGTCATCCTCTTCTCTGCCATCCCTCATTGTCCTCACTATGGTTGGAACGGCC _{TTTTTTATGTATAATGCCTTTGGGAAGCCGTTTGAAACCCTGCACGGACCCCTGGGA} CTCTATCTCCTGAGCTTCATCTCCGGCTCTTGCGGCTGCCTCGTGATGATCCTCTTTG CCTCTGAAGTCAAAATTCACCACCTGTCTGAGAAAATTGCTAATTACAAAGAAGGG ACATACGTTTACAAAACGCAGAGCGAAAAGTATACGACCAGCTTCTGGCTGACCAA GGGCCACTCTGGATCCGACTACAAAGACCATGACGGTGATTATAAAGATCATGACA TCGATTACAAGGATGACGATGA CAAGTAAGAGCTCGCTGATCAGCCTCGACTGTGC CTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGA AGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCT GAGTAGGTGTCATTCTATTCTGGGGTGGGGTGGGGCAGCAGCAAGGGGGAGG ATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTG GGCTCTATGGAAGCTTGA ATTCAGCTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCC CTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCC GGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

- 128 045887

SEQ ID NO: 51 - CLRN-11:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC

- 129 045887

GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGC GAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTAT TGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGC CTGGG AGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGT TCGCCAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGATCCTATCCCT ATGATGTGCCAGACTATGCTAAGCGGAAGAGA AGAGGCGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGTGGAAGAGAACCCCG GACCTATGCAGGCTCTGCAGCAGCAGCCAGTGTTCCCCGATCTGCTGAAAGCCATTC CTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCTCATTGTCCTCACTAT GGTTGGAACGGCCTTTTTTATGTATAATGCCTTTGGGAAGCC GTTTGAAACCCTGCA CGGACCCCTGGGACTCTATCTCCTGAGCTTCATCTCCGGCTCTTGCGGCTGCCTCGTG ATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTCTGAGAAAATTGCTAAT TACAAAGAAGGGACATACGTTTACAAAACGCAGAGCGAAAAGTATACGACCAGCTT CTGGCTGACCAAGGGCCACTCTGGATCCGACTACAAAGACCATGACGGTGATTATA AAGATCAT GACATCGATTACAAGGATGACGATGACAAGTAAGAGCTCAAGGCAAAC CTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTTTAGATGTGGTTAAT TTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCCTTCGTGACAATGTT TACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAAGCAGAAGGAAGGC TTTGAAAAGTTGTTTTATCTGGTGGG TTGCTTGACCCAGGTAGTCAAAGGCAGT TGACTAGAATCGACAAATTGTTACTCCATATATATATATGTGTGTGTGTGTGTAA GATGTCTTCCTATCAAAAAGATATCAAAGGCACATGGAATATATTTTTAATAAAAACA AATAATATCTCTAATATATCCACACATTTGTTGCCAGATTTCAGAAAACTGAGCTGC AATCGCTTTCCTAAAACAGTAGTGTATTAAATGAACATCTATAAAATGTATCA ACAC ACATTTTTAAAAAATTTGTTTTAAAGTATACTCTTAGGCCAGGCGTGGTGACTCACACC

- 130 045887

TGTAATTCCAGCACTTCAGGAGGCCAAGGTGGGAAGATCATTTGAGTTCAGGAGTTC GAGTTACAGCCTGGGCAATAAAGTGAGACCCTGTCACTAACAAAATTAAAAAATAA AATAAATATAAAATATAGGCTTTAAAAAAGCATAGTCTTATTAACCATGTCTGTTGG TCAAAATCTGCAAACTCTAAAAGAAGAAAAGAAGAAAAAACCAACGTTAGGGTATT TTTCCTCCCGTGCCTGAGTCCCAAT TACATTCACGACAGTACTTTCAATGAACATAAT TGTTAGGACCACTGAGGAATCATGAAAAATGATCTCTGCTTAGTACATTTGATGCAA AATGACTTATTAGGGGCTGTTTTTCTAGCTATAGTGTCTCGAGTACTAATATGCAATT ATGAAAATTATATTAAATCTGGGATTATGACGGTATCACTGTATCATCTTGGTCTTGT TCTGGCTGTCACCAAGCATGACCCAGGTCAACTTTTTTT TTCCCCTGAATTACCCATC AAATTGATCTGCAGCTGACTAAAGGCCACAGCTGAGCCTGGAACTGACCCTTCCTTC ATCCTCAACCTGCTGTCCTCCAGAAAGCACCAAGGAAAAAGCAGAGAATGACAGCA AACAGATCACTAGGCCTCTGACCACAGGTGCTGAGTACTCAGCAGCCCTCATATAAT AGGTTTGAAAGTACTCCTTAAAATAAAACACTGTTTCCCTTTGGAACTATTTACAAG GA TGAAACAACCGTATACCTGAGAAATAACTTGCTCTGGTGTCAATTCGCTATTCGC CAGCAGACATCAGAACACACCGAGTTTCCAGATGCTGGTTTTTCCCCTTAAATCAGG AAATACACCTGGACAATTTCTAGAAGACAGGCCTCTGTGCCTTCTAGTTGCCAGCCA TCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTG TCCTTTCCTAATAAAATGA GGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTA TTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAG CAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCT CGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCT CGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCG GGCTTTGCCCGGGCG GCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

SEQ ID NO: 52 - CLRN-11myc:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG

- 131 045887

GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCGTGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGCGTGGGGAGCGCCGGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGGGGCTTTGTGCGCTCC GCGTGTGCG CGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCATG GGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAA TGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAG CAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCAGATTCAGCT TCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGAAGTGAAGATCCACCACCTGA GCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGATCCGAGCAGAAACTCATCTCTGAAGAAGATCTGGAACAAAA GTTGATTTCAGAAGAAGATCTGGAACAGAAGCTCATCTCTGAGGAAGATCTGAAGC GGAAGAGAAGAGGCGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGTGGAAGA GAACCCCGGACCTATGCAGGCTCTGCAGCAGCAGCCAGTGTTCCCCGATCTGCTGAA AGCCATTCCTGTCAGCATCCATGTCAACGTCATCCTCTTCTCTGCCATCCTCATTGTC CTCACTATGGTTGGAACG GCCTTTTTTATGTATAATGCCTTTGGGAAGCCGTTTGAA ACCCTGCACGGACCCCTGGGACTCTATCTCCTGAGCTTCATCTCCGGCTCTTGCGGCT GCCTCGTGATGATCCTCTTTGCCTCTGAAGTCAAAATTCACCACCTGTCTGAGAAAA TTGCTAATTACAAAGAAGGGACATACGTTTACAAAACGCAGAGCGAAAAGTATACG ACCAGCTTCTGGCTGACCAAGGGCCACTCTGGATCCGACTAC AAAGACCATGACGG TGATTATAAAGATCATGACATCGATTACAAGGATGACGATGACAAGTAAGAGCTCA

- 132 045887

AGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTTTAGAT GTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCCTTCGT GACAATGTTTACAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAAGCAGA AGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGTAGTCA AAGGCAGTTGACTAG AATCGACAAATTGTTACTCCATATATATATATATGTGTGTGT GTGTGTAAGATGTCTTCCTATCAAAAAGATATCAAAGGCACATGGAATATATTTTAA TAAAAACAAATAATATCTCTAATATCCACACATTTGTTGCCAGATTTCAGAAAAC TGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATTAAATGAACATCTATAAAATGT ATCAACACACATTTTTAAAAAATTTGTTTTAAAGTATACTCTTA GGCCAGGCGTGGTGA CTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTGGGAAGATCATTTGAGTTC AGGAGTTCGAGTTACAGCCTGGGCAATAAAGTGAGACCCTGTCACTAAACAAAATTA AAAAATAAAATAAATATAAAATATAGGCTTTAAAAAAGCATAGTCTTATTAACCAT GCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGAAAAGAAGAAAAAACCAACGT TAGGGTATTTTTC CTCCCGTGCCTGAGTCCCAATTACATTCACGACAGTACTTTCAAT GAACATAATTGTTAGGACCACTGAGGAATCATGAAAAATGATCTCTGCTTAGTACAT TTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAGCTATAGTGTCTCGAGTACTA ATATGCAATTATGAAAATTATATTAAATCTGGGATTATGACGGTATCACTGTATCAT CTTGGTCTTGTTCTGGCTGTCACCAAGCATGA CCCAGGTCAACTTTTTTTTTCCCCTG AATTACCCATCAAATTGATCTGCAGCTGACTAAAGGCCACAGCTGAGCCTGGAACT GACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAAGCACCAAGGAAAAAGCAGA GAATGACAGCAAACAGATCACTAGGCCTCTGACCACAGGTGCTGAGTACTCAGCAG CCCTCATATAATAGGTTTGAAAGTACTCCTTAAAATAAAACACTGTTTCCCTTTGGA ACTA TTTACAAGGATGAAACAACCGTATACCTGAGAAATAACTTGCTCTGGTGTCAA TTCGCTATTCGCCAGCAGACATCAGAACACACCGAGTTTCCAGATGCTGGTTTTTCC CCTTAAATCAGGAAATACACCTGGACAATTTCTAGAAGACAGGCCTCTGTGCCTTCT AGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTG CCACTCCCACTGTCCTTTCCTAAT AAAATGAGGAAATTGCATCGCATTGTCTGAGTA GGTGTCATTCTATTCTGGGGTGGGGTGGGGCAGCAGCAAGGGGGAGGATTGG GAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCA GCTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTC TGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCC GACGCCCGGGC TTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

SEQ ID NO: 53 - CLRN-11NF:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC

- 133 045887

ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGG GGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCG TTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCGTGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGCGTGGGGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGGGGCTT TGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCC GCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGGGGCGAAGCGTG CGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACC AGC CAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTC CATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGG AACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACC TCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGAT TCTGTTCGCCAGCGA AGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACA AAGAGGGCACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACCAGCTTTTGG GTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCG GCTTCCAGTTTCCATTCGCCAAGCAAGGACGCCGAAACCACAAACGTGGCCGCC GATCTGATGTACGGATCCTATCCCTATGATGTGCC AGACTATGCTAAGGGCGAAGGC AGAGGCAGCCTGCTTACATGTGGCGACGTGGAAGAGAACCCCGGACCTATGCAGGC

- 134 045887

TCTGCAGCAGCAGCCAGTGTTCCCCGATCTGCTGAAAGCCATTCCTGTCAGCATCCA TGTCAACGTCATCCTCTTCTCTGCCATCCCTCATTGTCCTCACTATGGTTGGAACGGCC _{TTTTTTATGTATAATGCCTTTGGGAAGCCGTTTGAAACCCTGCACGGACCCCTGGGA} CTCTATCTCCTGAGCTTCATCTCCGGCTCTTGCGGCTGCCTCGTGATGATCCTCTTTG CCTCTGAAGTCAAAATTCACCACCTGTCTGAGAAAATTGCTAATTACAAAGAAGGG ACATACGTTTACAAAACGCAGAGCGAAAGTATACGACCAGCTTCTGGCTGACCAA GGGCCACTCTGGATCCGACTACAAAGACCATGACGGTGATTATAAAGATCATGACA TCGATTACAAGGATGACGATGA CAAGTAAGAGCTCAAGGCAAACCTTTTCTATAATTT TACAAGGGAGTAGACTTGCTTTGGTCACTTTTAGATGTGGTTAATTTTGCATATCCTT TTAGTCTGCATATATTAAAGCATCAGGACCCTTCGTGACAATGTTTACAAATTACGT ACTAAGGATACAGGCTGGAAAGTAAGGGAAGCAGAAGGAAGGCTTTGAAAAGTTG TTTTATCTGGTGGGAAATTGCTTGACCCAGGTAGTCAAA CAGTTGACTAGAATCG ACAAATTGTTACTCCATATATATATATATGTGTGTGTGTGTAAGATGTCTTCCTAT CAAAAAGATATCAAAGGCACATGGAATATATTTTAATAAAAACAAAATAATATCTCT AATATATCCACACATTTGTTGCCAGATTTCAGAAAACTGAGCTGCAATCGCTTTCCT AAAACAGTAGTGTATTAAATGAACATCTATAAAATGTATCAACACACATTTTAAAA AATTTGTTTTAAAG TATACTCTTAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAG CACTTCAGGAGGCCAAGGTGGGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGC CTGGGCAATAAAGTGAGACCCTGTCACTAACAAAATTAAAAAATAAAATAAATATA AAATATAGGCTTTAAAAAAGCATAGTCTTATTAACCATGTCTGTTGGTCAAAATCTG CAAACTCTAAAAGAAGAAAAGAAGGGAAAAAACCAACGTTAG TATTTTTCCTCCCG TGCCTGAGTCCCAATTACATTCACGACAGTACTTTCAATGAACATAATTGTTAGGAC CACTGAGGAATCATGAAAAATGATCTCTGCTTAGTACATTTGATGCAAAATGACTTA TTAGGGGCTGTTTTTCTAGCTATAGTGTCTCGAGTACTAATATGCAATTATGAAAATT ATATTAAATCTGGGATTATGACGGTATCACTGTATCATCTGGTCTTGTTCTGGCTG T CACCAAGCATGACCCAGGTCAACTTTTTTTTTTCCCCTGAATTACCCATCAAATTGATC TGCAGCTGACTAAAGGCCACAGCTGAGCCTGGAACTGACCCTTCCTTCATCCTCAAC CTGCTGTCCTCCAGAAAGCACCAAGGAAAAAGCAGAGAATGACAGCAAACAGATC ACTAGGCCTCTGACCACAGGTGCTGAGTACTCAGCAGCCCTCATATAATAGGTTTGA AAGTACTCCTTAAAATAAAACACT GTTTCCCTTTGGAACTATTTACAAGGATGAAAC AACCGTATACCTGAGAAATAACTTGCTCTGGTGTCAATTCGCTATTCGCCAGCAGAC ATCAGAACACACCGAGTTTCCAGATGCTGGTTTTTCCCCTTAAAATCAGGAAATACAC CTGGACAATTTCTAGAAGACAGGCCTCTGTGCCTTCTAGTTGCCAGCCATCTGTTGTT TGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACT CCCACTGTCCTTTCCT AATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGG GTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGC TGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCT AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTG AGGCC GGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTG AGCGAGCGAGCGCGCAGCTGCCTGCAGG

- 135 045887

SEQ ID NO: 54 - CLRN-12:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCCCTCTCCAGCCTC GGGGCTGTCCGCG GGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTAGGAGATACT TGAAGGCAGTTTGAAAGACTTGTTTTACAGATTCTTAGTCCAAAGATTTCCAATTAG GGAGAAGAAGCAGCAGAAAAGGAGAAAAGCCA AGTATGAGTGATGATGAGGCCTT CATCTACTGACATTTAACCTGGCGAGAACCGTCGATGGTGAAGTTGCCTTTTCAGCT GGGAGCTGTCCGTTCAGCTTCCGTAATAAATGCAGTCAAAGAGGCAGTCCCTTCCCA TTGCTCACAAAGGTCTTGTTTTTGAACCTCGCCCTCACAGAAGCCGTTTCTCATCGCC ACCATGCCTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCA GCTTC

- 136 045887

GCCTGTGCTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACA GTGCTGTGCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAA GTTCATGGGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTG GCCTGGGAGCCAGACCTTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCC CCGTCCATCCACG TGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAA TGGTCGGAACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGC ATGGACCTCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGG TCATGATTCTGTTCGCCAGCGAAGTGAAGATCCACCCTGAGCGAGAAGATCGCC AACTACAAAGAGGGCACCTACGTCTACAAGAC CCAGTCCGAGAAGTACACCACCAG CTTTTGGGTTATCTTCTTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGA CTGGCCGGCTTCCAGTTTCCATTCGCCAAGAGCAAGGACGCCGAAACCACAAACGT GGCCGCCGATCTGATGTACGGATCCTATCCCTATGATGTGCCAGACTATGCTTAAGA GCTCAAGGCAAACCTTCTTAATTTTACAAGGGAGTAGACTTGCTTT GGTCACTTTT AGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCCT TCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAAG CAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGTA GTCAAAGGCAGTTGACTAGAATCGACAAATTGTTACTCCATATATATATATGTGTGT GTGTGTGTG TAAGATGTCTTCCTATCAAAAAGATATCAAAGGCACATGGAATATATT TTAATAAAAACAAATAATATCTCTAATATATATCCACACATTTGTTGCCAGATTTCAGA AAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATTAAATGAACATCTATAAA ATGTATCAACACACATTTTTAAAAAATTTGTTTAAAGTATACTCTTAGGCCAGGCGTG GTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCC AAGGTGGGAAGATCATTTG AGTTCAGGAGTTCGAGTTACAGTCTGGGCAATAAAGTGAGACCCTGTCACTAACAA AATTAAAAAATAAAATAAATATAAAAATATAGGCTTTAAAAAAGCATAGTCTTATTA ACCATGTCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGAAAAGAAGAAAAAACC AACGTTAGGGTATTTTTCCTCCCGTGCCTGAGTCCCAATTACATTCACGACAGTACTT TCAATGA ACATAATTGTTAGGACCACTGAGGAATCATGAAAAATGATCTCTGCTTAG TACATTTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAGCTATAGTGTCTCGAGT ACTAATATGCAATTATGAAAATTATATTAAATCTGGGATTATGACGGTATCACTGTA TCATCTTGGTCTTGTTCTGGCTGTCACCAAGCATGACCCAGGTCAACTTTTTTTTTCC CCTGAATTACCCATCAAATTGATCTGCA GCTGACTAAAGGCCACAGCTGAGCCTGGA ACTGACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAAGCACCAAGGAAAAAGC AGAGAATGACAGCAAACAGATCACTAGGCCTCTGACCACAGGTGCTGAGTACTCAG CAGCCCTCATATAATAGGTTTGAAAGTACTCCTTAAAATAAAACACTGTTTCCCTTT GGAACTATTTACAAGGATGAAACAACCGTATACCTGAGGGAAATAACTTGCTCTTG t GCAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGA

ATTCAGCTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCC CTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGAACGCCC GGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

- 137 045887

SEQ ID NO: 55 - CLRN-13:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCCCTCTCCAGCCTC GGGGCTGTCCGCG GGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCT CTGTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG

- 138 045887

GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCCGGTTCAGCTGCTACTTTCTGGACCCCTTCATGGGCCTGCCTACC GGCGTTCCACATCTGCTGTCTCTGCCTTGCAGCACCAGCTGCAGAAGAGAGCACACC AGCGAGAGAGTGCAAGAGCCTGCCGGCTGTTTTTCTGCCGTGCGGTCTAAACTGCAC GCCGG ACCTGCTGCCGCCACCAGCTTTTCTAGATTCGCCCAGAGCAACCCCAGCGAG CACCCTAGACAGTGTCACAGCCTGCTGTGTCACCCCTACTGTGTGAATCACGGCGGC GATTCTCTGCTGCATGTGCAGTGCTTTTGGAAAACCTTCGGCAGCGACTACAAGGAC CACGACGGCGATTATAAGGATCACGATATCGATTACAAGGACGATGACGACAAGGG CGAAGGCAGAGGCTCCCTGCTGACAT GCGGAGATGTCGAAGAACCCCGGACCTA TGCCTTCTCAGCAGAAAAAGATTATTTTCTGTATGGCTGGGGTGTTCTCCTTCGCTTG CGCCCTGGGTGTTGTTACCGCTCTCGGAACACCACTGTGGATTAAGGCTACCGTCCT GTGTAAAACCGGCGCTCTGCTCGTGAATGCCAGCGGACAAGAACTGGATAAGTTTA TGGGAGAAATGCAATATGGGCTCTTTCACGGCGAGGGTGTT AGACAGTGCGGACTC GGCGCTAGACCCTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTG TCCATCCACGTGAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTC GGAACCGCCTTCTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGA CCTCTGGGCCTGTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGGTCAT A GCGGCTACCCCTACGACGTGCCAGATTATGCATAAGAGCTCA AGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTTTAGAT GTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCCTTCGT GACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAAGCAGA AGGAAGGCTTTGAAAAGTTGTTTTATCTGGGG T CTATAAAATGTATCAACACACATTTTTAAAAAATTTGTTTTAAAGTATACTCTTAGGC CAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTGGGAAG ATCATTTGAGTTCAGGAGTTCGAGTTACAGGCTGATCAGCCTCGACTGTGCCTTCTA GTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGC CACTCCCACTGTCCTTTCC TAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAG GTGTCATTCTATTCTGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGG AAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCAG CTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCT GCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAATC GCCCGACGCCCGGGCT TTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

- 139 045887

SEQ ID NO: 56 - CLRN-14:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAAGGCTGCGTGCGGTGTG TGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCCG GCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCCCTCTCCAGCCTC GGGGCTGTCCGCG GGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCT CTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCCGGTTCAGCTGCTACTTTCTGGACCCCTTCATGGGCCTGCCTACC GGCGTTCCACATCTGCTGTCTCTGCCTTGCAGCACCAGCTG CAGAAGAGAGCACACC

- 140 045887

AGCGAGAGAGTGCAAGAGCCTGCCGGCTGTTTTTCTGCCGTGCGGTCTAAACTGCAC GCCGGACCTGCTGCCGCCACCAGCTTTTCTAGATTCGCCCAGAGCAACCCCAGCGAG CACCCTAGACAGTGTCACAGCCTGCTGTGTCACCCCTACTGTGTGAATCACGGCGGC GATTCCTGCTGCATGTGCAGTGCTTTTGGAAAACCTTCGGCAGCGGCGAAGGCAGA GGCTCCCTG CTGACATGCGGAGATGTCGAAGAGAACCCCGGACCTATGCCTTCTCAG CAGAAAAAGATTATTTTCTGTATGGCTGGGGTGTTCTCCTTCGCTTGCGCCCTGGGT GTTGTTACCGCTCTCGGAACACCACTGTGGATTAAGGCTACCGTCCTGTGTAAAACC GGCGCTCTGCTCGTGAATGCCAGCGGACAAGAACTGGATAAGTTTATGGGAGAAAT GCAATATGGGCTTTCACGGCGAG TGTTAGACAGTGCGGACTCGGCGCTAGAC CCTTCAGATTCAGCTTCTTCCCAGACCTGCTGAAGGCTATCCCCGTGTCCATCCACGT GAACGTGATCCTGTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGGAACCGCCTT CTTCATGTACAACGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACCTCTGGGCCT GTACCTGCTGAGCTTTATCAGCGGCAGCTGTGGCTGCCTGG ATGATTCTGTTCGC CAGCGAAGTGAAGATCCACCACCTGAGCGAGAAGATCGCCAACTACAAAGAGGGC ACCTACGTCTACAAGACCCAGTCCGAGAAGTACACCACAAGCTTTTGGGTTATCTTC TTCTGTTTCTTCGTGCACTTCCTGAACGGCCTGCTGATCAGACTGGCCGGCTTCCAGT TTCCATTCGCCAAGTCCAAGGACGCCGAAACCACAAACGTGGCCGCCGACCTGATG TACTAA GAGCTCAAGGCAAACCTTCTTAATTTTACAAGGGAGTAGACTTGCTTTG GTCACTTTTAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCAT CAGGACCCTTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAG TAAGGGAAGCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTT GACCCAGGTAGTCAAAGGCAGTTGACT AGAATCGACAAATTGTTACTCCATATATAT ATATGTGTGTGTGTGTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATA TCAAAGGCACATGGAATATATTTTTAATAAAAACAAAATAATATCTCTAATATATCCAC ACATTTGTTGCCAGATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGT GTATTAAATGAACATCTATAAAATGTATCAACACACATTTTAAAATTTGTTT AAA GTATACTCTTAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGG CCAAGGTGGGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGgctgatcagcctcgaCTGT GCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTG GAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGT CTG AGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGA GGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTT GAATTCAGCTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACT CCCTCTCTGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGC CCGGGCTTTGCCCGGGGCCTC AGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

SEQ ID NO: 57 - CLRN-15:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG

- 141 045887

TTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTAT GGGACTTTCCTACTTGGCAGTACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCA ATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTT TCT TTTCTGTGGCTGCGTGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGTGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT GCGAGGGGAACAAA GGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCTCGGGGGAGGGGCGC CGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAG CCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTG CTCTGGGAGTTG TGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCCGGTTCAGCTGCTACTTTCTGGACCCCTTCATGGGCCTGCCTACC GGCGTTCCACATCTGCTGTCTC TGCCTTGCAGCACCAGCTGCAGAAGAGAGCACACC AGCGAGAGAGTGCAAGAGCCTGCCGGCTGTTTTTCTGCCGTGCGGTCTAAACTGCAC GCCGGACCTGCTGCCGCCACCAGCTTTTCTAGATTCGCCCAGAGCAACCCCAGCGAG CACCCTAGACAGTGTCACAGCCTGCTGTGTCACCCCTACTGTGTGAATCACGGCGGC GATTCTCTGCTGCATGTGCAGTGCTTTTGGAAAA CCTTCGGCAGCGACTACAAGGAC CACGACGGCGATTATAAGGATCACGATATCGATTACAAGGACGATGACGACAAGTA AGAGCTCAAGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCAC TTTTAGATGTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGA CCCTTCGTGACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAG G GAAGCAGAAGGAAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTTGACCC AGGTAGTCAAAGGCAGTTGACTAGAATCGACAAATTGTTACTCCATATATATATATG TGTGTGTGTGTGTGTGTGTGTGTGTAAGATGTCTTTCCTATCAAAAAGATATCAAA GGCACATGGAATATATTTTAATAAAAACAAATAATATCTCTAATATATCCACACATT TGTTGCCAGATTTCAGAAA ACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATT AAATGAACATCTATAAAATGTATCAACACACATTTTTAAAAAATTTGTTTTAAAGTATA CTCTTAGGCCAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAG GTGGGAAGATCATTTGAGTTCAGGAGTTCGAGTTACAGgctgatcagcctcgaCTGTGCCTTC TAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGT GCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGT AGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTG GGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTC AGCTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCT CTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGG CTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

- 142 045887

SEO ID NO: 58 - CLRN-16:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCT TTTCTGTGGCTGCG TGAAAGCCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGG GAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCC CGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCC GCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGCT

- 143 045887

GCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTG AGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCC GTGCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTC GGGCCGGGGAGGGCT CGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTG TCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGC AGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGC ACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGG GCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCC CTTCTCCCTCTCCAGCCTC GGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTC GGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTC TTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGACCGGTGCCACCATGC CTAGCCAGCAGAAGAAAATCATCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTG TG CTCTGGGAGTTGTGACAGCCCTGGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGT GCAAGACAGGCGCCCTGCTGGTTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATG GGCGAGATGCAGTACGGCCTGTTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGG AGCCAGACCTTTCCGGTTCAGCTGCTACTTTCTGGACCCCTTCATGGGCCTGCCTACC GGCGT TCCACATCTGCTGTCTCTGCCTTGCAGCACCAGCTGCAGAAGAGAGCACACC AGCGAGAGAGTGCAAGAGCCTGCCGGCTGTTTTTCTGCCGTGCGGTCTAAACTGCAC GCCGGACCTGCTGCCGCCACCAGCTTTTCTAGATTCGCCCAGAGCAACCCCAGCGAG CACCCTAGACAGTGTCACAGCCTGCTGTGTCACCCCTACTGTGTGAATCACGGCGGC GATTCCTGCTGCATGTG CAGTGCTTTTGGAAAACCTTCGGCAGCTAAGAGCTCAAG GCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTTTAGATGTG GTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCCTTCGTGAC AATGTTTACAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAAGCAGAAGG AAGGCTTTGAAAAGTTGTTTTATCTGGTGGGAAATTGCTT GACCCAGGTAGTCAAAG GCAGTTGACTAGAATCGACAAATTGTTACTCCATATATATATGTGTGTGTGTGTGTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATATCAAAGGCACATGGAAT ATATTTTAATAAAAACAAAATATATCTCTAATATATCCACACATTTGTTGCCAGATT CAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGTAGTGTATTAAATGAACATCTA TAAAA TGTATCAACACACATTTTTAAAAAATTTGTTTTAAAGTATACTCTTAGGCCAGG CGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTGGGAAGATCA TTTGAGTTCAGGAGTTCGAGTTACAGgctgatcagcctcgaCTGTGCCTTCTAGTTGCCAGCC ATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACT GTCCTTT CCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCT ATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATA GCAGGCATGCTGGGGATGCGGTGGGCTCTATGGAAGCTTGAATTCAGCTGACGTGC CTCGGACCGCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCG CTCGCTCACTGAGGCCGGGCGACCAAAGGTC GCCCGACGCCCGGGCTTTGCCCGGG CGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

SEQ ID NO: 59 - CLRN-17:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCT

- 144 045887

SEQ ID NO: 60 - CLRN-18:

CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGG CGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCC AACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGACATTGATTATTGACTAGTT ATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCG TTACATAACTTACGGT AAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGAC GTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATT ATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG TACATCTACGTATTAG TCATCGCTATTACCATGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCCATCT CCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCG ATGGGGGCGGGGGGGGGGGGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTC CGAAAGTTTCCTTTTATGGCGAGGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAG CGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTagcgcttggtttaatgacggcttgtttctttt ctgtggctgcgtgaaag ccttgaggggctccgggagctagagcctctgctaaccatgttcatgccttcttctttttcctacagctcctgggcaacgtgctggttattgtgctg tctcatcattttggcaaagAGGAGATACTTGAAGGCAGTTTGAAAGACTTGTTTTACAGATTCTT AGTCCAAAGATTTCCAATTAGGGAGAAGAAGCA GCAGAAAAGGAGAAAAGCCAAG TATGAGTGATGATGAGGCCTTCATCTACTGACATTTAACCTGGCGAGAACCGTCGAT GGTGAAGTTGCCTTTTCAGCTGGGAGCTGTCCGTTCAGCTTCCGTAATAAATGCAGT CAAAGAGGCAGTCCCTTCCCATTGCTCACAAAAGGTCTTGTTTTTGAACCTCGCCCTC ACAGAAGCCGTTTCTCATCACCGGTGCCACCATGCCTAGCCAGCAGAAGAAAAT CA TCTTCTGCATGGCCGGCGTGTTCAGCTTCGCCTGTGCTCTGGGAGTTGTGACAGCCCT GGGAACCCCTCTGTGGATCAAAGCCACAGTGCTGTGCAAGACAGGCGCCCTGCTGG TTAATGCCTCTGGCCAAGAGCTGGACAAGTTCATGGGCGAGATGCAGTACGGCCTG TTCCATGGCGAAGGCGTCAGACAGTGTGGCCTGGGAGCCAGACCTTTCAGATTCAG CTTCTTCCCAGACC TGCTGAAGGCTATCCCCGTGTCCATCCACGTGAACGTGATCCT GTTCAGCGCCATCCTGATCGTGCTGACAATGGTCGGAACCGCCTTCTTCATGTACAA CGCCTTCGGCAAGCCCTTCGAGACACTGCATGGACCTCTGGGCCTGTACCTGCTGAG CTTTATCAGCGGCAGCTGTGGCTGCCTGGTCATGATTCTGTTCGCCAGCGAAGTGAA GATCCACCACCTGAGCGAGAAGATC GCCAACTACAAAGAGGGCACCTACGTCTACA AGACCCAGTCCGAGAAGTACACCACCAGCTTTTGGGTTATCTTCTTCTGTTTCTTCGT GCACTTCCTGAACGGCCTGCTGATCAGACTGGCCGGCTTCCAGTTTCCATTCGCCAA

- 145 -

Claims (4)

GAGCAAGGACGCCGAAACCACAAACGTGGCCGCCGATCTGATGTACTAAGAGCTCA AGGCAAACCTTTTCTATAATTTTACAAGGGAGTAGACTTGCTTTGGTCACTTTTAGAT GTGGTTAATTTTGCATATCCTTTTAGTCTGCATATATTAAAGCATCAGGACCCTTCGT GACAATGTTTACAAATTACGTACTAAGGATACAGGCTGGAAAGTAAGGGAAGCAGA AGGAAGGCTTTGAAAAG TTGTTTTATCTGGTGGGAAATTGCTTGACCCAGGTAGTCA AAGGCAGTTGACTAGAATCGACAAATTGTTACTCCATATATATATATGTGTGTGTGT GTGTGTGTGTGTGTGTAAGATGTCTTCCTATCAAAAAGATATCAAAGGCACATGG AATATATTTTTAATAAAAACAAAATATATCTCTAATATATCCACACATTTGTTGCCAG ATTTCAGAAAACTGAGCTGCAATCGCTTTCCTAAAACAGTA GTGTATTAAATGAACA TCTATAAAATGTATCAACACACATTTTAAAAAAATTTGTTTAAAGTATACTCTTAGGC CAGGCGTGGTGACTCACACCTGTAATTCCAGCACTTCAGGAGGCCAAGGTGGGAAG ATCATTTGAGTTCAGGAGTTCGAGTTACAGCCTGGGCAATAAAGTGAGACCCTGTCA CTAACAAAATTAAAAAATAAAATAAATATAAAATATAGGCTTTAAAAAAGCATAGT CTTATTAACCAT GTCTGTTGGTCAAAATCTGCAAACTCTAAAAGAAGAAAAGAAGA AAAAACCAACGTTAGGGTATTTTTCCTCCCGTGCCTGAGTCCCAATTACATTCACGA CAGTACTTTCAATGAACATAATTGTTAGGACCACTGAGGAATCATGAAAAATGATCT CTGCTTAGTACATTTGATGCAAAATGACTTATTAGGGGCTGTTTTTCTAGCTATAGTG TCTCGAGTACTAATATGCAATTATGAAAATTATATT AAATCTGGGATTATGACGGTA TCACTGTATCATCTTGGTCTTGTTCTGGCTGTCACCAAGCATGACCCAGGTCAACTTT _{TTTTTTCCCCTGAATTACCCATCAAATTGATCTGCAGCTGACTAAAGGCCACAGCTG} AGCCTGGAACTGACCCTTCCTTCATCCTCAACCTGCTGTCCTCCAGAAAGCACCAAG GAAAAAGCAGAGAATGACAGCAAACAGATCACTAGGCCTCTGACCACAGGTGCTGA GTACTCAGCAGCCCTCATATAATAGGTTTGAAAGTACTCCTTAAAATAAAACACTGT TTCCCTTTGGAACTATTTACAAGGATGAAACAACCGTATACCTGAGAAAATAACTTGC TCTGGTGTCAATTCGCTATTCGCC AGCAGACATCAGAACACACCGAGTTTCCAGATG CTGGTTTTTCCCCTAAATCAGGAAATACACCTGGACAATTTCTAGAAGACTACAAT TCAGTCTAGCCACAAAGGGGATTTTTTTTTTTTGGTAACAGGCTAGAGCCCGGTTCT GTAAGTCTTTAGCTGAAATGGTCCAGTACAAAAGCACTGGAAATGAGTGGGCTAGG AGGACAAGCACGTCTCCTGCGTGAGGAGTTGGTTGGA GGTCCCCAAGGCCAGGTA CCCCCTGCACTCTTATTGGATTCCTCTCTGTCTTCTTGGAGTTTTGAAAAACTCCTTC GAACACCAGGCTTTTTTCTTTAGAAAACAAGTCTCCAATCGTTCTCTGTTCCGTAGA AAGAGAAAGAAAACCTGGAGCAGCTGCTGAAAAATCTAATGAGGAACTAAGAGGC AAACCCACCACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGT GC CTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAA TTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGTGGGGTGGGGCAGG ACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGG CTCTATGGAAGCTTGAATTCAGCTGACGTGCCTCGGACCGCTAGGAACCCCTAGTGA TGGAGTTGGCCACTCCCT CTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAA AGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGC AGCTGCCTGCAGG CLAIM 1. A composition for increasing the expression of CLRN 1 protein isoform 1 in a mammalian cell, comprising a single AAV-based nucleic acid vector, where the vector contains: (i) 5'-ITR (ii) cytomegalovirus (CMV) enhancer; (iii) chicken β-actin (CBA) promoter; (iv) a chimeric intron containing the sequence SEQ ID NO: 16; (v) 5' (untranslated regions) UTR; (vi) a coding sequence encoding the CLRN1 protein isoform of SEQ ID NO: 3, wherein the coding sequence comprises a nucleotide sequence spanning two consecutive exons of the CLRN 1 genomic DNA and lacking the intronic sequence between the two consecutive exons; (vii) 3'-UTR; (viii) a polyadenylation signal sequence and (ix) a 3'-ITR. 2. The composition according to claim 1, wherein the CMV enhancer contains the sequence SEQ ID NO: 17. 3. The composition according to claim 1 or 2, wherein the CBA promoter contains at least 80 contiguous nucleotides from SEQ ID NO: 18. 4. The composition according to any one of claims 1-3, where the 5'-UTR contains at least 10 adjacent nucleotides - 146 -