Adeno-associated virus vectors

Abstract

This disclosure relates to AAV vectors. For example, AAV vectors comprising an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence, such AAV capsid polypeptides, nucleic acid molecules encoding such vectors, nucleic acid molecules encoding such AAV capsid polypeptides, host cells containing and / or expressing such nucleic acid molecules, and methods and materials for making or using such vectors and / or AAV capsid polypeptides are provided.

Description

Attorney Docket No.: AVI-006WOADENO-ASSOCIATED VIRUS VECTORSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U. S. Provisional Patent Application No. 63 / 761,801, filed February 21, 2025, and U. S. Provisional Patent Application No. 63 / 761,780, filed February 21, 2025, the contents of each of which are hereby incorporated by reference in their entireties for all purposes.SEQUENCE LISTING

[0002] This application contains a Sequence Listing XML, which has been submitted electronically and is hereby incorporated by reference in its entirety. The XML copy of the Sequence Listing, created on February 11, 2026, is named AVI-006WO_SL.xml and is 279,010 bytes in size.TECHNICAL FIELD

[0003] This disclosure relates to adeno-associated virus (AAV) vectors. For example, this disclosure provides methods and materials for making and using AAV vectors having the ability to deliver nucleic acid to retinal cells.BACKGROUND

[0004] Viral vectors, such as AAV vectors, are efficient vehicles for in vivo nucleic acid delivery, and their use in the clinic is expanding. Improved AAV vectors and AAV production techniques for making effective AAV vector preparations should further expand the use of AAV vectors in the laboratory and clinic.SUMMARY

[0005] The present disclosure provides AAV vectors (e.g., AAV8 vectors, AAV9 vectors, AAVrhlO vectors, etc.). In one aspect, provided herein is an adeno-associated virus (AAV) vector comprising an AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162. In another aspect, provided herein is an adeno-associated virus (AAV) vector comprising an AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 5 (RATGKV).

[0006] In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that an amino acid sequencePage 1 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcomprising any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acids corresponding to positions 582 and 583, between amino acid positions corresponding to positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

[0007] In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located at an amino acid position corresponding to an position between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In certain embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 1. In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids corresponding to position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-94. In certain embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from positions corresponding to positions 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9.

[0008] In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In certain embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of Page 2 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOSEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109. In certain embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from positions corresponding to positions 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9.

[0009] In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In certain embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162. In certain embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9.

[0010] In some embodiments, the AAV vector is an AAV2 vector. In some embodiments, the AAV vector is an AAV8 vector. In some embodiments, the AAV vector is an AAV9 vector. In some embodiments, the AAV vector is an AAVrhlO vector. In some embodiments, the AAV vector further comprises an exogenous nucleic acid encoding an RNA or a therapeutic polypeptide. In some embodiments, the exogenous nucleic acid encodes an RNA. In some embodiments, the RNA comprises an siRNA or microRNA. In some embodiments, the exogenous nucleic acid encodes a therapeutic polypeptide. In some embodiments, the therapeutic polypeptide is a VEGF polypeptide, a RS 1 polypeptide, a PRPF31 polypeptide, an ABCA4 polypeptide, a CRB 1 polypeptide, an NPHP5 polypeptide, or an NR2E3 polypeptide.Page 3 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO

[0011] In some embodiments, AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 4 except that the amino acid sequence of any one of SEQ ID NOs: 20-162 is located between amino acid positions corresponding to positions 587 and 588 of SEQ ID NO: 4. In some embodiments, AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17. In certain embodiments, AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17. In some embodiments, AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 95-109 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18. In certain embodiments, AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18. In some embodiments, AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19. In certain embodiments, AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19.

[0012] Also disclosed herein is one aspect, is an AAV capsid polypeptide having an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162. In another aspect the disclosure provides an AAV capsid polypeptide having an amino acid sequence comprising any one of SEQ ID NOs: 5-9. In some embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid Page 4 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOpositions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In certain embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

[0013] In some embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94. In some embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9. In an embodiment, the polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17. In some embodiments, the polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17.

[0014] In some embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or Page 5 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO95-109. In certain embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9. In an embodiment, the polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18. In an embodiment, the polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18.

[0015] In some embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162. In certain embodiments, the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9. In an embodiment, the polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19. In some embodiments, the polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19.

[0016] In another aspect, the present disclosure provides one or more nucleic acid molecules encoding an AAV vector. In some embodiments, the one or more nucleic acid molecules encode a capsid polypeptide. In some embodiments, the nucleic acid molecule comprises a DNA.

[0017] In yet another aspect, the present disclosure provides a host cell comprising a nucleic acid molecule. In some embodiments, the host cell comprises a capsid polypeptide. In some embodiments, the host cell comprises a vector. In some embodiments, the host cell expressesPage 6 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOany of AAV vectors disclosed herein. In some embodiments, the host cell expresses any of the polypeptides disclosed herein. In some embodiments, the host cell is a retinal cell.

[0018] In another aspect, the present disclosure provides a composition comprising an AAV vector comprising an AAV capsid polypeptide and a pharmaceutically acceptable excipient. The composition can comprise from about 1 x 107to about 1 x 1014of the AAV vector. In some embodiments, the composition can comprise phosphate buffered saline, Hank's Balanced Salt Solution (e.g., a buffer comprising salts such as sodium chloride, potassium chloride, calcium chloride, magnesium sulfate, magnesium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate, and / or glucose), or Pluronic F68.

[0019] In another aspect, the present disclosure provides a method for delivering an exogenous nucleic acid sequence to a retinal cell of a mammal, wherein the method comprises contacting the retinal cell with an AAV vector comprising an AAV capsid polypeptide and the exogenous nucleic acid sequence, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162, wherein the AAV vector infects the retinal cell, thereby delivering the exogenous nucleic acid sequence to the retinal cell. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino Page 7 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOacids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162.

[0020] In some embodiments, the mammal is a human. In some embodiments, the human is juvenile (e.g., an infant, a child, an adolescent, a teenager) or an adult. In some embodiments, the vector is an AAV2 vector. In some embodiments, the vector is an AAV8 vector. In some embodiments, the AAV vector is an AAV9 vector. In some embodiments, the AAV vector is an AAVrhlO vector. In some embodiments, the exogenous nucleic acid sequence encodes an RNA or a polypeptide. In some embodiments, the exogenous nucleic acid encodes an RNA (e.g., therapeutic). In some embodiments, the RNA is an siRNA or microRNA. In some embodiments, the exogenous nucleic acid encodes a polypeptide (e.g., therapeutic). In some embodiments, the polypeptide is a VEGF polypeptide, a RSI polypeptide, a PRPF31 polypeptide, an ABCA4 polypeptide, a CRB1 polypeptide, an NPHP5 polypeptide, or an NR2E3 polypeptide. In some embodiments, the method comprises intravitreally administering a composition comprising the vector to the mammal, thereby contacting the retinal cell with the vector. In some embodiments, the composition comprises from about 1 x 107to about 1 x 1014of the vector.

[0021] In another aspect, the present disclosure provides a method for treating a retinal condition. In some embodiments, the present disclosure provides a method for treating a retinal condition in a mammal in need thereof, wherein the method comprises contacting a retinal cell of a mammal having the retinal condition with a therapeutically effective amount of an AAV vector comprising an AAV capsid polypeptide and an exogenous nucleic acid sequence, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162, wherein the AAV vector infects the retinal cell and drive expression of the exogenous nucleic acid sequence within the retinal cell, thereby treating the retinal condition. In certain embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9. In some embodiments, the contacting comprises a population of retinal cells. In some embodiments, the method comprises contacting the retinal cells of a mammal having the retinal condition with AAV vectors comprising an AAV capsid polypeptide and an exogenous nucleic acid sequence disclosed herein, wherein the AAV vectors infect the retinal cells and drive expression of the exogenous nucleic acid sequence within the retinal cells, thereby treating the retinal condition. In some embodiments, the mammal is a human. In some embodiments, the human is juvenile (e.g., an infant, a child, an adolescent, a teenager) or an adult. In some embodiments, the retinal condition is selected from the group consisting of cone dystrophy, cone / rod dystrophy, retinitis pigmentosa, macular Page 8 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOdegeneration, achromatopsia, blue cone monochromacy, and color blindness. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94. In some embodiments, the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109. In some embodiments, the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18. In some embodiments, the capsid polypeptide has an amino acid sequence Page 9 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcomprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162. In some embodiments, the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19. In some embodiments, the vector is an AAV2 vector. In some embodiments, the vector is an AAV8 vector. In some embodiments, the AAV vector is an AAV9 vector. In some embodiments, the AAV vector is an AAVrhlO vector. In some embodiments, the exogenous nucleic acid sequence encodes an RNA or a polypeptide. In some embodiments, the RNA is an siRNA or a microRNA. In some embodiments, the polypeptide is a VEGF polypeptide, a RSI polypeptide, a PRPF31 polypeptide, an ABCA4 polypeptide, a CRB 1 polypeptide, an NPHP5 polypeptide, or an NR2E3 polypeptide. In some embodiments, the method comprises intravitreally administering a composition comprising the vector to the mammal, thereby contacting the retinal cell with the vector. In some embodiments, the composition comprises from about 1 x 107to about 1 x 1014of the vectors.

[0022] In another aspect, provided herein is a non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 581 and 582, between amino acid positions corresponding to positions 582 and 583, between amino acid positions corresponding to positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:Page 10 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO-Li-[6-mer or 8-mer polypeptide] -L2-,wherein the Li and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 6-mer or 8-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162.

[0023] In another aspect, the present disclosure provides a recombinant AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 581 and 582, between amino acid positions corresponding to positions 582 and 583, between amino acid positions corresponding to positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-Li-[6-mer or 8-mer polypeptide] -L2-,wherein the Li and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 6-mer or 8-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162.

[0024] In another aspect, the present disclosure provides a non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94.Page 11 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO

[0025] In another aspect, the present disclosure provides a non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the L1 and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 94-109.

[0026] In another aspect, the present disclosure provides a non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162.

[0027] In some embodiments, the Li is one amino acid Xi. In some embodiments, Li is two amino acids X2-X1. In some embodiments, Li is three amino acids X3-X2-X1.

[0028] In some embodiments, the Xi is selected from the group of amino acid residues consisting of A, V, I, and L. In some embodiments, Xi is A. In some embodiments, X2 is selected from the group of amino acid residues consisting of A, V, I, and L. In some embodiments, X2 is L. In some embodiments, X2-X1 is LA. In some embodiments, X3 is selected from the group of amino acid residues consisting of A, V, I, and L. In some embodiments, Li is absent. In some embodiments, L2 is one amino acid Zi. In some embodiments, L2 is two amino acids Z1-Z2. In some embodiments, L2 is three amino acids Zi-Z2-Z3. In some embodiments, Zi is selected from the group of amino acid residues consisting of A, V, I, and L. In some embodiments, Zi is A. In some embodiments, Z2 is selected from the group of amino acid residues consisting of A, V, I, and L. In some embodiments, Z2 is L. In some embodiments, Z1-Z2 is AL. In some embodiments, Z3 is selected from the group of amino acid residues consisting of A, V, I, and L. In some embodiments, L2 is absent.

[0029] In another aspect, the present disclosure provides a non-naturally occurring adeno-associated virus (AAV) vector comprising any AAV capsid polypeptide disclosed herein. In Page 12 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOanother aspect, the present disclosure provides a recombinant adeno-associated virus (AAV) vector comprising any AAV capsid polypeptide disclosed herein.

[0030] In yet another aspect, the present disclosure provides a viral particle comprising any capsid polypeptide disclosed herein.

[0031] In another aspect, the present disclosure provides a method for administering an exogenous nucleic acid sequence to a mammal in need thereof, wherein the method comprises administering an effective amount of a AAV vector disclosed herein to the mammal, wherein the vector comprising the exogenous nucleic acid sequence. In some embodiments, the mammal is a human. In some embodiments, the human is an infant, a child, or an adult. In some embodiments, administering comprises administering the effective amount to an eye of the mammal. In some embodiments, administering is sufficient to allow for expression of the exogenous nucleic acid sequence in a cell of the mammal. In some embodiments, exogenous nucleic acid sequence encodes a therapeutic polypeptide.

[0032] In another aspect, the present disclosure provides a method of treating a retinal disorder in a patient in need thereof, comprising administering to the patient’s eye an effective amount of an AAV vector, wherein the AAV vector comprises an AAV capsid polypeptide and an exogenous nucleic acid sequence, wherein the AAV capsid polypeptide is represented by Formula A.

[0033] In another aspect, the disclosure provides A method of treating a retinal disorder in a patient in need thereof, comprising administering to the patient’s eye an effective amount of an AAV vector, wherein the AAV vector comprises an AAV capsid polypeptide and an exogenous nucleic acid sequence, wherein the AAV capsid polypeptide comprises an amino acid sequence insert of Formula A, wherein the Formula A is: -Ll-[6-mer polypeptide] -L2-, wherein the LI and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 6-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162. In certain embodiments, the 6-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

[0034] In some cases, an AAV vector (e.g., an AAV2 vector, an AAV8 vector, an AAV9 vector, or an AAVrhlO vector) provided herein having an AAV capsid polypeptide that comprises an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can be used in place of the 7m8 AAV2 vector (Dalkara et al., Sci. Transl. Med., 5(189):189ra76 (2013) and Bennett et al.. J. Struct. Biol., 209(2): 107433 (2020)) or in place of the K912 AAV2 vector (Oztiirk et al., eLife, 10:e64175 (2021)) to deliver nucleic acid to retinal cells. In some cases, an AAV vector Page 13 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO(e.g., an AAV8 vector) provided herein having an AAV capsid polypeptide that comprises an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 (or a variant thereof) or according to Formula A based on such a set forth sequence can be used in place of a parental serotype AAV8 to deliver nucleic acid to retinal cells. In some cases, an AAV vector e.g., an AAV9 vector) provided herein having an AAV capsid polypeptide that comprises an amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 (or a variant thereof) or according to Formula A based on such a set forth sequence can be used in place of a parental serotype AAV9 to deliver nucleic acid to retinal cells. In some cases, an AAV vector e.g., an AAVrhlO vector) provided herein having an AAV capsid polypeptide that comprises an amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can be used in place of a parental serotype AAVrhlO to deliver nucleic acid to retinal cells.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used to practice any inventio provided herein, suitable methods and methods are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0036] The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Other features, objects, and advantages of any invention disclosed herein will be apparent from the description and from the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The disclosure can be more completely understood with reference to the following figures.

[0038] FIG. 1A shows a schematic of an exemplary AAV vector that comprises a wild type AAV2 Rep polypeptide and an AAV8 capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 20-94 or a sequence of Formula A) located between positions corresponding to positions 590 and 591 of SEQ ID NO: 17. FIG. IB shows a schematic of an exemplary AAV vector that comprises a mutant AAV2 Rep polypeptide (AAV2-M1T-REP) and an AAV8 capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 20-94 or a sequence of Formula A) locatedPage 14 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WObetween positions corresponding to positions 590 and 591 of SEQ ID NO: 17. FIG. 1C shows a schematic of an exemplary AAV vector that comprises a wild type AAV2 Rep polypeptide and an AAV8 capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 20-94 or a sequence of Formula A) as a replacement of amino acid residues at positions corresponding to positions 588 to 593 of SEQ ID NO: 17. FIG. ID shows a schematic of an exemplary AAV vector that comprises a mutant AAV2 Rep polypeptide (AAV2-M1T-REP) and an AAV8 capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 20-94 or a sequence of Formula A) as a replacement of amino acid residues at positions corresponding to positions 588 to 593 of SEQ ID NO: 17.

[0039] FIG. 2A shows a schematic of an AAV vector that comprise a wild type AAV2 Rep polypeptide and an AAV9 capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 95-109 or a sequence of Formula A) located between positions corresponding to positions 588 and 589 of SEQ ID NO: 18. FIG. 2B shows a schematic of an AAV vector that comprise a mutant AAV2 Rep polypeptide (AAV2-M1T-REP) and an AAV9 capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 95-109 or a sequence of Formula A) located between positions corresponding to positions 588 and 589 of SEQ ID NO: 18. FIG. 2C shows a schematic of an AAV vector that comprise a wild type AAV2 Rep polypeptide and an AAV9 capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 95-109 or a sequence of Formula A) as a replacement of amino acid residues at positions corresponding to 586 to 591 of SEQ ID NO: 18. FIG. 2D shows a schematic of an AAV vector that comprise a mutant AAV2 Rep polypeptide (AAV2-M1T-REP) and an AAV9 capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 95-109 or a sequence of Formula A) as a replacement of amino acid residues at positions corresponding to positions 586 to 591 of SEQ ID NO: 18.

[0040] FIG. 3A shows a schematic of an AAV vector that comprise a wild type AAV2 Rep polypeptide and an AAVrhlO capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 110-162 or a sequence of Formula A) located between positions corresponding to 590 and 591 of SEQ ID NO: 19. FIG. 3B shows a schematic of an AAV vector that comprise a mutant AAV2 Rep polypeptide (AAV2-M1T-REP) and an AAVrhlO capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 110-162 or a sequence of Formula A) located between positions corresponding to positions 590 and 591 of SEQ ID NO: 1. FIG. 3C shows a schematic of an AAV vector Page 15 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOthat comprise a wild type AAV2 Rep polypeptide and an AAVrhIO capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 110-162 or a sequence of Formula A) as a replacement of amino acid residues at positions corresponding to positions 588 to 593 of SEQ ID NO: 19. FIG. 3D shows a schematic of an AAV vector that comprise a mutant AAV2 Rep polypeptide (AAV2-M1T-REP) and an AAVrhIO capsid polypeptide engineered to comprise an insert sequence (e.g., any one of SEQ ID NOs: 5-9 or 110-162 or a sequence of Formula A) as a replacement of amino acid residues at positions corresponding to 588 to 593 of SEQ ID NO: 19.DETAILED DESCRIPTION

[0041] The present disclosure provides AAV vectors (e.g., AAV2 vectors, AAV8 vectors, AAV9 vectors, or AAVrhIO vectors). For example, the disclosure provides AAV vectors (e.g., AAV2 vectors, AAV8 vectors, AAV9 vectors, or AAVrhIO vectors) comprising a capsid polypeptide that comprises an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A. Any appropriate AAV vector can be designed to include a capsid polypeptide described herein e.g., a capsid polypeptide that comprises an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A. For example, AAV2, AAV8, AAV9, and AAVrhIO can be designed to include a capsid polypeptide that comprises an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A.

[0042] Any appropriate AAV capsid polypeptide can be designed to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A. For example, AAV2, AAV6, AAV8, AAV9, and AAVrhIO capsid polypeptides can be designed to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A. In some embodiments, an AAV2 capsid polypeptide can be designed to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A. In some embodiments, an AAV8 capsid polypeptide can be designed to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-94 (or a variant thereof) or according to Formula A. In certain embodiments, an AAV8 capsid polypeptide can be designed to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9. In some embodiments, an AAV9 capsid polypeptide can be designed to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 95-109 (or a variant thereof) or according to Formula A. In some embodiments, an AAVrhIO capsid polypeptide can be designed to include an amino acidPage 16 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOsequence selected from any one of SEQ ID NOs: 5-9 or 110-162 (or a variant thereof) or according to Formula A. Table 1 provides amino acid sequences of exemplary AAV2, AAV8, AAV9, and AAVrhlO capsid polypeptides that can be designed to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A.Table 1: Amino Acid Sequences of Exemplary Capsid Polypeptides.SEQ ID Amino Acid SequenceNO:1 MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGY KYLGPFNGLDKGEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAE FQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSP VEPDSSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTN TMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTSTRTWALP TYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLIN NNWGFRPKRLNFKLFN1QVKEVTQNDGTTT1ANNLTSTVQVFTDSEYQLPY VLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQML RTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTT TQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGAT KYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNVDIEKV MITDEEEIRTTNPVATEOYGSVSTNLQRGNROAATADVNTOGVLPGMVWO DRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTT FSAAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDF TVDTNGVYSEPRPIGTRYLTRNLThe two bold amino acid residues (“NR”) in the amino acid sequence denote positions 587 and 588, respectively, and the underlined amino acids (“RGNRQA” (SEQ ID NO: 311)) denote positions 585 to 590.2 MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGY KYLGPFNGLDKGEPVNAADAAALEHDKAYDRQLDSGDNPYLKYNHADAE FQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSP VEPDSSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTN TMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTSTRTWALP TYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLIN NNWGFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPY VLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQML RTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTT TQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGAT KYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNVDIEKV MITDEEEIRTTNPVATEOYGSVSTNLQRGNROAATADVNTOGVLPGMVWO DRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTT FSAAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDF TVDTNGVYSEPRPIGTRYLTRNLThe two bold amino acid residues (“NR”) in the amino acid sequence denotepositions 587 and 588, respectively, and the underlined amino acids (“RGNRQA”Page 17 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO(SEQ ID NO: 311)) denote positions 585 to 590. Bolded, italicized, and underlined amino acid residue denote amino acid substitution (E67A) relative to wild-type. 3 MAADGYEPDWLEDTESEG1RQWWKLKPGPPPPKPAERHKDDSRGLVEPGY KYLGPFNGLDKGEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAE FQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSP VEPDSSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTN TMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTSTRTWALP TYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLIN NNWGFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPY VLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQML RTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTT TQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGAT KYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNVDIEKV MITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTOGVLPGMVWO DRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTT FSAAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKS7NVDF TVDTNGVYSEPRPIGTRYLTRNLThe two bold amino acid residues (“NR”) in the amino acid sequence denote positions 587 and 588, respectively, and the underlined amino acids (“RGNRQA” (SEQ ID NO: 311)) denote positions 585 to 590. Bolded, italicized, and underlined amino acid residue denote amino acid substitution (V708I) relative to wild-type.4 MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGY KYLGPFNGLDKGEPVNAADAAALEHDKAYDRQLDSGDNPYLKYNHADAE FQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSP VEPDSSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTN TMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTSTRTWALP TYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLIN NNWGFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPY VLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQML RTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTT TQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGAT KYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNVDIEKV MITDEEEIRTTNPVATEOYGSVSTNLORGNROAATADVNTOGVLPGMVWO DRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTT FSAAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKS7NVDF TVDTNGVYSEPRPIGTRYLTRNLThe two bold amino acid residues (“NR”) in the amino acid sequence denote positions 587 and 588, respectively, and the underlined amino acids (“RGNRQA” (SEQ ID NO: 311) denote positions 585 to 590. Bolded, italicized, and underlined amino acid residues denote amino acid substitutions (E67A and V708I) relative to wild-type.17 MAADGYLPDWLEDNLSEGIREWWALKPGAPKPKANQQKQDDGRGLVLPG YKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADA EFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPS PQRSPDSSTGIGKKGQQPARKRLNFGQTGDSESVPDPQPLGEPPAAPSGVGP NTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWAL PTYNNHLYKQISNGTSGGATNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLSFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPage 18 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQ MLRTGNNFQFTYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQTTG GTANTQTLGFSQGGPNTMANQAKNWLPGPCYRQQRVSTTTGQNNNSNFA WTAGTKYHLNGRNSLANPGIAMATHKDDEERFFPSNGILIFGKQNAARDNA DYSDVMLTSEEEIKTTNPVATEEYGIVADNLQQQNTAPQIGTVNSQGALPG MVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVP ADPPTTFNQSKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYK STSVDFAVNTEGVYSEPRPIGTRYLTRNLThe two bold amino acid residues (“NT”) in the amino acid sequence denote positions 590 and 591, respectively, and the underlined amino acids (“QQNTAP” (SEQ ID NO: 312)) denote positions 588 to 59318 MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPG YKYLGPGNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHAD AEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQ SPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSL TMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITTSTRTWALP TYNNHLYKQ1SNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRE INNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQL PYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQM LRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQ NQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGA SSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGOVATNHOSAOAOAQTGWVONOGILPGMV WQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPAD PPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSN NVEFAVNTEGVYSEPRPIGTRYLTRNLThe two bold amino acid residues (“QA”) in the amino acid sequence denote positions 588 and 589, respectively, and the underlined amino acids (“SAQAQA” (SEQ ID NO: 313)) denote positions 586 to 59119 MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPG YKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADA EFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPS PQRSPDSSTGIGKKGQQPAKKRLNFGQTGDSESVPDPQPIGEPPAGPSGLGSG TMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALP TYNNHLYKQISNGTSGGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRL INNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLP YVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQM LRTGNNFEFSYQFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGT AGTQQLLFSQAGPNNMSAQAKNWLPGPCYRQQRVSTTLSQNNNSNFAWT GATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKDNV DYSSVMLTSEEEIKTTNPVATEOYGVVADNLQOONAAPIVGAVNSOGALPG MVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVP ADPPTTFSQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYK STNVDFAVNTDGTYSEPRPIGTRYLTRNLThe two bold amino acid residues (NA) in the amino acid sequence denote positions 590 and 591, respectively, and the underlined amino acids (“QQNAAP” (SEQ IDNO: 314)) denote positions 588 to 593.Page 19 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO

[0043] In some embodiments, an AAV capsid polypeptide (e.g., an AAV2 capsid polypeptide, an AAV8 capsid polypeptide, an AAV9 capsid polypeptide, or an AAVrhlO capsid polypeptide) comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in Table 1 and can be designed to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or Formula A.

[0044] In some embodiments, AAV capsid polypeptide sequences contemplated herein can comprise modifications or mutations in SEQ ID NO: 1. In some embodiments, the AAV capsid polypeptide sequence of the present disclosure comprises a E67A substitution (SEQ ID NO: 2 in Table 1). In some embodiments, the AAV capsid polypeptide sequence of the present disclosure comprises a V708I substitution (SEQ ID NO: 3 in Table 1). In some embodiments, the AAV capsid polypeptide sequence of the present disclosure comprises both E67A and V708I substitutions (SEQ ID NO: 4 in Table 1).

[0045] In some embodiments, AAV capsid polypeptide sequences contemplated herein can comprise an AAV8 capsid polypeptide (SEQ ID NO: 17 in Table 1). In some embodiments, the AAV8 capsid polypeptide sequences contemplated herein can comprise modifications or mutations in SEQ ID NO: 17. In some embodiments, AAV capsid polypeptide sequences contemplated herein can comprise a AAV9 capsid polypeptide (SEQ ID NO: 18 in Table 1). In some embodiments, the AAV9 capsid polypeptide sequences contemplated herein can comprise modifications or mutations in SEQ ID NO: 18. In some embodiments, AAV capsid polypeptide sequences contemplated herein can comprise a AAVrhlO capsid polypeptide (SEQ ID NO: 19 in Table 1). In some embodiments, the AAVrhlO capsid polypeptide sequences contemplated herein can comprise modifications or mutations in SEQ ID NO: 19.

[0046] When designing an AAV capsid polypeptide (e.g., an exemplary capsid polypeptide listed in Table 1) to include an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A, that included amino acid sequence can be located at any appropriate location along the AAV capsid polypeptide (e.g., the AAV2 capsid polypeptide, an AAV8 capsid polypeptide, an AAV9 capsid polypeptide, or an AAVrhlO capsid polypeptide). For example, an amino acid sequence selected from any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A can be located between the naturally-occurring amino acid residues corresponding to position 585 to 590 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAV2 capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and Page 20 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAV8 capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAV9 capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino Page 21 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOacid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, the AAVrhlO capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

[0047] In some embodiments, the AAV8 capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of SEQ ID NO: 17. In certain embodiments, the AAV8 capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17, except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acids corresponding to positions 590 and 591.

[0048] In some embodiments, the AAV9 capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to Page 22 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOpositions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of SEQ ID NO: 18.

[0049] In some embodiments, the AAVrhlO capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of SEQ ID NO: 19.

[0050] In some embodiments, the present disclosure provides an AAV vector (e.g., AAV2) that comprises an AAV Rep coding sequence e.g., AAV2 Rep 78 and AAV2 Rep 68 polypeptides) and an AAV Cap coding sequence. In some embodiments, the present disclosure provides an AAV vector (e.g., AAV2) that comprises a variant AAV Rep coding sequence. In some embodiments, the AAV Rep polypeptide has an ACG start codon encoding an AAV2 Rep comprising a substitution of methionine to threonine at position 1 (“MIT”). Table 2 provides exemplary AAV Rep polypeptide sequences.Table 2: Exemplary AAV Rep polypeptide sequences.SEQ ID Amino Acid SequenceNO:SEQ ID MPGFYEIVIKVPSDLDGHLPGISDSFVNWVAEKEWELPPDSDMDLNLIEQAP NO: 10 LTVAEKLQRDFLTEWRRVSKAPEALFFVQFEKGESYFHMHVLVETTGVKS MVLGRFLSQIREKLIQRIYRGIEPTLPNWFAVTKTRNGAGGGNKVVDECYIP NYLLPKTQPELQWAWTNMEQYLSACLNLTERKRLVAQHLTHVSQTQEQN KENQNPNSDAPVIRSKTSARYMELVGWLVDKGITSEKQWTQEDQASYISFN AASNSRSQIKAALDNAGKIMSLTKTAPDYLVGQQPVEDISSNRIYKILELNGYDPQYAASVFLGWATKKFGKRNTIWLFGPATTGKTNIAEAIAHTVPFYGCV Page 23 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WONWTNENFPFNDCVDKMVIWWEEGKMTAKVVESAKAILGGSKVRVDQKCK SSAQIDPTPVIVTSNTNMCAVIDGNSTTFEHQQPLQDRMFKFELTRRLDHDF GKVTKQEVKDFFRWAKDHVVEVEHEFYVKKGGAKKRPAPSDADISEPKRV RESVAQPSTSDAEASINYADRLARGHSLRep 68 amino acid sequence (wild-type)SEQ ID TPGFYEIVIKVPSDLDGHLPGISDSFVNWVAEKEWELPPDSDMDLNLIEQAP NO: 11 LTVAEKLQRDFLTEWRRVSKAPEALFFVQFEKGESYFHMHVLVETTGVKS MVLGRFLSQIREKLIQRIYRGIEPTLPNWFAVTKTRNGAGGGNKVVDECYIP NYLLPKTQPELQWAWTNMEQYLSACLNLTERKRLVAQHLTHVSQTQEQN KENQNPNSDAPVIRSKTSARYMELVGWLVDKGITSEKQWIQEDQASYISFN AASNSRSQIKAALDNAGKIMSLTKTAPDYLVGQQPVEDISSNRIYKILELNG YDPQYAASVFLGWATKKFGKRNTIWLFGPATTGKTNIAEAIAHTVPFYGCV NWTNENFPFNDCVDKMVIWWEEGKMTAKVVESAKAILGGSKVRVDQKCK SSAQIDPTPVIVTSNTNMCAVIDGNSTTFEHQQPLQDRMFKFELTRRLDHDF GKVTKQEVKDFFRWAKDHVVEVEHEFYVKKGGAKKRPAPSDADISEPKRV RESVAQPSTSDAEASINYADRLARGHSLRep 68 amino acid sequence (MIT)SEQ ID TPGFYEIVIKVPSDLDEHLPGISDSFVNWVAEKEWELPPDSDMDLNLIEQAPL NO: 12 TVAEKLQRDFLTEWRRVSKAPEALFFVQFEKGESYFHMHVLVETTGVKSM VLGRFLSQIREKLIQRIYRGIEPTLPNWFAVTKTRNGAGGGNKVVDECYIPN YLLPKTQPELQWAWTNMEQYLSACLNLTERKRLVAQHLTHVSQTQEQNKE NQNPNSDAPVIRSKTSARYMELVGWLVDKGITSEKQWIQEDQASYISFNAA SNSRSQIKAALDNAGKIMSLTKTAPDYLVGQQPVEDISSNRIYKILELNGYDP QYAASVFLGWATKKFGKRNTIWLFGPATTGKTNIAEAIAHTVPFYGCVNWT NENFPFNDCVDKMVIWWEEGKMTAKVVESAKAILGGSKVRVDQKCKSSA QIDPTPVIVTSNTNMCAVIDGNSTTFEHQQPLQDRMFKFELTRRLDHDFGKV TKQEVKDFFRWAKDHVVEVEHEFYVKKGGAKKRPAPSDADISEPKRVRES VAQPSTSDAEASINYADRLARGHSLRep 68 amino acid sequence with two mutations MIT and G17ESEQ ID MPGFYEIVIKVPSDLDGHLPGISDSFVNWVAEKEWELPPDSDMDLNLIEQAP NO: 13 LTVAEKLQRDFLTEWRRVSKAPEALFFVQFEKGESYFHMHVLVETTGVKS MVLGRFLSQIREKLIQRIYRGIEPTLPNWFAVTKTRNGAGGGNKVVDECYIP NYLLPKTQPELQWAWTNMEQYLSACLNLTERKRLVAQHLTHVSQTQEQN KENQNPNSDAPVIRSKTSARYMELVGWLVDKGITSEKQWIQEDQASYISFN AASNSRSQIKAALDNAGKIMSLTKTAPDYLVGQQPVEDISSNRIYKILELNG YDPQYAASVFLGWATKKFGKRNTIWLFGPATTGKTNIAEAIAHTVPFYGCV NWTNENFPFNDCVDKMVIWWEEGKMTAKVVESAKAILGGSKVRVDQKCK S S AQIDPTPVI VTS NTNMC A VIDGNSTTFEHQQPLQDRMFKFELTRRLDHDF GKVTKQEVKDFFRWAKDHVVEVEHEFYVKKGGAKKRPAPSDADISEPKRV RESVAQPSTSDAEASINYADRYQNKCSRHVGMNLMLFPCRQCERMNQNSNI CFTHGQKDCLECFPVSESQPVSVVKKAYQKLCYIHHIMGKVPDACTACDLV NVDLDDCIFEQRep 78 amino acid sequence (wild-type)SEQ ID TPGFYEIVIKVPSDLDGHLPGISDSFVNWVAEKEWELPPDSDMDLNLIEQAP NO: 14 LTVAEKLQRDFLTEWRRVSKAPEALFFVQFEKGESYFHMHVLVETTGVKSMVLGRFLSQIREKLIQRIYRGIEPTLPNWFAVTKTRNGAGGGNKVVDECYIPPage 24 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WONYLLPKTQPELQWAWTNMEQYLSACLNLTERKRLVAQHLTHVSQTQEQN KENQNPNSDAPVIRSKTSARYMELVGWLVDKGITSEKQWTQEDQASYISFN AASNSRSQIKAALDNAGKIMSLTKTAPDYLVGQQPVEDISSNRIYKILELNG YDPQYAASVFLGWATKKFGKRNTIWLFGPATTGKTNIAEAIAHTVPFYGCV NWTNENFPFNDCVDKMVIWWEEGKMTAKVVESAKAILGGSKVRVDQKCK S S AQIDPTPVI VTS NTNMC A VIDGNSTTFEHQQPLQDRMFKFELTRRLDHDF GKVTKQEVKDFFRWAKDHVVEVEHEFYVKKGGAKKRPAPSDADISEPKRV RESVAQPSTSDAEASINYADRYQNKCSRHVGMNLMLFPCRQCERMNQNSNI CFTHGQKDCLECFPVSESQPVSVVKKAYQKLCYIHHIMGKVPDACTACDLV NVDLDDCIFEQRep 78 amino acid sequence (MIT)SEQ ID TPGFYEIVIKVPSDLDEHLPGISDSFVNWVAEKEWELPPDSDMDLNLIEQAPL NO: 15 TVAEKLQRDFLTEWRRVSKAPEALFFVQFEKGESYFHMHVLVETTGVKSM VLGRFLSQIREKLIQRIYRGIEPTLPNWFAVTKTRNGAGGGNKVVDECYIPN YLLPKTQPELQWAWTNMEQYLSACLNLTERKRLVAQHLTHVSQTQEQNKE NQNPNSDAPVIRSKTSARYMELVGWLVDKGITSEKQWIQEDQASYISFNAA SNSRSQIKAALDNAGKIMSLTKTAPDYLVGQQPVEDISSNRIYKILELNGYDP QYAASVFLGWATKKFGKRNTIWLFGPATTGKTNIAEAIAHTVPFYGCVNWT NENFPFNDCVDKMVIWWEEGKMTAKVVESAKAILGGSKVRVDQKCKSSA QIDPTPVIVTSNTNMCAVIDGNSTTFEHQQPLQDRMFKFELTRRLDHDFGKV TKQEVKDFFRWAKDHVVEVEHEFYVKKGGAKKRPAPSDADISEPKRVRES VAQPSTSDAEASINYADRYQNKCSRHVGMNLMLFPCRQCERMNQNSNICFT HGQKDCLECFPVSESQPVSVVKKAYQKLCYIHHIMGKVPDACTACDLVNV DLDDCIFEQRep 78 amino acid sequence with two mutations MIT and G17ETable 3A: Exemplary sequences that can be inserted into an AAV capsid with an optional exemplary linker.Amino Acid Sequence Nucleic Acid Sequence6-mer polypeptide with an N-terminus “LA” linkerLARATGKV (SEQ ID NO: 6) CTAGCACGGGCCACCGGCAAGGTG (SEQ ID NO: 307)6-mer polypeptide with a C-terminus “A” linkerRATGKVA (SEQ ID NO: 7) CGGGCCACCGGCAAGGTGGCT(SEQ ID NO: 308)6-mer polypeptide with an N-terminus “A” linkerARATGKV (SEQ ID NO: 8) GCACGGGCCACCGGCAAGGTG(SEQ ID NO: 309)6-mer polypeptide with both N-terminus and C-terminus Linkers LARATGKVA (SEQ ID NO: 9) CTAGCACGGGCCACCGGCAAGGTGGCT(SEQ ID NO: 310)Table 3B: Exemplary sequences that can be inserted into an AAV capsid.Amino Acid SEQ ID Nucleic Acid Sequence SEQ ID Sequence NO: NO:RATGKV 5 CGGGCCACCGGCAAGGTG 306Page 25 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOAmino Acid SEQ ID Nucleic Acid Sequence SEQ ID Sequence NO: NO: LARATGKV 6 CTAGCACGGGCCACCGGCAAGGTG 307 RATGKVA 7 CGGGCCACCGGCAAGGTGGCT 308 ARATGKV 8 GCACGGGCCACCGGCAAGGTG 309 LARATGKVA 9 CTAGCACGGGCCACCGGCAAGGTGGCT 310 NTKMIR 20 AACACCAAGATGATCCGG 163 VRSNMQ 21 GTGCGGAGCAACATGCAG 164 NSTSRE 22 AACAGCACCAGCCGGGAG 165 LNVAKP 23 CTGAACGTGGCCAAGCCC 166 HNTTKT 24 CACAACACCACCAAGACC 167 DVRGNK 25 GACGTGCGGGGCAACAAG 168 TAGARG 26 ACCGCCGGCGCCCGGGGC 169 F1KAPS 27 TTCATCAAGGCCCCCAGC 170 TKKNIE 28 ACCAAGAAGAACATCGAG 171 TMAGFS 29 ACCATGGCCGGCTTCAGC 172 ENASRK 30 GAGAACGCCAGCCGGAAG 173 YTRPKD 31 TACACCCGGCCCAAGGAC 174 SAHRSN 32 AGCGCCCACCGGAGCAAC 175 DTRPQR 33 GACACCCGGCCCCAGCGG 176 MNGVKA 34 ATGAACGGCGTGAAGGCC 177 NNRGTS 35 AACAACCGGGGCACCAGC 178 YQTSKT 36 TACCAGACCAGCAAGACC 179 ETKTRW 37 GAGACCAAGACCCGGTGG 180 LNNTRA 38 CTGAACAACACCCGGGCC 181 GNRLPS 39 GGCAACCGGCTGCCCAGC 182 NQVGRF 40 AACCAGGTGGGCCGGTTC 183 STRPLT 41 AGCACCCGGCCCCTGACC 184 EKATRS 42 GAGAAGGCCACCCGGAGC 185 TGHKGS 43 ACCGGCCACAAGGGCAGC 186 TKGQGV 44 ACCAAGGGCCAGGGCGTG 187 EAKGWS 45 GAGGCCAAGGGCTGGAGC 188 HFTGEI 46 CACTTCACCGGCGAGATC 189 PNGVRY 47 CCCAACGGCGTGCGGTAC 190 TTNATR 48 ACCACCAACGCCACCCGG 191 RAPTAM 49 CGGGCCCCCACCGCCATG 192 NGTKQW 50 AACGGCACCAAGCAGTGG 193 DTKARW 51 GACACCAAGGCCCGGTGG 194 SNQIMR 52 AGCAACCAGATCATGCGG 195 ANFTKQ 53 GCCAACTTCACCAAGCAG 196 IQLGKS 54 ATCCAGCTGGGCAAGAGC 197 NHTARQ 55 AACCACACCGCCCGGCAG 198 FTKKQE 56 TTCACCAAGAAGCAGGAG 199HTRSSP 57 CACACCCGGAGCAGCCCC 200 Page 26 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO Amino Acid SEQ ID Nucleic Acid Sequence SEQ ID Sequence NO: NO: NSVKMA 58 AATTCCGTGAAGATGGCC 201 NRTDWK 59 AACCGGACCGACTGGAAG 202 NFTKGS 60 AACTTCACCAAGGGCAGC 203 NNIKAG 61 AACAACATCAAGGCCGGC 204 NSTSFK 62 AACAGCACCAGCTTCAAG 205 NRTSGG 63 AACCGGACCAGCGGCGGC 206 NNIKGN 64 AACAACATCAAGGGCAAC 207 DNRMHG 65 GACAACCGGATGCACGGC 208 INKTKD 66 ATCAACAAGACCAAGGAC 209 ERLGKQ 67 GAGCGGCTGGGCAAGCAG 210 QFGAGK 68 CAGTTCGGCGCCGGCAAG 211 NSKARD 69 AACAGCAAGGCCCGGGAC 212 QKNNME 70 CAGAAGAACAACATGGAG 213 FNNTKL 71 TTCAACAACACCAAGCTG 214 YENKIK 72 TACGAGAACAAGATCAAG 215 HNSTHY 73 CACAACAGCACCCACTAC 216 NTKLSN 74 AACACCAAGCTGAGCAAC 217 THLSIG 75 ACCCACCTGAGCATCGGC 218 DHGRAS 76 GACCACGGCCGGGCCAGC 219 NKVKQD 77 AACAAGGTGAAGCAGGAC 220 PNGVRH 78 CCCAACGGCGTGCGGCAC 221 NASKPH 79 AACGCCAGCAAGCCCCAC 222 PNNTRY 80 CCCAACAACACCCGGTAC 223 NRTDYK 81 AACCGGACCGACTACAAG 224 YEMKTS 82 TACGAGATGAAGACCAGC 225 TTKPSP 83 ACCACCAAGCCCAGCCCC 226 VNHIKT 84 GTGAACCACATCAAGACC 227 TTKEYK 85 ACCACCAAGGAGTACAAG 228 GNHTKD 86 GGCAACCACACCAAGGAC 229 NHTKAG 87 AACCACACCAAGGCCGGC 230 GQKKES 88 GGCCAGAAGAAGGAGAGC 231 NGTKPL 89 AACGGCACCAAGCCCCTG 232 HNQTKS 90 CACAACCAGACCAAGAGC 233 NFTKTN 91 AACTTCACCAAGACCAAC 234 GLPKSQ 92 GGCCTGCCCAAGAGCCAG 235 GNKISP 93 GGCAACAAGATCAGCCCC 236 ARGDHY 94 GCCCGGGGCGACCACTAC 237 SSSGQKAS 95 AGCAGCAGCGGCCAGAAGGCCAGC 238 WPRQDG 96 TGGCCCCGGCAGGACGGC 239 VTKILP 97 GTGACCAAGATCCTGCCC 240 TTSNTRMG 98 ACCACCAGCAACACCCGGATGGGC241 Page 27 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOAmino Acid SEQ ID Nucleic Acid Sequence SEQ ID Sequence NO: NO: SNQKNL 99 AGCAACCAGAAGAACCTG 242 NPSDVS 100 AACCCCAGCGACGTGAGC 243 QNSYHA 101 CAGAACAGCTACCACGCC 244 VYQGEY 102 GTGTACCAGGGCGAGTAC 245 QQNSVR 103 CAGCAGAACAGCGTGCGG 246 VTNLHM 104 GTGACCAACCTGCACATG 247 HKSRED 105 CACAAGAGCCGGGAGGAC 248 GSDHRSSS 106 GGCAGCGACCACCGGAGCAGCAGC 249 LPSTQD 107 CTGCCCAGCACCCAGGAC 250 KTDHIE 108 AAGACCGACCACATCGAG 251 HSIEHK 109 CACAGCATCGAGCACAAG 252 YNKTRE 110 TACAACAAGACCCGGGAG 253 NVTRHQ 111 AACGTGACCCGGCACCAG 254 NNMVRN 112 AACAACATGGTGCGGAAC 255 NTRKDW 113 AACACCCGGAAGGACTGG 256 WTGKPM 114 TGGACCGGCAAGCCCATG 257 QNQTKW 115 CAGAACCAGACCAAGTGG 258 STRQHM 116 AGCACCCGGCAGCACATG 259 SNHARQ 117 AGCAACCACGCCCGGCAG 260 ARPAQS 118 GCCCGGCCCGCCCAGAGC 261 NKPAFS 119 AACAAGCCCGCCTTCAGC 262 INSVKG 120 ATCAACAGCGTGAAGGGC 263 NNRIPG 121 AACAACCGGATCCCCGGC 264 NRIKAD 122 AACCGGATCAAGGCCGAC 265 NRTNAG 123 AACCGGACCAACGCCGGC 266 KGDKGW 124 AAGGGCGACAAGGGCTGG 267 NVNYTR 125 AACGTGAACTACACCCGG 268 STKHQY 126 AGCACCAAGCACCAGTAC 269 NRVSVQ 127 AACCGGGTGAGCGTGCAG 270 VNLVKQ 128 GTGAACCTGGTGAAGCAG 271 TNLTRM 129 ACCAACCTGACCCGGATG 272 RTSSFG 130 CGGACCAGCAGCTTCGGC 273 NRVPRD 131 AACCGGGTGCCCCGGGAC 274 NMTRNN 132 AACATGACCCGGAACAAC 275 NNSAKQ 133 AACAACAGCGCCAAGCAG 276 NVKPVT 134 AACGTGAAGCCCGTGACC 277 NKVGQY 135 AACAAGGTGGGCCAGTAC 278 TNITKP 136 ACCAACATCACCAAGCCC 279 NNVGRL 137 AACAACGTGGGCCGGCTG 280NRVPHQ 138 AACCGGGTGCCCCACCAG 281Page 28 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOAmino Acid SEQ ID Nucleic Acid Sequence SEQ ID Sequence NO: NO: NNRIPA 139 AACAACCGGATCCCCGCC 282 NNRMPG 140 AACAACCGGATGCCCGGC 283 YVKPGT 141 TACGTGAAGCCCGGCACC 284 GNNTRG 142 GGCAACAACACCCGGGGC 285 NKVPYS 143 AACAAGGTGCCCTACAGC 286 NQIRMT 144 AACCAGATCCGGATGACC 287 NNIRAA 145 AACAACATCCGGGCCGCC 288 GNTTRM 146 GGCAACACCACCCGGATG 289 VNAVTR 147 GTGAACGCCGTGACCCGG 290 NTVQRQ 148 AACACCGTGCAGCGGCAG 291 HNTVKQ 149 CACAACACCGTGAAGCAG 292 NSIKPA 150 AACAGCATCAAGCCCGCC 293 NQVKST 151 AACCAGGTGAAGAGCACC 294 LAKVAG 152 CTGGCCAAGGTGGCCGGC 295 SPEYRG 153 AGCCCCGAGTACCGGGGC 296 NMRGPV 154 AACATGCGGGGCCCCGTG 297 QNSTRM 155 CAGAACAGCACCCGGATG 298 GNAVRL 156 GGCAACGCCGTGCGGCTG 299 DNRLPG 157 GACAACCGGCTGCCCGGC 300 HTAAMM 158 CACACCGCCGCCATGATG 301 GNNTKA 159 GGCAACAACACCAAGGCC 302 NNQIPA 160 AACAACCAGATCCCCGCC 303 ILAEAQ 161 ATCCTGGCCGAGGCCCAG 304IDLTKA 162 ATCGACCTGACCAAGGCC 305

[0051] The polypeptides listed in Tables 3A and 3B can be inserted between amino acid positions corresponding to positions 581 and 582, between amino acid positions corresponding to positions 582 and 583, between amino acid positions corresponding to positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. For clarity, it is understood to one of ordinary skill in the art, that a polypeptide being inserted into a capsid can also be accomplished by a polynucleotidePage 29 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WObeing inserted into a vector that encodes for the capsid, using corresponding positions within a polynucleotide vector, to achieve a capsid comprising an amino acid sequence inserted into a particular position, such as disclosed herein.

[0052] In some embodiments, any one of the polypeptides listed in Tables 3A and 3B is inserted between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, any one of the polypeptides listed in Tables 3A and 3B is inserted between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, any one of the polypeptides listed in Tables 3A and 3B is inserted between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17. In some embodiments, any one of the polypeptides listed in Tables 3A and 3B replaces the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, any one of the polypeptides listed in Tables 3 A and 3B is inserted between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18. In some embodiments, any one of the polypeptides listed in Tables 3 A and 3B replaces the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, any one of the polypeptides listed in Tables 3A and 3B is inserted between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19. In some embodiments, any one of the polypeptides listed in Tables 3A and 3B replaces the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17. 18, and 19.

[0053] Many of the amino acid sequences set forth in Tables 3A and 3B can start with “LA” and end with “A.” In some embodiments, that “LA” sequence can be a first linker sequence Li, and that “A” amino acid can be a second linker sequence L2, with the Li and L2 linkers each independently being optional amino acid linkers having one, two, or three amino acids according to the following Formula A:-L1-INSERT-L2-,wherein Li and L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162. In certain embodiments, INSERT represents the amino acid of SEQ ID NO: 5. In some embodiments, INSERT comprises or consists of no fewer than five amino acids. In certain embodiments, INSERT comprises or consists of no more than nine, eight, seven, or six amino acids. In certain embodiments, an AAV vector can be designed to have an AAV capsid polypeptide that comprises an amino acid sequence comprising any one of SEQPage 30 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOID NOs: 5-9 or 20-162. In some embodiments, an AAV capsid polypeptide comprises an amino acid sequence comprising any on of SEQ ID NOs: 5-9.

[0054] In some embodiments, the present disclosure provides a non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162.

[0055] In some embodiments, the present disclosure provides a non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162.

[0056] In some embodiments, the present disclosure provides a non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 581 and 582, between amino acid positions corresponding to positions 582 and 583, between amino acid positions corresponding to positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positionsPage 31 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcorresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-Li-[6-mer or 8-mer polypeptide]-L2-,wherein the Li and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 6-mer or 8-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162. In some embodiments, the 6-mer is selected from any one of SEQ ID NOs: 5, 20-94, 97, 97, 99-105, and 107-162. In certain embodiments, the 8-mer is selected from any one of SEQ ID NOs: 95, 98, and 106.

[0057] In some embodiments, the present disclosure provides a recombinant AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 581 and 582, between amino acid positions corresponding to positions 582 and 583, between amino acid positions corresponding to positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-Li-[6-mer or 8-mer polypeptide]-L2-,wherein the Li and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 6-mer or 8-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162. In some embodiments, the 6-mer is selected from any one of SEQ ID NOs: 5, 20-94, 97, 97, 99-105, and 107-162. In certain embodiments, the 8-mer is selected from any one of SEQ ID NOs: 95, 98, and 106.

[0058] In some embodiments, the present disclosure provides a recombinant AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 581 and 582, between amino acid positions corresponding to positions 582 and 583, between amino acid positions Page 32 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcorresponding to positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-[7-mer or 8-mer polypeptide]-L2-,wherein the Li and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 7-mer or 8-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 95, 98, or 106.

[0059] As disclosed herein, an AAV vector can be designed to have an AAV capsid polypeptide that comprises an amino acid sequence of Formula A based on any one of SEQ ID NOs: 5-9 or 20-162. For example, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 1 (or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 1) that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 20-162 located between amino acid positions corresponding to positions 587 and 588 of SEQ ID NO: 1 (or the appropriate amino acid positions of the alternative sequence).

[0060] In some embodiments, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 2 (or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 2) that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 20-162 located between amino acid positions corresponding to positions 587 and 588 of SEQ ID NO: 2 (or the appropriate amino acid positions of the alternative sequence). In some embodiments, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 3 (or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 3) that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 20-162 located between amino acid positions Page 33 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcorresponding to positions 587 and 588 of SEQ ID NO: 3 (or the appropriate amino acid positions of the alternative sequence). In some embodiments, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 4 (or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 4) that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 20-162 located between amino acid positions corresponding to positions 587 and 588 of SEQ ID NO: 4 (or the appropriate amino acid positions of the alternative sequence).

[0061] As described herein, an AAV vector can be designed to have an AAV capsid polypeptide that comprises an amino acid sequence of Formula A based on any one of SEQ ID NOs: 5-9 or 20-162. For example, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 17 or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 17 that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 20-162 located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17 (or the appropriate amino acid positions of the alternative sequence). In certain embodiments, the capsid comprises or consists of SEQ ID NO: 17 and the amino acid sequence inserted between amino acid positions corresponding to positions 590 and 591 is selected from any one of SEQ ID NOs: 5-9.

[0062] As described herein, an AAV vector can be designed to have an AAV capsid polypeptide that comprises an amino acid sequence of Formula A based on any one of SEQ ID NOs: 5-9 or 20-94. For example, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 17 or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 17 that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 20-94 located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17 (or the appropriate amino acid positions of the alternative sequence).

[0063] As described herein, an AAV vector can be designed to have an AAV capsid polypeptide that comprises an amino acid sequence of Formula A based on any one of SEQ ID NOs: 5-9. For example, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 17 or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 17 that includes an amino acid sequence of Formula A based on any of the amino acid sequences Page 34 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOof SEQ ID NOs: 5-9 located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17 (or the appropriate amino acid positions of the alternative sequence).

[0064] In some embodiments, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 18 or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 18 that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 20-162 located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18 (or the appropriate amino acid positions of the alternative sequence).

[0065] In some embodiments, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 18 or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 18 that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 95-109 located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18 (or the appropriate amino acid positions of the alternative sequence).

[0066] In some embodiments, an AAV vector can be designed to have an AAV capsid polypeptide of SEQ ID NO: 19 or an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 19 that includes an amino acid sequence of Formula A based on any of the amino acid sequences of SEQ ID NOs: 5-9 or 110-162 located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19 (or the appropriate amino acid positions of the alternative sequence).

[0067] In some embodiments, Li, L2, or both Li and L2 can be absent. For example, an AAV capsid polypeptide that includes an amino acid sequence of Formula A based on any one of SEQ ID NOs: 5-9 or 20-162 can be included in the absence of the starting “LA” and the ending “A.” In some embodiments, Li can be one amino acid Xi, two amino acids X2-X1, or three amino acids X3-X2-X1. When Xi is present, it can be an amino acid residue selected from the group consisting of A, V, I, and L. When X2 is present, it can be an amino acid residue selected from the group consisting of A, V, I, and L. When X3 is present, it can be an amino acid residue selected from the group consisting of A, V, I, and L. In some cases, L2 can be one amino acid Zi, two amino acids Z1-Z2, or three amino acids Z1-Z2-Z3. When Zi is present, it can be an amino acid residue selected from the group consisting of A, V, I, and L. When Z2 is present, it can be an amino acid residue selected from the group consisting of A, V, I, and L. When Z3 is Page 35 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOpresent, it can be an amino acid residue selected from the group consisting of A, V, I, and L. Examples of an Li linkers comprises, without limitation. A, V, I, L, AA, AV, Al, AL, VA, VV, VI, VL, IA, IV, II, IL, LA, LV, LI, LL, AAA, AAV, AAI, AAL, AVA, AVV, AVI, AVL, AIA, AIV, All, AIL, ALA, ALV, ALI, ALL, VAA, VAV, VAI, VAL, VVA, VVV, VVI, VVL, VIA, VIV, VII, VIL, VLA, VLV, VLI, VLL, IAA, IAV, IAI, IAL, IVA, IVV, IVI, IVL, IIA, IIV, III, IIL, ILA, ILV, ILI, ILL, LAA, LAV, LAI, LAL, LVA, LVV, LVI, LVL, LIA, LIV, LII, LIL, LLA, LLV, LLI, and LLL. Examples of an L2 linkers comprises, without limitation, A, V, I, L, AA, AV, Al, AL, VA, VV, VI, VL, IA, IV, II, IL, LA, LV, LI, LL, AAA, AAV, AAI, AAL, AVA, AVV, AVI, AVL, AIA, AIV, All, AIL, ALA, ALV, ALI, ALL, VAA, VAV, VAI, VAL, VVA, VVV, VVI, VVL, VIA, VIV, VII, VIL, VLA, VLV, VLI, VLL, IAA, IAV, IAI, IAL, IVA, IVV, IVI, IVL, IIA, IIV, III, IIL, ILA, ILV, ILI, ILL, LAA, LAV, LAI, LAL, LVA, LVV, LVI, LVL, LIA, LIV, LII, LIL, LLA, LLV, LLI, and LLL.

[0068] In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth in any one of SEQ ID NOs: 1-4, 17, 18, and 19 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4, 17, 18, and 19) with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A between positions corresponding to asparagine-587 and arginine-588 (or the appropriate amino acid positions of the alternative sequence) in any of SEQ ID NOs: 1-4, 17, 18, and 19. In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth of SEQ ID NO: 1 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 1) with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A between positions corresponding to asparagine-587 and arginine-588 of SEQ ID NO: 1 (or the appropriate amino acid positions of the alternative sequence). In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth of SEQ ID NO: 2 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 2) with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A between positions corresponding to asparagine-587 and arginine-588 of SEQ ID NO: 2 (or the appropriate amino acid positions of the alternative sequence). In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth of SEQ ID NO: 3 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 3) with an amino Page 36 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOacid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A between positions corresponding to asparagine-587 and arginine-588 of SEQ ID NO: 3 (or the appropriate amino acid positions of the alternative sequence). In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth of SEQ ID NO: 4 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 4) with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A between positions corresponding asparagine-587 and arginine-588 of SEQ ID NO: 4 (or the appropriate amino acid positions of the alternative sequence).

[0069] In some embodiments, an AAV8 capsid polypeptide provided herein can have the sequence set forth of SEQ ID NO: 17 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 17) with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 (or a variant thereof) or according to Formula A between positions corresponding to asparagine-590 and threonine-591 of SEQ ID NO: 17 (or the appropriate amino acid positions of the alternative sequence). In some embodiments, an AAV8 capsid polypeptide provided herein can have the sequence set forth of SEQ ID NO: 17 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 17) with an amino acid sequence of any one of SEQ ID NOs: 5-9 according to Formula A between positions corresponding to asparagine-590 and threonine-591 (or the appropriate amino acid positions of the alternative sequence) of SEQ ID NO: 17.

[0070] In some embodiments, an AAV9 capsid polypeptide provided herein can have the sequence set forth of SEQ ID NO: 18 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 18) with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 (or a variant thereof) or according to Formula A between positions corresponding to glutamine-588 and alanine-589 of SEQ ID NO: 18 (or the appropriate amino acid positions of the alternative sequence).

[0071] In some embodiments, an AAVrhlO capsid polypeptide provided herein can have the sequence set forth of SEQ ID NO: 19 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 19) with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 (or a variant thereof) or according to Formula A between positions corresponding to asparagine-590 and alanine-591 of SEQ ID NO: 19(or the appropriate amino acid positions of the alternative sequence).Page 37 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO

[0072] In some embodiments, when designing an AAV capsid polypeptide to include an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A, that included amino acid sequence can be used to replace one or more naturally-occurring amino acid residues located at any appropriate location along the AAV capsid polypeptide. For example, an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-94 (or a variant thereof) can be used to replace any or all of the naturally-occurring amino acid residues at positions corresponding to positions 588 to 593 of an AAV capsid polypeptide of any of SEQ ID NOs: 1-4, 17, 18, or 19 (e.g., an AAV8 capsid polypeptide). For example, an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 95-109 (or a variant thereof) can be used to replace any or all of the naturally -occurring amino acid residues at positions corresponding to positions 586 to 591 of an AAV capsid polypeptide (e.g., an AAV9 capsid polypeptide). For example, an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 110-162 (or a variant thereof) can be used to replace any or all of the naturally-occurring amino acid residues at positions corresponding to positions 588 to 593 of an AAV capsid polypeptide (e.g., an AAVrhlO capsid polypeptide).

[0073] In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth in any one of SEQ ID NOs: 1-4, (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4,) except that the amino acid residues at positions corresponding to positions 585 to 590 of any of SEQ ID NOs: 1-4 (or the appropriate amino acid positions of the alternative sequence) are replaced with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth in SEQ ID NO: 1 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 1) except that the amino acid residues at positions corresponding to positions 585 to 590 of SEQ ID NO: l(or the appropriate amino acid positions of the alternative sequence) are replaced with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth in SEQ ID NO: 2 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 2) except that the amino acid residues at positions corresponding to positions 585 to 590 of SEQ ID NO: 2 (or the appropriate amino acid positions of the alternative sequence) are replaced with an amino acid sequence of any one Page 38 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOof SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth in SEQ ID NO: 3 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 3) except that the amino acid residues at positions corresponding to positions 585 to 590 of SEQ ID NO: 3 (or the appropriate amino acid positions of the alternative sequence) are replaced with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. In some embodiments, an AAV2 capsid polypeptide provided herein can have the sequence set forth in SEQ ID NO: 4 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 4) except that the amino acid residues at positions corresponding to positions 585 to 590 of SEQ ID NO: 4 (or the appropriate amino acid positions of the alternative sequence) are replaced with an amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence.

[0074] In some embodiments, an AAV8 capsid polypeptide provided herein can have the sequence set forth in SEQ ID NO: 17 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 17) except that one or more of the amino acid residues as positions corresponding to positions 588 to 593 of SEQ ID NO: 17(or the appropriate amino acid positions of the alternative sequence) are replaced with an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 5-9 or 20-94 (or a variant thereof) or according to Formula A based on such a set forth sequence. In certain embodiments, all of amino acids corresponding to 588 to 593 are replaced. In some embodiments, 1, 2, 3, 4, or 5 amino acids corresponding to any positions between 588 to 593 are replaced.

[0075] In some embodiments, an AAV9 capsid polypeptide provided herein can have the sequence set forth in SEQ ID NO: 18 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 18) except that the amino acid residues at positions corresponding to positions 586 to 591 (or the appropriate amino acid positions of the alternative sequence) are replaced with an amino acid sequence comprising or consisting of SEQ ID NOs: 5-9 or 95-109 (or a variant thereof) or according to Formula A based on such a set forth sequence. In certain embodiments, all of amino acids corresponding to 586 to 591 are replaced. In some embodiments, 1, 2, 3, 4, or 5 amino acids corresponding to any positions between 586 to 591 are replaced.Page 39 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO

[0076] In some embodiments, an AAVrhlO capsid polypeptide provided herein can have the sequence set forth in SEQ ID NO: 19 (or an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 19) except that the amino acid residues at positions corresponding to positions 588 to 593 (or the appropriate amino acid positions of the alternative sequence) are replaced with an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 5-9 or 110-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. In certain embodiments, all of amino acids corresponding to 588 to 593 are replaced. In some embodiments, 1, 2, 3, 4, or 5 amino acids corresponding to any positions between 588 to 59 are replaced.

[0077] In some embodiments, an AAV capsid polypeptide (e.g., an AAV2, an AAV8, an AAV9, or an AAVrhlO capsid polypeptide) can be designed to include two or more amino acid sequences set forth in any one of SEQ ID NO: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. For example, an AAV capsid polypeptide (e.g., an AAV2, an AAV8, an AAV9, or an AAVrhlO capsid polypeptide) can be designed to include two, three, or four amino acid sequences set forth in any one of SEQ ID NO: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence.

[0078] As described herein, an AAV capsid polypeptide (e.g., an AAV2, an AAV8, an AAV9, or an AAVrhlO capsid polypeptide) can be designed to include an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. A variant of an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 refers to an amino acid sequence that is identical to that amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 except that it has one, two, or three amino acid additions, deletions, substitutions, or combinations thereof. For example, a variant of SEQ ID NO: 5 can be SEQ ID NO: 5 except that it has one, two, or three amino acid additions, deletions, substitutions, or combinations thereof. In some cases, a variant provided herein can be the amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 except that it contains one, two, or three amino acid additions. In some embodiments, a variant provided herein can be the amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 except that it contains one, two, or three amino acid deletions. In some embodiments, a variant provided herein can be the amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 except that it contains one, two, or three amino acid substitutions. In some cases, a variant provided herein can be the amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 except that it contains one amino acid addition, deletion, or substitution. In some cases, a variant provided herein can be the amino acid sequence set forth in any one of SEQ ID Page 40 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WONOs: 5-9 or 20-162 except that it contains two amino acid additions, deletions, substitutions, or a combination thereof. In some cases, a variant provided herein can be the amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 except that it contains three amino acid additions, deletions, substitutions, or a combination thereof.

[0079] In some embodiments, an amino acid substitution present in a variant can be a conservative amino acid substitution. For example, conservative amino acid substitutions can be made by substituting one amino acid residue for another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains can include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0080] In some embodiments, an amino acid substitution present in a variant can be a nonconservative amino acid substitution. Non-conservative amino acid substitutions can be made by substituting one amino acid residue for another amino acid residue having a dissimilar side chain. Examples of non-conservative substitutions include, without limitation, substituting (a) a hydrophilic residue (e.g., serine or threonine) for a hydrophobic residue (e.g., leucine, isoleucine, phenylalanine, valine, or alanine); (b) a cysteine or proline for any other residue; (c) a residue having a basic side chain (e.g., lysine, arginine, or histidine) for a residue having an acidic side chain (e.g., aspartic acid or glutamic acid); and (d) a residue having a bulky7side chain (e.g., phenylalanine) for glycine or other residue having a small side chain.

[0081] The percent sequence identity between a particular amino acid sequence and an amino acid sequence referenced by a particular sequence identification number is determined as follows. First, an amino acid sequence is compared to the sequence set forth in a particular sequence identification number using the BLAST 2 Sequences (B12seq) program from the stand-alone version of BLASTZ containing BLASTP version 2.0.14. This stand-alone version of BLASTZ can be obtained from Fish & Richardson’s web site (e.g., www.fr.com / blast / ) or the U. S. government’s National Center for Biotechnology Information web site (www.ncbi.nlm.nih.gov). Instructions explaining how to use the B12seq program can be found in the readme file accompanying BLASTZ. B12seq performs a comparison between two sequences using either the BLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. To compare Page 41 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOtwo amino acid sequences, the options of B12seq are set as follows: -i is set to a file containing the first amino acid sequence to be compared (e.g., C:\seql.txt); -j is set to a file containing the second amino acid sequence to be compared (e.g., C:\seq2.txt); -p is set to blastp; -o is set to any desired file name (e.g., C:\output.txt); and all other options are left at their default setting. For example, the following command can be used to generate an output file containing a comparison between two amino acid sequences: C:\B12seq -i c:\seql.txt -j c:\seq2.txt -p blastp -o c:\output.txt. If the two compared sequences share homology, then the designated output file will present those regions of homology as aligned sequences. If the two compared sequences do not share homology, then the designated output file will not present aligned sequences. Once aligned, the number of matches is detemiined by counting the number of positions where an identical amino acid residue is presented in both sequences. A matched position refers to a position in which an identical amino acid residue occurs at the same position in aligned sequences. The percent sequence identity is determined by dividing the number of matches by the length of the sequence set forth in the identified sequence (e.g., SEQ ID NO: 1), followed by multiplying the resulting value by 100. For example, an amino acid sequence that has 725 matches when aligned with the sequence set forth in SEQ ID NO: 1 is 98.6 percent identical to the sequence set forth in SEQ ID NO: 1 (i.e., 725 A 735 x 100 = 98.6). It is noted that the percent sequence identity value is rounded to the nearest tenth. For example, 78.11, 78.12, 78.13, and 78.14 is rounded down to 78.1, while 78.15, 78.16, 78.17, 78.18, and 78.19 is rounded up to 78.2. It also is noted that the length value will always be an integer.

[0082] Methods for generating an amino acid sequence variant can include site-specific mutagenesis or random mutagenesis (e.g., by PCR) of a nucleic acid encoding an AAV capsid polypeptide. See, for example, Zoller, Curt Opin. Biotechnol. 3: 348-354 (1992).

[0083] The AAV vectors (e.g.. AAV2, AAV8, AAV9, or AAVrhlO vectors) described herein can be designed to comprise one or more exogenous nucleic acid sequences. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein can be designed to comprise an exogenous nucleic acid sequence that encodes an RNA of interest and / or a polypeptide of interest. An exogenous nucleic acid sequence can be designed to encode any appropriate RNA of interest. Examples of RNAs of interest that can be encoded by an exogenous nucleic acid sequence designed to be included within an AAV vector provided herein include, without limitation, siRNAs, RNA components for gene editing, and microRNAs. In some embodiments, an RNA of interest that can be encoded by an exogenous nucleic acid sequence included within an AAV vector provided herein can be SIRNA-027 to treat, e.g., sub-foveal CNVM secondary to age-related macular degeneration (see, e.g.,Page 42 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WONCT00363714), Cand5 / Bevasiranib to treat, e.g., diabetic macular edema (see, e.g., NCT00306904), PF-04523655 to treat, e.g., diabetic macular edema (see, e.g., NCT01445899), QPI-1007 to treat, e.g., optic nerve atrophy in NAION (see, e.g., NCT01064505), Aganirsen to treat, e.g., ischemic CRVO to prevent neovascular glaucoma (see, e.g., NCT02947867), QR-421a to treat, e.g., retinitis pigmentosa / Usher syndrome type 2 (see, e.g., NCT03780257), QR-1123 to treat, e.g., autosomal dominant retinitis pigmentosa (see, e.g., NCT04123626), IONIS-FB-LRx to treat, e.g., geographic atrophy secondary to age-related macular degeneration (see, e.g., NCT03815825), or Sepofarsen / QR-110 to treat, e.g., Leber’s congenital amaurosis (see, e.g., NCT03913143).

[0084] An exogenous nucleic acid sequence can be designed to encode any appropriate polypeptide of interest. Examples of polypeptides of interest that can be encoded by an exogenous nucleic acid sequence designed to be included within an AAV vector provided herein include, without limitation, therapeutic polypeptides, trophic factor polypeptides, gene editing polypeptides (e.g., a Cas9 polypeptide, a TALEN polypeptide, or a zinc finger polypeptide), enzymes, optogenetic tool polypeptides (e.g., a ChR polypeptide, an NhpR polypeptide, or a ReachR polypeptide), antibodies, antibody domains (e.g., VH domains), cytokines, anti-angiogenic polypeptides, and neuroprotective polypeptides. Examples of polypeptides of interest that can be encoded by an exogenous nucleic acid sequence designed to be included within an AAV vector provided herein include, without limitation, an ABCA4 polypeptide, a CRB1 polypeptide, an NPHP5 polypeptide, an NR2E3 polypeptide, a PDE6A polypeptide, a PDE6B polypeptide, a PDE6C polypeptide, a PRPF31 polypeptide, a RPE65 polypeptide, a RPGR polypeptide, a RSI polypeptide, a TYR polypeptide, a USH2A polypeptide, an MY07A polypeptide, an REP1 polypeptide, an 0PN1LW polypeptide, an 0PN1MW polypeptide, a CNGA3 polypeptide, a CNGB3 polypeptide, a GUCY2D polypeptide, a GACA1 A polypeptide, a GNAT2 polypeptide, a PDE6H polypeptide, a PROMI polypeptide, a PRPH2 polypeptide, a CRX polypeptide, an NPHP5 polypeptide, an EYS polypeptide, an ND4 polypeptide, a CLN1-14 polypeptide (e.g., a CLN3 polypeptide, a CLN5 polypeptide, a CLN6 polypeptide, or a CLN8 polypeptide), an NYX polypeptide, a GRM6 polypeptide, a TRPM1 polypeptide, a GPR179 polypeptide, an LRIT3 polypeptide, a glial cell derived neurotrophic factor (GDNF) polypeptide, a brain-derived neurotrophic factor (BDNF) polypeptide, a fibroblast growth factor (FGF) polypeptide, a truncated rod-derived cone viability factor (RdCVF) polypeptide, a full-length rod-derived cone viability factor (RdCVFL) polypeptide, an X-linked inhibitor of apoptosis (XIAP) polypeptide, a soluble fms-related receptor tyrosine kinase 1 (sFLT) polypeptide, a CYP4V2 polypeptide, a palmitoyl protein Page 43 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOthioesterase 1 polypeptide, a tripeptidyl peptidase 1 polypeptide, a DNAJC5 polypeptide, an MFSD8 polypeptide, a cathepsin D polypeptide, a granulin polypeptide, an ATP13A2 polypeptide, a cathepsin F polypeptide, a KCTD7 polypeptide, a “P” gene polypeptide, a TRP1 polypeptide, an MATP (SLC45A2) polypeptide, a SLC24A5 polypeptide, a LRMDA polypeptide, a GPR143 polypeptide, an RPGR-exon 1-ORF15 polypeptide, an USH2b polypeptide, an USH1C polypeptide, a CDH23 polypeptide, a PCDH15 polypeptide, a SANS polypeptide, an USH1H polypeptide, a C1B2 polypeptide, an USH1K polypeptide, an ADGRV 1 polypeptide, a WHRN polypeptide, a PDZD7 polypeptide, a CLRN 1 polypeptide, a HARS polypeptide, an RP2 polypeptide, a FAM161 polypeptide, a DLK polypeptide, a RHO polypeptide, a CHM polypeptide, a BEST1 polypeptide, a RP1 polypeptide, an OPA1 polypeptide, a CEP290 polypeptide, a RDH12 polypeptide, a CACNA1F polypeptide, a BBS1 polypeptide, a FAM161 A polypeptide, a CERKL polypeptide, a PRPF8 polypeptide, a RP1L1 polypeptide, a SNRNP200 polypeptide, an IMPG2 polypeptide, a CDHR1 polypeptide, an IMPDH1 polypeptide, a CNGB 1 polypeptide, an MERTK polypeptide, a KCNV2 polypeptide, an AIPL1 polypeptide, a RPGRIP1 polypeptide, a TULP1 polypeptide, a C2ORF71 (aka PCARE) polypeptide, an MAK polypeptide, a TIMP3 polypeptide, a GUCA1A polypeptide, an ALMS1 polypeptide, a BBS 10 polypeptide, an IFT140 polypeptide, a CNGA1 polypeptide, a NMNAT1 polypeptide, a COL2A1 polypeptide, an EFEMP1 polypeptide, a WFS1 polypeptide, a RDH5 polypeptide, a PRPF3 polypeptide, a LRP5 polypeptide, a TOPORS polypeptide, a DHDDS polypeptide, a LCA5 polypeptide, an IQCB1 polypeptide, a RP9 polypeptide, an ATXN7 polypeptide, a BBS2 polypeptide, a SAG RLBP1 polypeptide, a ND6 (MT-ND6) polypeptide, a C1QTNF5 polypeptide, a VPS13B polypeptide, a KIF11 polypeptide, an MT-TL1 polypeptide, a KLHL7 polypeptide, an ACO2 polypeptide, a C21orf2 (aka CFAP410) polypeptide, an AHI1 polypeptide, a KIZ polypeptide, a SPATA7 polypeptide, a TTLL5 polypeptide, an HGSNAT polypeptide, a NRL polypeptide, an OAT polypeptide, a FLVCR1 polypeptide, an ABCC6 polypeptide, a LRAT polypeptide, a CEP78 polypeptide, a CDH3 polypeptide, a FZD4 polypeptide, a BBS12 polypeptide, an HK1 polypeptide, a PRDM13 polypeptide, an ADAM9 polypeptide, a BBS7 polypeptide, a CABP4 polypeptide, an ABHD12 polypeptide, a C0L18A1 polypeptide, an MFRP polypeptide, a RIMS1 polypeptide, a R0M1 polypeptide, a BBS4 polypeptide, an IMPG1 polypeptide, an INPP5E polypeptide, a VCAN polypeptide, a POC1B polypeptide, a RAX2 polypeptide, a TSPAN12 polypeptide, a CACNA2D4 polypeptide, a JAG1 polypeptide, an MKKS polypeptide, a NPHP4 polypeptide, a BBS9 polypeptide, a COL11A1 polypeptide, an ELOVL4 polypeptide, a NDP polypeptide, a NPHP1 polypeptide, a RGR polypeptide, a BBS5 polypeptide, a WDR19Page 44 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOpolypeptide, a C8ORF37 polypeptide, a CTNNA1 polypeptide, a LAMP2 polypeptide, a PEX1 polypeptide, a PHYH polypeptide, an ATF6 polypeptide, a PRPS 1 polypeptide, a SEMA4A polypeptide, an ARL6 polypeptide, a CNNM4 polypeptide, an 0TX2 polypeptide, a PRPF6 polypeptide, a RBP3 polypeptide, a PNPLA6 polypeptide, a SLC24A1 polypeptide, an USH1G polypeptide, a PITPNM3 polypeptide, a TTC8 polypeptide, an ARSG polypeptide, a CWC27 polypeptide, a DRAM2 polypeptide, a PRCD polypeptide, a REEP6 polypeptide, a SSBP1 polypeptide, a LAMA1 polypeptide, a RAB28 polypeptide, a ZNF408 polypeptide, a GNAT1 polypeptide, an IDH3A polypeptide, a PDE6G polypeptide, a PEX6 polypeptide, a TUB polypeptide, a CEP250 polypeptide, a FSCN2 polypeptide, a GRK1 polypeptide, a RBP4 polypeptide, a RD3 polypeptide, an AGBL5 polypeptide, a CAPN5 polypeptide, an IFT172 polypeptide, a KCNJ13 polypeptide, a PAX2 polypeptide, a CC2D2A polypeptide, a HMCN1 polypeptide, an MT-ATP6 polypeptide, a RCBTB1 polypeptide, an ARL2BP polypeptide, a CA4 polypeptide, a DFNB31 polypeptide, a GNB3 polypeptide, an MMACHC polypeptide, a PRPF4 polypeptide, a RGS9 polypeptide, an ARHGEF18 polypeptide, a KIAA1549 polypeptide, an MKS1 polypeptide, an MTTP (not MT-TP) polypeptide, a PLK4 polypeptide, a RPGRIP1L polypeptide, a SDCCAG8 polypeptide, a SRD5A3 polypeptide, a TUBB4B polypeptide, an ADAMTS18 polypeptide, an ARL3 polypeptide, a COL11 A2 polypeptide, an MVK polypeptide, a NBAS polypeptide, an OFD1 polypeptide, a P3H2 polypeptide, a RGS9BP polypeptide, a CSPP1 polypeptide, an ITM2B polypeptide, a PANK2 polypeptide, a PEX7 polypeptide, a P0MGNT1 polypeptide, a SLC4A7 polypeptide, a TMEM231 polypeptide, a TRNT1 polypeptide, a TUBGCP6 polypeptide, a ZNF513 polypeptide, an AFG3L2 polypeptide, an ARL13B polypeptide, a C5ORF42 aka CPLANE1) polypeptide, a COL9A1 polypeptide, a CTSD polypeptide, a DTHD1 polypeptide, a DYNC2H1 polypeptide, an IFT81 polypeptide, a KIAA0586 polypeptide, an MFN2 polypeptide, a NPHP3 polypeptide, a PCYT1 A polypeptide, a PEX12 polypeptide, a PLA2G5 polypeptide, a POC5 polypeptide, a SCAPER polypeptide, a SLC25A46 polypeptide, a TMEM237 polypeptide, a TRAF3IP1 polypeptide, a TTC21B polypeptide, a TUBGCP4 polypeptide, an ADIP0R1 polypeptide, a CEP 164 polypeptide, a CLCC1 polypeptide, a COL9A2 polypeptide, a CTNNB1 polypeptide, a DHX38 polypeptide, a GNPTG polypeptide, a GRN polypeptide, a GUCA1B polypeptide, an IFT27 polypeptide, an IFT74 polypeptide, a KIAA0556 polypeptide, a LRP2 polypeptide, an MAPKAPK3 polypeptide, an MIR204 polypeptide, an MT-ND3 polypeptide, an MT-RNR1 polypeptide, an MT-TS2 polypeptide, a ND5 (MT-ND5) polypeptide, a NEK2 polypeptide, an OPN1SW polypeptide, a PEX13 polypeptide, a PEX2 polypeptide, a RHBDD2 polypeptide, a SAMD11 polypeptide, a SCLT1 polypeptide, a SLC7A 14 polypeptide, a TCTN1 polypeptide,Page 45 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOa TCTN2 polypeptide, a TLCD3B polypeptide, a TREX1 polypeptide, a TTPA polypeptide, an UNCI 19 polypeptide, a WDPCP polypeptide, an ACBD5 polypeptide, an AHR polypeptide, an ARMC9 polypeptide, an ASRGL1 polypeptide, an AT0H7 polypeptide, a B9D1 polypeptide, a B9D2 polypeptide, a BBIP1 polypeptide, a C12ORF65 polypeptide, a C2CD3 polypeptide, a C5AR2 polypeptide, a CCDC188 polypeptide, a CCT2 polypeptide, a CEP 104 polypeptide, a CEP 120 polypeptide, a CEP 19 polypeptide, a CEP41 polypeptide, a C1SD2 polypeptide, a CLUAP1 polypeptide, a COL9A3 polypeptide, a CRB2 polypeptide, a CTC1 polypeptide, a DACT2 polypeptide, a DDR1 polypeptide, an ENSA polypeptide, an ESPN polypeptide, an EXOSC2 polypeptide, a FBN3 polypeptide, a GDF6 polypeptide, a GPR125 polypeptide, a HKDC1 polypeptide, a HMX1 polypeptide, an IDH3B polypeptide, an IFT43 polypeptide, an IFT80 polypeptide, an INVS polypeptide, a KIAA0753 polypeptide, a KIF3B polypeptide, a KIF7 polypeptide, a LRRTM4 polypeptide, a LZTFL1 polypeptide, an MT-ATP8 polypeptide, an MT-C01 polypeptide, an MT-C02 polypeptide, an MT-C03 polypeptide, an MT-CYB polypeptide, an MT-ND2 polypeptide, an MT-ND4L polypeptide, an MT-RNR2 polypeptide, an MT-TA polypeptide, an MT-TC polypeptide, an MT-TD polypeptide, an MT-TE polypeptide, an MT-TF polypeptide, an MT-TG polypeptide, an MT-TH polypeptide, an MT-TI polypeptide, an MT-TK polypeptide, an MT-TL2 polypeptide, an MT-TM polypeptide, an MT-TN polypeptide, an MT-TP (Not MTTP) polypeptide, an MT-TQ polypeptide, an MT-TR polypeptide, an MT-TS1 polypeptide, an MT-TT polypeptide, an MT-TV polypeptide, an MT-TW polypeptide, an MT-TY polypeptide, a NEURODI polypeptide, a PDE6D polypeptide, a PEX10 polypeptide, a PEX1 IB polypeptide, a PEX14 polypeptide, a PEX16 polypeptide, a PEX19 polypeptide, a PEX26 polypeptide, a PEX3 polypeptide, a PEX5 polypeptide, a PGK1 polypeptide, a PISD polypeptide, a PPP2R3C polypeptide, a PROS1 polypeptide, a PSEN1 polypeptide, a RDH11 polypeptide, a RRM2B polypeptide, a SMARCA4 polypeptide, a SPP2 polypeptide, a TCTN3 polypeptide, a TEAD1 polypeptide, a TMEM107 polypeptide, a TMEM138 polypeptide, a TMEM216 polypeptide, a TMEM67 polypeptide, a TPP1 polypeptide, a TRIM32 polypeptide, a USP45 polypeptide, and aZNF423 polypeptide. In some cases, a polypeptide of interest that can be encoded by an exogenous nucleic acid sequence designed to be included within an AAV vector provided herein can be an MY07A polypeptide, an USH1C polypeptide, a PCDH15 polypeptide, an USH2A polypeptide, or CLRN1 polypeptide to treat, e.g., Usher Syndrome.

[0085] In some embodiments, one or more AAV vectors provided herein can be designed to carry out gene editing within one or more cells (e.g., retinal cells). Such gene editing can result in a genomic modification of one or more cells. Examples of such genomic modifications Page 46 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOinclude, without limitation, a targeted insertion of a nucleic acid encoding an RNA and / or polypeptide of interest into one or more cells, a targeted modification {e.g., targeted inactivation or knock-out) of a genomic sequence of one or more cells, and a targeted replacement of nucleic acid {e.g., nucleic acid encoding an RNA, a regulatory nucleic acid sequence, and / or nucleic acid encoding a polypeptide of interest) within one or more cells.

[0086] Any appropriate gene editing components can be engineered into one or more AAV vectors provided herein such that those one or more AAV vectors can be used to deliver the gene editing components to target cells e.g., one or more retinal cells) within a mammal {e.g., a human or a non-human primate) in a manner effective to edit the genome of those cells. Typically, the gene editing components include, without limitation, a component that is capable of cleaving genomic nucleic acid at a desired location and an optional donor nucleic acid designed to be inserted into that desired location once it is cleaved. Any appropriate rare-cutting endonuclease can be used to cleave genomic nucleic acid at a desired location. Examples of such rare-cutting endonucleases include, without limitation, meganucleases, transcription activator-like effector (TALE) nucleases (TALENs™; Cellectis, Paris, France), zinc-finger-nucleases (ZFNs), and endonucleases of a clustered regularly interspaced short palindromic repeats (CRISPR)ZCas system {e.g., endonucleases of a CRISPR / Cas 9 system). See, e.g., Baker, Nature Methods, 9:23-26 (2012); International PCT Patent Application Publication No. WO 2004 / 067736; International PCT Patent Application Publication No. WO 2011 / 072246; U. S. Patent No. 8,586,363; Porteus and Canoil, Nature Biotechnol., 23:967-973 (2005); linek et al., Science, 337:816-821 (2012); Mali etal., Science, 339:823-826 (2013); Li et al., Nature Biotechnology, 31(8):688-691 (2013); and Makarova etal., Nat. Rev. Microbiol., 9(6):467-477 (2011)).

[0087] In some embodiments, to facilitate gene replacement, two sequences in genomic nucleic acid of a cell {e.g., a retinal cell) - one on either side of a sequence to be removed - can be targeted for endonuclease cleavage. For example, a first target sequence adjacent to the 5’ end of a sequence to be removed and a second target sequence adjacent to the 3’ end of the sequence to be removed can be targeted by guide RNAs to enable Cas9 cleavage or can be targeted by TALENs designed to specifically recognize those targets. Delivery using one or more AAV vectors provided herein of (a) endonucleases targeted to the genomic DNA and (b) a donor nucleic acid construct can allow cleavage at both genomic targets, removal of the sequence between the genomic targets, and insertion of the donor sequence into the location of the deletion.Page 47 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO

[0088] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can include any appropriate promoter and / or other regulatory sequence (e.g., enhancers, transcription initiation sites, translation initiation sites, and termination signals) operably linked an exogenous nucleic acid sequence designed to be expressed. In some cases, a promoter used to drive expression can be a constitutive promoter, a regulatable promoter, a tissue-specific promoter, or a viral promoter. Examples of constitutive promoters that can be used as described herein include, without limitation, chicken -actin (CBA) promoters, CAG promoters e.g., CMV early enhancer / chicken actin), SV40 promoters, cytomegalovirus (CMV) promoters, and E1ALPHA promoters. Examples of regulatable promoters that can be used as described herein include, without limitation, inducible promoters and repressible promoters. Examples of tissue-specific promoters that can be used as described herein include, without limitation, rhodopsin promoters, cone arrestin promoters, and synapsin promoters. Examples of viral promoters that can be used as described herein include, without limitation, adenoviral promoters, vaccinia vims promoters, CMV promoters (e.g., immediate early CMV promoters), and AAV promoters.

[0089] In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can include a total number of nucleotides up to about 5 kb. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can include a total number of nucleotides that is from about 1 kb to about 5 kb, from about 1 kb to about 4 kb, from about 1 kb to about 3 kb, from about 2 kb to about 5 kb, from about 2 kb to about 4 kb, from about 2 kb to about 3 kb, from about 3 kb to about 5 kb, from about 3 kb to about 4 kb, or from about 4 kb to about 5 kb.

[0090] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect retinal cells in vivo and deliver exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an exogenous nucleic acid sequence in retinal cells present in a mammal (e.g., a human or a non-human primate) when compared to wild-type parental vector (e.g., AAV2, AAV8, AAV9, or AAVrhlO). In some embodiments, an AAV vector (e.g., an AAV2 vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence Page 48 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOin retinal cells of a mammal (e.g., a human or a non-human primate) that is greater than the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector (e.g., wild-type AAV2) having an AAV capsid polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 1 (e.g., a wild-type AAV2 vector) in retinal cells of a control mammal (e.g., a control human or a control non-human primate). In some embodiments, an AAV vector (e.g., an AAV8 vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in retinal cells of a mammal (e.g., a human or a non-human primate) that is greater than the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector (e.g., wildtype AAV8) having an AAV capsid polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 17 (e.g., a wild-type AAV8 vector) in retinal cells of a control mammal (e.g., a control human or a control non-human primate). In some embodiments, an AAV vector (e.g., an AAV9 vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in retinal cells of a mammal (e.g., a human or a non-human primate) that is greater than the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector (e.g., wild-type AAV9) having an AAV capsid polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 18 (e.g., a wildtype AAV9 vector) in retinal cells of a control mammal (e.g., a control human or a control non-human primate). In some embodiments, an AAV vector (e.g., an AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in retinal cells of a mammal (e.g., a human or a non-human primate) that is greater than the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector (e.g., wild-type AAVrhlO) having an AAV capsid polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 19 (e.g., a wild-type AAVrhlO vector) in retinal cells of a control mammal (e.g., a control human or a control non-human primate).

[0091] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprising an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect retinal cells (e.g., retinal ganglion cells, photoreceptor cells, and bipolar cells) in vivo and deliver exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence (e.g., at high levels). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an Page 49 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOexogenous nucleic acid sequence in at least 2 percent (e.g., at least 2.5 percent, at least 5 percent, at least 7.5 percent, at least 10 percent, or at least 25 percent) of retinal cells of an eye of a mammal (e.g., a human or a non-human primate). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in retinal cells (e.g., retinal ganglion cells, photoreceptor cells, and bipolar cells) of a mammal (e.g., a human or a non-human primate) that is greater than (e.g., at least 2 percent greater than, at least 2.5 percent greater than, at least 5 percent greater than, at least 7.5 percent greater than, at least 10 percent greater than, at least 25 percent greater than, at least 50 percent greater than, at least 75 percent greater than, or at least 100 percent greater than) the level of mRNA expression of an exogenous nucleic acid driven by a comparable AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence of any one of SEQ ID NO: 1 (e.g., a wildtype AAV2 vector), SEQ ID NO: 17 (e.g., a wild-type AAV8 vector), SEQ ID NO: 18 (e.g., a wild-type AAV9 vector), and SEQ ID NO: 19 (e.g., a wild-type AAVrhlO vector) in retinal cells of a control mammal (e.g., a control human or a control non-human primate).

[0092] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprising an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect retinal cells (e.g., retinal ganglion cells, photoreceptor cells, and bipolar cells) across retinal regions (e.g., across two, three, or four retinal regions) in vivo and deliver exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence (e.g., a high levels). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an exogenous nucleic acid sequence in at least about 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the retinal cells of a mammal (e.g., a human or a non-human primate). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in retinal cells (e.g., retinal ganglion cells, photoreceptor cells, and bipolar cells) in at least two, three, or four different regions of an eye of a mammal (e.g., a human or a non-human primate) that is greater than the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence set Page 50 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOforth in any one of SEQ ID NO: 1 (e.g., a wild-type AAV2 vector), SEQ ID NO: 17 (e.g., a wild-type AAV8 vector), SEQ ID NO: 18 (e.g., a wild-type AAV9 vector), and SEQ ID NO: 19 (e.g., a wild-type AAVrhlO vector) in retinal cells of those regions in a control mammal (e.g., a control human or a control non-human primate).

[0093] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprising an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect retinal cells of the eye in vivo and deliver exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an exogenous nucleic acid sequence in at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of retinal cells of the eye of a mammal (e.g., a human or a non-human primate). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in retinal cells of the eye of a mammal (e.g., a human or a non-human primate) that is greater than (e.g., at least 10 percent greater than, at least 25 percent greater than, at least 50 percent greater than, at least 75 percent greater than, or at least 100 percent greater than) the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence set forth in any one of SEQ ID NO: 1 (e.g., a wild type AAV2 vector), SEQ ID NO: 17 (e.g., a wild-type AAV8 vector), SEQ ID NO: 18 (e.g., a wild-type AAV9 vector), and SEQ ID NO: 19 (e.g., a wild-type AAVrhlO vector) in retinal cells of the eye of a control mammal (e.g., a control human or a control non-human primate).

[0094] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect two or more (e.g., two or more, three or more, four or more, five or more, six or more, or seven or more) different retinal cell types within an eye in vivo and deliver exogenous nucleic acid to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid. For example, an AAV vector (e.g., an AAV2, AAV8,Page 51 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOAAV9, or AAVrhlO vector) described herein comprising an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect two, three, four, five, six, or seven of the following retinal cell types: retinal ganglion cells, amacrine cells, horizontal cells, bipolar cells, Muller glia cells, photoreceptor cells, and RPE cells. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprising an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect (a) retinal ganglion cells, amacrine cells, and horizontal cells, (b) retinal ganglion cells, amacrine cells, and bipolar cells, (c) retinal ganglion cells, amacrine cells, and Muller glia cells, (d) retinal ganglion cells, amacrine cells, and photoreceptor cells, (e) retinal ganglion cells, amacrine cells, and RPE cells, (f) amacrine cells, horizontal cells, and bipolar cells, (g) amacrine cells, horizontal cells, and Muller glia cells, (h) amacrine cells, horizontal cells, and photoreceptor cells, (i) amacrine cells, horizontal cells, and RPE cells, (j) horizontal cells, bipolar cells, and Muller glia cells, (k) horizontal cells, bipolar cells, and photoreceptor cells, (1) horizontal cells, bipolar cells, and RPE cells, (m) bipolar cells, Muller glia cells, and photoreceptor cells, (n) bipolar cells, Muller glia cells, and RPE cells, or (o) Muller glia cells, photoreceptor cells, and RPE cells. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive mRNA expression of an exogenous nucleic acid in at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the retinal ganglion cells, at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the amacrine cells, at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the horizontal cells, at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the bipolar cells, at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the Muller glia cells, at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the photoreceptor cells, and / or at least 2 percent (e.g., at least about 2.5 percent, at Page 52 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOleast about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the RPE cells of an eye of a mammal (e.g., a human or a non-human primate) following, for example, an intravitreal administration.

[0095] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprising an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect RPE cells in vivo and deliver exogenous nucleic acid sequence to the infected RPE cells such that the infected RPE cells express the exogenous nucleic acid sequence (e.g., at high levels). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an exogenous nucleic acid sequence in at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of RPE cells of an eye of a mammal (e.g., a human or a non-human primate). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in RPE cells of an eye of a mammal (e.g., a human or a non-human primate) that is greater than (e.g., at least 10 percent greater than, at least 25 percent greater than, at least 50 percent greater than, at least 75 percent greater than, or at least 100 percent greater than) the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence set forth in any one of SEQ ID NO: 1, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19 in RPE cells of an eye of a control mammal (e.g., a control human or a control non-human primate).

[0096] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect photoreceptor cells in vivo and deliver exogenous nucleic acid sequence to the infected photoreceptor cells such that the infected photoreceptor cells express the exogenous nucleic acid sequence. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprising an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect photoreceptor Page 53 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcells in vivo to a greater extent than any other retinal cell type of an eye and deliver exogenous nucleic acid sequence to the infected photoreceptor cells such that the infected photoreceptor cells express the exogenous nucleic acid sequence. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an exogenous nucleic acid sequence in at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of photoreceptor cells of an eye of a mammal (e.g., a human or a non-human primate). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in photoreceptor cells of an eye of a mammal (e.g., a human or a non-human primate) that is greater than (e.g., at least 10 percent greater than, at least 25 percent greater than, at least 50 percent greater than, at least 75 percent greater than, or at least 100 percent greater than) the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence set forth in any one of SEQ ID NO: 1, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19 in photoreceptor cells of an eye of a control mammal (e.g., a control human or a control non-human primate).

[0097] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect retinal ganglion cells in vivo and deliver exogenous nucleic acid sequence to the infected retinal ganglion cells such that the infected retinal ganglion cells express the exogenous nucleic acid sequence. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect retinal ganglion cells in vivo to a greater extent than any other retinal cell type of an eye and deliver exogenous nucleic acid sequence to the infected retinal ganglion cells such that the infected retinal ganglion cells express the exogenous nucleic acid sequence. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an exogenous nucleic acid sequence in at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about Page 54 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO10 percent, or at least about 25 percent) of retinal ganglion cells of an eye of a mammal (e.g., a human or a non-human primate). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in retinal ganglion cells of an eye of a mammal (e.g., a human or a non-human primate) that is greater than (e.g., at least 10 percent greater than, at least 25 percent greater than, at least 50 percent greater than, at least 75 percent greater than, or at least 100 percent greater than) the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence set forth in any one of SEQ ID NO: 1, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19 in retinal ganglion cells of an eye of a control mammal (e.g., a control human or a control non-human primate).

[0098] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect bipolar cells of the retina in vivo and deliver exogenous nucleic acid sequence to the infected bipolar cells such that the infected bipolar cells express the exogenous nucleic acid sequence. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect bipolar cells of the retina in vivo to a greater extent than any other retinal cell type of an eye and deliver exogenous nucleic acid sequence to the infected bipolar cells such that the infected bipolar cells express the exogenous nucleic acid sequence. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an exogenous nucleic acid sequence in at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of bipolar cells of the retina of an eye of a mammal (e.g., a human or a non-human primate). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in bipolar cells of the retina of an eye of a mammal (e.g., a human or a non-human primate) that is greater than (e.g., at least 10 percent greater than, at least 25 percent greater than, at least 50 percent greater than, at least 75 percent greater Page 55 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOthan, or at least 100 percent greater than) the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence set forth in any one of SEQ ID NO: 1, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19 in bipolar cells of the retina of an eye of a control mammal (e.g., a control human or a control non-human primate).

[0099] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have the ability to infect retinal cells in vivo and deliver exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence. In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to infect and drive RNA expression of an exogenous nucleic acid sequence in at least 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of retinal cells of an eye of a mammal (e.g., a human or a non-human primate). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have the ability to drive a level of RNA expression of an exogenous nucleic acid sequence in retinal cells of an eye of a mammal (e.g., a human or a non-human primate) that is greater than (e.g., at least 10 percent greater than, at least 25 percent greater than, at least 50 percent greater than, at least 75 percent greater than, or at least 100 percent greater than) the level of RNA expression of an exogenous nucleic acid sequence driven by a control AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence set forth in any one of SEQ ID NO: 1, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19 in retinal cells of an eye of a control mammal (e.g., a control human or a control non-human primate).

[0100] An AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence can have increased packaging efficiency, the ability to infect cells (e.g., retinal cells) in vivo or in vitro, and the ability to deliver exogenous nucleic acid sequence to the infected cells such that the infected cells express the exogenous nucleic acid sequence (e.g., at high levels). In some embodiments, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can have a packaging efficiency that is greater than (e.g., at least 10 percent Page 56 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOgreater than, at least 25 percent greater than, at least 50 percent greater than, at least 75 percent greater than, or at least 100 percent greater than) the packaging efficiency of a comparable AAV vector having an AAV capsid polypeptide that comprises the amino acid sequence of SEQ ID NO: 1 (e.g., a wild-type AAV2 vector), SEQ ID NO: 17 (e.g., a wild-type AAV8 vector), SEQ ID NO: 18 (e.g., a wild-type AAV9 vector), or SEQ ID NO: 19 e.g., a wild-type AAVrhlO vector).

[0101] Examples of retinal cells that can be infected by an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein comprises an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or Formula A include, without limitation, retinal ganglion cells, retinal pigment epithelium cells, photoreceptor cells, bipolar cells, amacrine cells, Muller glia, and horizontal cells.

[0102] The present disclosure also provides compositions comprising one or more AAV vectors provided herein (e.g., one or more vectors provided herein). For example, one or more AAV vectors provided herein can be formulated as a pharmaceutical composition for administration to a mammal (e.g., a human or a non-human primate) to treat that mammal. In some embodiments, one or more AAV vectors provided herein can be formulated as a pharmaceutical composition for administration to a mammal (e.g., a human or a non-human primate) to deliver an exogenous nucleic acid sequence to retinal cells for expression within retinal cells. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can be formulated as a pharmaceutical composition for administration to a mammal (e.g., a human or a non-human primate). In some cases, a pharmaceutical composition provided herein can include a pharmaceutically acceptable carrier such as a buffer, a salt, a surfactant, a sugar, a tonicity modifier, or combinations thereof as, for example, described elsewhere (Gervasi el al., Eur. J. Pharmaceutics and Biopharmaceutics, 131:8-24 (2018)). Examples of pharmaceutically acceptable carriers that can be used to make a pharmaceutical composition provided herein include, without limitation, water, lactic acid, citric acid, sodium chloride, sodium citrate, sodium succinate, sodium phosphate, a surfactant (e.g., polysorbate 20, polysorbate 80, or poloxamer 188), dextran 40, or a sugar (e.g., sorbitol, mannitol, sucrose, dextrose, or trehalose), or combinations thereof. For example, a pharmaceutical composition designed to include an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can be formulated to include a buffer (e.g., an acetate, citrate, histidine, succinate, phosphate, or hydroxymethyl-aminomethane (Tris) buffer), a surfactant (e.g., polysorbate 20, polysorbate 80, or poloxamer 188), and a sugar such as sucrose. Other Page 57 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOingredients that can be included within a pharmaceutical composition provided herein include, without limitation, amino acids such as glycine or arginine, antioxidants such as ascorbic acid, methionine, or ethylenediaminetetraacetic acid (EDTA), or combinations thereof.

[0103] In some embodiments, when a pharmaceutical composition is formulated to include one or more AAV vectors provided herein, any appropriate titer of the AAV vectors can be used. For example, a pharmaceutical composition provided herein can be formulated to have AAV vectors (e.g., AAV2, AAV8, AAV9, or AAVrhlO vectors) provided herein at a titer that is greater than 1 x 107viral genomes per mL (vg / mL) (e.g., greater than 1 x 108vg / mL, greater than 1 x 109vg / mL, greater than 1 x IO10vg / mL, greater than 1 x 1011vg / mL, greater than 1 x IO’2vg / mL, greater than 1 x 1013vg / mL, or greater than 1 x 1014vg / mL). In some embodiments, a pharmaceutical composition provided herein can be formulated to have AAV vectors (e.g., AAV2, AAV8, AAV9, or AAVrhlO vectors) provided herein at a titer that is from about 1 x 107vg / mL to about 1 x 1014vg / mL e.g., from about 1 x 107vg / mL to about 1 x 1013vg / mL, from about 1 x 107vg / mL to about 1 x 1012vg / mL, from about 1 x 107vg / mL to about 1 x 1011vg / mL, from about 1 x 107vg / mL to about 1 x IO10vg / mL, from about 1 x 108vg / mL to about 1 x 1014vg / mL, from about 1 x 109vg / mL to about 1 x 1014vg / mL, from about 1 x 1010vg / mL to about 1 x 1014vg / mL, from about 1 x 108vg / mL to about 1 x 1012vg / mL, or from about 1 x 109vg / mL to about 1 x 1011vg / mL). In some embodiments, the titer is vgs / dose, wherein the dose may be administered systemically or directly. In some embodiments, the titer is in vg / eye. In some embodiments, the titer is in vgs / mL.

[0104] A pharmaceutical composition provided herein can be in any appropriate form. For example, a pharmaceutical composition provided herein can be designed to be a liquid, a semisolid, or a solid. In some embodiments, a pharmaceutical composition provided herein can be a liquid solution (e.g., an injectable and / or infusible solution), a dispersion, a suspension, a tablet, a pill, a powder, a microemulsion, a liposome, or a suppository. In some embodiments, a pharmaceutical composition provided herein can be lyophilized. In some embodiments, a pharmaceutical composition provided herein (e.g., a pharmaceutical composition that includes one or more AAV vectors provided herein can be formulated with a carrier or coating designed to protect against rapid release. For example, a pharmaceutical composition provided herein can be formulated as a controlled release formulation or as a regulated release formulation as described elsewhere (U. S. Patent Application Publication Nos. 2019 / 0241667; 2019 / 0233522; and 2019 / 0233498).

[0105] The present disclosure also provides nucleic acid molecules encoding an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9Page 58 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOor 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. In some embodiments, a nucleic acid molecule can be designed to encode an AAV capsid polypeptide that comprises an amino acid sequence that is encoded by a DNA sequence set forth in any one of SEQ ID NOs: 163-310.

[0106] The present disclosure also provides nucleic acid molecules encoding an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) described herein. For example, an isolated nucleic acid molecule can be designed to encode one or more AAV vectors provided herein (e.g., an AAV having an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence). In some embodiments, a nucleic acid molecule can be designed to encode an AAV vector having an AAV capsid polypeptide that comprises an amino acid sequence that is encoded by a DNA sequence set forth in any one of SEQ ID NOs: 163-310.

[0107] The present disclosure also provides host cells comprising a nucleic acid molecule provided herein. For example, a host cell can be designed to comprise a nucleic acid molecule encoding an AAV capsid polypeptide described herein and / or a nucleic acid molecule encoding an AAV vector described herein. In some embodiments, a host cell can be designed to comprise a nucleic acid molecule encoding an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. In some embodiments, a host cell can be designed to comprise a nucleic acid molecule encoding an AAV vector having an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. Examples of host cells that can be designed to comprise a nucleic acid molecule encoding an AAV capsid polypeptide described herein and / or a nucleic acid molecule encoding an AAV vector described herein include, without limitation, HEK293T cells (ATCC), 293AAV cells (Cell Biolabs), NEB 5-alpha cells, TakaraBio Stellar cells, and MegaX cells. Any appropriate method can be used to introduce a nucleic acid molecule provided herein (e.g., a nucleic acid molecule encoding an AAV capsid polypeptide described herein and / or an AAV vector described herein) into a cell. For example, viral transfection, electroporation, transient transfection, and gene gun techniques can be used to introduce a nucleic acid molecule provided herein into a cell.

[0108] The present disclosure also provides methods and materials for making an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein. For example, the Page 59 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOdisclosure provides methods and materials for making AAV vectors (e.g., AAV2, AAV8, AAV9, or AAVrhlO vectors) comprising an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. As described herein, an AAV vector can be constructed to comprise an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. Any appropriate method can be used to construct an AAV vector having an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) provided herein (e.g., a capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence). For example, molecular cloning and AAV vector production techniques such as those described elsewhere can be used to construct and produce an AAV vector having an AAV capsid polypeptide (e.g., an AAV2, AAV8, AAV9, or AAVrhlO capsid polypeptide) provided herein (see, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd edition, Cold Spring Harbor Laboratory, NY (1989); Ausubel et al., Current Protocols in Molecular Biology, Green Publishing Associates and John Wiley & Sons, New York, N. Y. (1994); Grieger et al., Nat. Protoc., 1 (3): 1412-28 (2006); and Flannery et al., Methods Mol. Biol., 935:351-69 (2013)). In some cases, AAV vectors can be produced in HEK293T cells (ATCC) or 293 AAV cells (Cell Biolabs) using a double or triple transfection method (see, e.g., Grieger et al., Nat. Protoc., l(3):1412-28 (2006); and Flannery et al., Methods Mol. Biol., 935:351-69 (2013)).

[0109] The present disclosure also provides methods and materials for using an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein. For example, the disclosure provides methods and materials for using AAV vectors (e.g., AAV2, AAV8, AAV9, or AAVrhlO vectors) comprising an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence. As described herein, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect retinal cells in vivo and to deliver an exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence.

[0110] As described herein, an AAV vector provided herein (e.g., an AAV vector comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ Page 60 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect retinal cells {e.g., retinal ganglion cells, photoreceptor cells, and bipolar cells) in vivo and to deliver an exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence {e.g., at high levels).

[0111] As described herein, an AAV vector provided herein {e.g., an AAV vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect retinal cells {e.g., retinal ganglion cells, photoreceptor cells, and bipolar cells) across retinal regions {e.g., across two, three, or four different retinal regions) in vivo and to deliver an exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence {e.g., at high levels). For example, an AAV vector provided herein {e.g., an AAV vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 20-162 or according to Formula A based on such a set forth sequence) can be used to infect retinal cells {e.g., retinal ganglion cells, photoreceptor cells, and bipolar cells) across retinal regions such that the AAV vector infects at least about 2 percent {e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the retinal cells, at least about 2 percent {e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the retinal cells, at least about 2 percent {e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the retinal cells in the vascular arcade region, and / or at least about 2 percent {e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the retinal cells in the periphery region of an eye of a mammal {e.g., a human or a non-human primate).

[0112] As described herein, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect retinal cells of the eye in vivo and to deliver an exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence.

[0113] As described herein, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect two or more {e.g., two or more, three or more, four or more, five or more, six or more, or seven Page 61 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOor more) different retinal cell types within an eye in vivo and to deliver an exogenous nucleic acid sequence to the infected retinal cells such that the infected retinal cells express the exogenous nucleic acid sequence (e.g., at high levels). For example, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence can be used to infect (a) at least about 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the retinal ganglion cells, (b) at least about 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the amacrine cells, (c) at least about 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the horizontal cells, (d) at least about 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the bipolar cells, (e) at least about 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the Muller glia cells, (f) at least about 2 percent e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the photoreceptor cells, (g) at least about 2 percent e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of the RPE cells, all of (a)-(g), or any combination of two, three, four, five, or six of (a)-(g) of an eye of a mammal (e.g., a human or a non-human primate) following, for example, an intravitreal administration.

[0114] As described herein, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect RPE cells in vivo and to deliver an exogenous nucleic acid sequence to the infected RPE cells such that the infected RPE cells express the exogenous nucleic acid sequence (e.g., at high levels). For example, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect RPE cells such that the AAV vector infects at least about 2 percent (e.g., at least about 2.5 percent, at least about 5 percent, at least about 7.5 percent, at least about 10 percent, or at least about 25 percent) of RPE cells of an eye of a mammal (e.g., a human or a non-human primate).Page 62 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO

[0115] As described herein, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect photoreceptor cells in vivo and to deliver an exogenous nucleic acid sequence to the infected photoreceptor cells such that the infected photoreceptor cells express the exogenous nucleic acid sequence. For example, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect photoreceptor cells in vivo to a greater extent than any other retinal cell type of an eye and to deliver an exogenous nucleic acid sequence to the infected photoreceptor cells such that the infected photoreceptor cells express the exogenous nucleic acid sequence to a greater extent than any other retinal cell type of an eye.

[0116] As described herein, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect retinal ganglion cells in vivo and to deliver an exogenous nucleic acid sequence to the infected retinal ganglion cells such that the infected retinal ganglion cells express the exogenous nucleic acid sequence. For example, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect retinal ganglion cells in vivo to a greater extent than any other retinal cell type of an eye and to deliver an exogenous nucleic acid sequence to the infected retinal ganglion cells such that the infected retinal ganglion cells express the exogenous nucleic acid sequence to a greater extent than any other retinal cell type of an eye.

[0117] As described herein, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect bipolar cells of the retina in vivo and to deliver an exogenous nucleic acid sequence to the infected bipolar cells such that the infected bipolar cells express the exogenous nucleic acid sequence. For example, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect bipolar cells of the retina in vivo to a greater extent than any other retinal cell type of an eye and to deliver an exogenous nucleic acid sequence to the infected bipolar cells such that the infected bipolar Page 63 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcells express the exogenous nucleic acid sequence to a greater extent than any other retinal cell type of an eye.

[0118] As described herein, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to improve packaging efficiency. In some embodiments, an AAV vector provided herein comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) can be used to infect cells (e.g., retinal cells) in vivo or in vitro and to deliver an exogenous nucleic acid sequence to the infected cells such that the infected cells express the exogenous nucleic acid sequence (e.g., at high levels).

[0119] In some cases, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 (or a variant thereof) or according to Formula A based on such a set forth sequence) can be used to treat a retinal condition (e.g., a retinal disease). For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a nonhuman primate) having a retinal condition in a manner such that the AAV vector (a) infects retinal cells (e.g., retinal ganglion cells, photoreceptor cells, and bipolar cells) and (b) drives expression of the delivered exogenous nucleic acid in the infected retinal cells (e.g., at high levels), thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that includes an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV Page 64 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOvector (a) infects retinal cells (e.g., retinal ganglion cells) across at least two, three, or four different retinal regions and (b) drives expression of the delivered exogenous nucleic acid in the infected retinal cells, thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects retinal cells of the eye and (b) drives expression of the delivered exogenous nucleic acid in the infected retinal cells, thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects two or more (e.g., two or more, three or more, four or more, five or more, six or more, or seven or more) different retinal cell types within an eye and (b) drives expression of the delivered exogenous nucleic acid in the infected retinal cells (e.g., at high levels), thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects RPE cells and (b) drives expression of the delivered exogenous nucleic Page 65 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOacid in the infected RPE cells (e.g., at high levels), thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects photoreceptor cells and (b) drives expression of the delivered exogenous nucleic acid in the infected photoreceptor cells, thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects retinal ganglion cells and (b) drives expression of the delivered exogenous nucleic acid in the infected retinal ganglion cells, thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects bipolar cells of the retina and (b) drives expression of the delivered exogenous nucleic acid in the infected bipolar cells, thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector)Page 66 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOprovided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects ON-retinal ganglion cells and (b) drives expression of the delivered exogenous nucleic acid in the infected ON-retinal ganglion cells, thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects OFF-retinal ganglion cells and (b) drives expression of the delivered exogenous nucleic acid in the infected OFF-retinal ganglion cells, thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition. For example, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence) that is designed to contain and drive expression of an exogenous nucleic acid sequence encoding an RNA and / or polypeptide capable of treating a retinal condition (e.g., a retinal disease) can be administered to a mammal (e.g., a human or a non-human primate) having a retinal condition in a manner such that the AAV vector (a) infects retinal cells and (b) drives expression of the delivered exogenous nucleic acid in the infected retinal cells (e.g., at high levels), thereby reducing the severity of one or more symptoms of the retinal condition and / or slowing the progression of the retinal condition.

[0120] As described herein, an AAV vector (e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein can be designed to include and drive expression of an exogenous nucleic acid sequence encoding any appropriate RNA of interest and / or polypeptide of interest.Page 67 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOWhen an AAV vector provided herein is designed to treat a retinal condition (e.g., a retinal disease), an exogenous nucleic acid sequence that encodes an RNA and / or polypeptide capable of treating the retinal condition can be included within the AAV vector. Examples of RNAs that can be encoded by an exogenous nucleic acid sequence designed to treat a retinal condition (e.g., a retinal disease) and designed to be included within an AAV vector have been provided herein. Examples of polypeptides that can be encoded by an exogenous nucleic acid sequence designed to treat a retinal condition (e.g., a retinal disease) and designed to be included within an AAV vector have been provided herein. In some embodiments, a polypeptide of interest that can be encoded by an exogenous nucleic acid sequence designed to be included within an AAV vector provided herein can be an MY07A polypeptide, an USH1C polypeptide, a PCDH15 polypeptide, an USH2A polypeptide, or CLRN1 polypeptide to treat, e.g., Usher Syndrome.

[0121] Any appropriate retinal condition (e.g., a retinal disease) can be treated using an AAV vector e.g., an AAV2, AAV8, AAV9, or AAVrhlO vector) provided herein (e.g., an AAV vector comprises an AAV capsid polypeptide that comprises an amino acid sequence set forth in any one of SEQ ID NOs: 5-9 or 20-162 or according to Formula A based on such a set forth sequence and an exogenous nucleic acid sequence encoding a therapeutic RNA and / or polypeptide). Examples of such retinal conditions include, without limitation, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), oculocutaneous albinism type 1 (OCA1), retinitis pigmentosa, rod / cone dystrophy, cone dystrophy, rod dystrophy, Stargardt Disease, Usher syndrome, X-linked retinitis pigmentosa (XLRP), X-linked retinoschisis (XLRS), choroideremia, achromatopsia, blue cone monochromacy, color blindness, glaucoma, optic atrophy, Batten disease, congenital stationary night blindness (CSNB), macular degeneration, CRB 1 -related retinal dystrophy, and foveal cone dystrophy.

[0122] Examples of therapeutic RNAs and polypeptides that can be delivered using an AAV vector provided herein to treat particular retinal conditions are set forth in Tables 4 and 5. Examples of genomic nucleic acids that can be inactivated and / or knocked out to treat particular retinal conditions using one or more AAV vectors provided herein that are designed to deliver gene editing components are set forth in Table 5. Examples of genomic nucleic acids of disease causing alleles that can be replaced with healthy alleles to treat particular retinal conditions using one or more AAV vectors provided herein that are designed to deliver gene editing components are set forth in Table 5.Page 68 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOTable 4: Examples of therapeutic polypeptide for treating retinal conditions.Retinal Condition Examples of therapeutic polypeptides Stargardt Disease ABCA4Leber congenital amaurosis 8 CRB1Leber congenital amaurosis NPHP5Retinitis pigmentosa 37 NR2E3Rod / Cone dystrophy PDE6A / PDE6BRod / Cone dystrophy PDE6cRetinitis pigmentosa 11 PRPF31Leber congenital amaurosis 2 RPE65X-linked retinitis pigmentosa RPGRX-linked retinoschisis RSIOculocutaneous albinism type 1 TYRUsher syndrome PCDH15Usher syndrome USH2aUsher syndrome USH2bUsher syndrome, subtype IB caused by MYO7Amutations in the MY07A geneUsher syndrome, subtype IC caused by USH1Cmutations in the USH1C geneUsher syndrome, subtype ID caused by CDH23mutations in the CDH23 geneUsher syndrome, subtype ID-F caused by PCDH15 and / or CDH23mutations in the PCDH15 and / or CDH23genesUsher syndrome, subtype IF caused by PCDH15mutations in the PCDH15 geneUsher syndrome, subtype IG caused by SANSmutations in the SANS geneUsher syndrome, subtype IH caused by USH1Hmutations in the USH1H geneUsher syndrome, subtype IJ caused by CIB2mutations in the CIB2 genePage 69 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WORetinal Condition Examples of therapeutic polypeptides Usher syndrome, subtype IK caused by USH1Kmutations in the USH1K geneUsher syndrome, subtype IIA, caused by USH2Amutations in the USH2AUsher syndrome, subtype IIC caused by ADGRV 1mutations in the ADGRV 1 geneUsher syndrome, subtype IID caused by WHRNmutations in the WHRN geneUsher syndrome, subtype 11C caused by GPR98 and / or PDZD7mutations in the GPR98 and / or PDZD7genes (ADGRV1 is also known as GPR98)Usher syndrome, subtype IIIA caused by CLRN1mutations in the CLRN 1 geneUsher syndrome, subtype IIIB caused by IIIB, caused by mutations in the HARS gene mutations in the HARS geneRetinitis pigmentosa One or more trophic factorsLeber congenital amaurosis One or more trophic factors Achromatopsia CNGA3, CNGB3, and / or PDE6HAny blinding disease Optogenetic tools: Chr, NhpR, ReachR, and / or othersBlue cone monochromacy OPN1LW and / or 0PN1MWCone dystrophy GNAT2Cone-rod dystrophy PDE6C and / or PROMITable 5: Examples of polypeptide that can be expressed to treat retinal conditions, examples of polypeptides that can be knocked out to treat retinal conditions, and / or examples of polypeptides that can be knocked out and replace with an alternative (e.g., wild-type or non-disease version) to treat retinal conditions. _Disease Polypeptide Gene Gene KO Gene expression editingreplacementAchromatopsia CNGA3 XPage 70 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WODisease Polypeptide Gene Gene KO Gene expression editingreplacement Achromatopsia CNGB3 XAchromatopsia PDE6H XAny blinding disease Optogenetic Xtools: Chr,NhpR, and / orReachRBatten disease CTSD XBietti crystalline dystrophy CYP4V2 X XBlue cone monochromacy OPN1LW XBlue cone monochromacy 0PN1MW XChoroideremia REP1 XCone dystrophy PDE6c XCone dystrophy GNAT2 XCone-rod dystrophy PDE6C XCone-rod dystrophy PROMI XCone / rod dystrophy PRPH2 X X XCSNB NYX X CSNB GRM6 XCSNB TRPM1 XCSNB GPR179 XCSNB LRIT3 XGlaucoma Trophic factors XGlaucoma Complement XinhibitionfactorsGlaucoma Apoptosis XinhibitionfactorsGlaucoma Survival factors XGlaucoma Neuroprotective XfactorsLCA NPHP5 XLCA GUCY2D XLeber congenital amaurosis RPE65 XLeber congenital amaurosis CRB1 X X8LHON ND4 XMacular dystrophy CRX X X X Oculocutaneous albinism TYR Xtype 1Optic atrophy CLN1-14 XRetinitis pigmentosa EYS X XPage 71 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WODisease Polypeptide Gene Gene KO Gene expression editingreplacement Retinitis pigmentosa RHO X X XRetinitis pigmentosa PRPF31 XRetinitis pigmentosa PDE6A XB e strophi nopathy BEST1 X XRetinitis pigmentosa PRPF3 XRetinitis pigmentosa PRPF8 XRetinitis pigmentosa TOPORS X X XRetinitis pigmentosa 37 NR2E3 X X X Rod / Cone dystrophy PDE6B XRP, LCA, Others Trophic factors XStargardt Disease ABCA4 X XUsher syndrome PCDH15 XUsher syndrome USH2A X XUsher syndrome MY07A X XXLRP RPGR X XLRS RSI XWet AMD Survival factors XDry AMD Survival factors XDiabetic retinopathy Survival factors XDiabetic Macular Edema Survival factors XRetinitis pigmentosa Survival factors XWet AMD Apoptosis XinhibitionfactorsDry AMD Apoptosis XinhibitionfactorsDiabetic retinopathy Apoptosis XinhibitionfactorsDiabetic Macular Edema Apoptosis XinhibitionfactorsRetinitis pigmentosa Apoptosis XinhibitionfactorsWet AMD Complement XinhibitionfactorsDry AMD Complement XinhibitionfactorsPage 72 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WODisease Polypeptide Gene Gene KO Gene expression editingreplacement Diabetic retinopathy Complement XinhibitionfactorsDiabetic Macular Edema Complement XinhibitionfactorsWet AMD Neuroprotective XfactorsDry AMD Neuroprotective XfactorsDiabetic retinopathy Neuroprotective XfactorsDiabetic Macular Edema Neuroprotective XfactorsRetinitis pigmentosa Neuroprotective XfactorsWet AMD Anti-VEGF XpolypeptidesDiabetic retinopathy Anti-VEGF XpolypeptidesDiabetic Macular Edema Anti-VEGF XpolypeptidesWet AMD Optogenetic Xtools: Chr,NhpR, and / orReachRDry AMD Optogenetic Xtools: Chr,NhpR, and / orReachRDiabetic retinopathy Optogenetic Xtools: Chr,NhpR, and / orReachRDiabetic Macular Edema Optogenetic Xtools: Chr,NhpR, and / orReachRRetinitis pigmentosa Optogenetic Xtools: Chr,NhpR, and / orReachR

[0123] In some embodiments, a retinal condition can be treated using an AAV vector provided herein that is designed to express one or more polypeptides having the ability to inhibit vascularPage 73 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOangiogenesis. Examples of polypeptides having the ability to inhibit vascular angiogenesis that can be used as described herein include, without limitation, monoclonal anti-VEGF antibody polypeptides, angiostatin polypeptides, siRNA polypeptides, and endostatin polypeptides. In some embodiments, wet AMD can be treated using an AAV vector provided herein that is designed to express a monoclonal anti-VEGF antibody polypeptide, an angiostatin polypeptide, an siRNA, and / or endostatin polypeptide. In some embodiments, diabetic retinopathy can be treated using an AAV vector provided herein that is designed to express a monoclonal anti-VEGF antibody polypeptide, an angiostatin polypeptide, an siRNA, and / or an endostatin polypeptide. In some embodiments, diabetic macular edema can be treated using an AAV vector provided herein that is designed to express a monoclonal anti-VEGF antibody polypeptide, an angiostatin polypeptide, an siRNA, and / or an endostatin polypeptide.

[0124] In some embodiments, a retinal condition can be treated using an AAV vector provided herein that is designed to express one or more polypeptides with neuroprotective capabilities. Examples of polypeptides having the ability to provide neuroprotective activity that can be used as described herein include, without limitation, GDNF polypeptides, CNTF polypeptides, IGF-1 polypeptides, VEGF polypeptides, and BDNF polypeptides. In some embodiments, wet AMD can be treated using an AAV vector provided herein that is designed to express a GDNF polypeptide, a CNTF polypeptide, an IGF-1 polypeptide, a VEGF polypeptide, and / or a BDNF polypeptide. In some embodiments, dry AMD can be treated using an AAV vector provided herein that is designed to express a GDNF polypeptide, a CNTF polypeptide, an IGF-1 polypeptide, a VEGF polypeptide, and / or a BDNF polypeptide. In some embodiments, diabetic retinopathy can be treated using an AAV vector provided herein that is designed to express a GDNF polypeptide, a CNTF polypeptide, an IGF-1 polypeptide, a VEGF polypeptide, and / or a BDNF polypeptide. In some embodiments, diabetic macular edema can be treated using an AAV vector provided herein that is designed to express a GDNF polypeptide, a CNTF polypeptide, an IGF-1 polypeptide, a VEGF polypeptide, and / or a BDNF polypeptide.

[0125] In some embodiments, a retinal condition can be treated using an AAV vector provided herein that is designed to express one or more polypeptides having the ability to provide optogenetic capabilities. Examples of polypeptides having the ability to provide optogenetic capabilities that can be used as described herein include, without limitation, ChR polypeptides, ChR2 polypeptides, ArchT polypeptides, NpHR polypeptides, and ChrimsonR polypeptides. In some embodiments, wet AMD can be treated using an AAV vector provided herein that is designed to express a ChR polypeptide, a ChR2 polypeptide, an ArchT polypeptide, a NpHR polypeptide, and / or a ChrimsonR polypeptide. In some embodiments, dry AMD can be treated Page 74 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOusing an AAV vector provided herein that is designed to express a ChR polypeptide, a ChR2 polypeptide, an ArchT polypeptide, a NpHR polypeptide, and / or a ChrimsonR polypeptide. In some embodiments, diabetic retinopathy can be treated using an AAV vector provided herein that is designed to express a ChR polypeptide, a ChR2 polypeptide, an ArchT polypeptide, a NpHR polypeptide, and / or a ChrimsonR polypeptide. In some embodiments, diabetic macular edema can be treated using an AAV vector provided herein that is designed to express a ChR polypeptide, a ChR2 polypeptide, an ArchT polypeptide, a NpHR polypeptide, and / or a ChrimsonR polypeptide.

[0126] In some embodiments, a retinal condition can be treated using an AAV vector provided herein that is designed to express one or more polypeptides having the ability to inhibit apoptosis. Examples of polypeptides having the ability to inhibit apoptosis that can be used as described herein include, without limitation, XIAP polypeptides, cIAPl polypeptides, C-IAP2 polypeptides, Livin polypeptides, and Survivin polypeptides. In some embodiments, wet AMD can be treated using an AAV vector provided herein that is designed to express a XIAP polypeptide, a cIAPl polypeptide, a C-IAP2 polypeptide, a Livin polypeptide, and / or a Survivin polypeptide. In some embodiments, diabetic retinopathy can be treated using an AAV vector provided herein that is designed to express a XIAP polypeptide, a cIAPl polypeptide, a C-IAP2 polypeptide, a Livin polypeptide, and / or a Survivin polypeptide. In some embodiments, diabetic macular edema can be treated using an AAV vector provided herein that is designed to express a XIAP polypeptide, a cIAPl polypeptide, a C-IAP2 polypeptide, a Livin polypeptide, and / or a Survivin polypeptide.

[0127] In some embodiments, a retinal condition can be treated using an AAV vector provided herein that is designed to express one or more polypeptides having the ability to inhibit complement. Examples of polypeptides having the ability to inhibit complement that can be used as described herein include, without limitation, Complement Factor I polypeptides, Complement factor H polypeptides, and sCD59 polypeptides. In some cases, wet AMD can be treated using an AAV vector provided herein that is designed to express a Complement Factor I polypeptide, a Complement factor H polypeptide, and / or a sCD59 polypeptide. In some cases, dry AMD can be treated using an AAV vector provided herein that is designed to express a Complement Factor I polypeptide, a Complement factor H polypeptide, and / or a sCD59 polypeptide. In some embodiments, diabetic retinopathy can be treated using an AAV vector provided herein that is designed to express a Complement Factor I polypeptide, a Complement factor H polypeptide, and / or a sCD59 polypeptide. In some embodiments, diabetic macular edema can be treated using an AAV vector provided herein that is designed to express a Page 75 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOComplement Factor I polypeptide, a Complement factor H polypeptide, and / or a sCD59 polypeptide.

[0128] In some embodiments, a retinal condition can be treated using an AAV vector provided herein that is designed to express one or more polypeptides having the ability to induce survival factors. Examples of polypeptides having the ability to induce survival factors that can be used as described herein include, without limitation, RdCVF polypeptides, RdCVFL polypeptides, H1F-1 polypeptides, 1AP family polypeptides, and BCE-2 family polypeptides. In some embodiments, wet AMD can be treated using an AAV vector provided herein that is designed to express a RdCVF polypeptide, a RdCVFL polypeptide, an HIF-1 polypeptide, an IAP family polypeptide, and / or a BCL-2 family polypeptide. In some embodiments, dry AMD can be treated using an AAV vector provided herein that is designed to express a RdCVF polypeptide, a RdCVFL polypeptide, an HIF-1 polypeptide, an IAP family polypeptide, and / or a BCL-2 family polypeptide. In some embodiments, diabetic retinopathy can be treated using an AAV vector provided herein that is designed to express a RdCVF polypeptide, a RdCVFL polypeptide, an HIF-1 polypeptide, an IAP family polypeptide, and / or a BCL-2 family polypeptide. In some embodiments, diabetic macular edema can be treated using an AAV vector provided herein that is designed to express a RdCVF polypeptide, a RdCVFL polypeptide, an HIF-1 polypeptide, an IAP family polypeptide, and / or a BCL-2 family polypeptide.

[0129] A “mammal” as described herein, refers to any animal at risk for, suffering from or diagnosed for a disease or disorder (for example, any disease or disorder associated with a retina) including, but not limited to, primates and humans. In certain embodiments, the mammal is a human. In some embodiments, the human is an infant, a child, or an adult. Any appropriate method can be used to administer an AAV vector provided herein or composition (e.g., a pharmaceutical composition) provided herein to a mammal (e.g., a human or a nonhuman primate). For example, a composition provided herein (e.g., a pharmaceutical composition containing one or more AAV vectors provided herein) can be administered to a mammal (e.g., a human or a non-human primate) intravitreally, intravenously (e.g., via an intravenous injection or infusion), subcutaneously (e.g., via a subcutaneous injection), intraperitoneally (e.g., via an intraperitoneal injection), orally, via inhalation, intramuscularly (e.g., via intramuscular injection), subretinally, intravitreally, systemically, or suprachoroi dally. In some embodiments, the route and / or mode of administration of a composition (e.g., a pharmaceutical composition provided herein) can be adjusted for the mammal being treated.Page 76 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO

[0130] In some embodiments, an effective amount of a composition containing an AAV vector provided herein (e.g., a pharmaceutical composition provided herein) to treat a retinal condition can be an amount that reduces the severity of one or more symptoms of the retinal condition and / or slows the progression of the retinal condition without producing significant toxicity to the mammal. For example, an effective amount of an AAV vector provided herein can be from about 1 x 107viral genomes to about IxlO14viral genomes (e.g., from about 1 x 107viral genomes to about 1 x 1013viral genomes, from about 1 x 107viral genomes to about 1 x 1012viral genomes, from about 1 x 107viral genomes to about 1 x 1011viral genomes, from about 1 x 107viral genomes to about 1 x IO10viral genomes, from about 1 x 108viral genomes to about 1 x 1014viral genomes, from about 1 x 109viral genomes to about 1 x 1014viral genomes, from about 1 x IO10viral genomes to about 1 x 1014viral genomes, from about 1 x 108viral genomes to about 1 x 1012viral genomes, or from about 1 x 109viral genomes to about 1 x 1011viral genomes). In some cases, an effective amount of an AAV vector provided herein can be from about 1 x IO10viral genomes / kg of body weight to about 1 x 1014viral genomes / kg of body weight (e.g., from about 1 x IO10viral genomes / kg of body weight to about 1 x 1013viral genomes / kg of body weight, from about 1 x IO10viral genomes / kg of body weight to about 1 x 1012viral genomes / kg of body weight, from about 1 x IO10viral genomes / kg of body weight to about 1 x 1011viral genomes / kg of body weight). The effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal's response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the severity of a retinal condition, the route of administration, the age and general health condition of the mammal, excipient usage, the possibility of co-usage with other therapeutic or prophylactic treatments such as use of other retinal drugs, and the judgment of the treating physician may require an increase or decrease in the actual effective amount of a composition provided herein e.g., a pharmaceutical composition containing an AAV vector provided herein) that is administered.

[0131] In some embodiments, an effective frequency of administration of a composition containing an AAV vector provided herein e.g., a pharmaceutical composition provided herein) can be a frequency that reduces the severity of one or more symptoms of the retinal condition and / or slows the progression of the retinal condition without producing significant toxicity to the mammal. Various factors can influence the actual effective frequency used for a particular application. For example, the severity of a retinal condition, the route of administration, the age and general health condition of the mammal, excipient usage, the possibility of co-usage with other therapeutic or prophylactic treatments such as use of other Page 77 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOretinal drugs, and the judgment of the treating physician may require an increase or decrease in the actual effective frequency of administration of a composition provided herein.

[0132] In some embodiments, an effective duration of administration of a composition containing an AAV vector provided herein (e.g., a pharmaceutical composition provided herein) can be a duration that reduces the severity of one or more symptoms of the retinal condition and / or slows the progression of the retinal condition without producing significant toxicity to the mammal. For example, an effective duration of administration of a pharmaceutical composition provided herein can vary from a single time point of administration to several weeks to several months (<?.g., 4 to 12 weeks). In some embodiments, the duration can be for as long as the mammal is alive. Multiple factors can influence the actual effective duration used for a particular application. For example, the severity of a retinal condition, the route of administration, the age and general health condition of the mammal, excipient usage, the possibility of co-usage with other therapeutic or prophylactic treatments such as use of other retinal drugs, and the judgment of the treating physician may require an increase or decrease in the actual effective duration of administration of a composition provided herein (e.g., a pharmaceutical composition containing an AAV vector provided herein).

[0133] In some embodiments, an effective amount of a composition containing an AAV vector provided herein (e.g., a pharmaceutical composition provided herein) to treat a retinal condition can be administered once or twice to a mammal (e.g., a human or a non-human primate) to treat that mammal.

[0134] The disclosure will be further described in the following examples, which do not limit the scope of any invention such as those set forth in the claims.EXAMPLESExample 1: Construction of AAV vectors comprising a variant capsid polypeptide.

[0135] A low-throughput method was used to create AAV vectors with mutated capsid polypeptides (capsid polypeptides of one or more certain serotypes with a inserted amino acid sequence in particular positions of the capsid) and to screen those created AAV vectors for particular AAV vectors having the ability to exhibit high efficiency and / or specificity for infecting retinal cells. Briefly, a set of AAV variants were cloned and packaged individually, then pooled together. The AAV variants were pooled and injected into the eyes of cynomolgus macaques non-human primates (n=2) via intravitreal injection. The AAVs were packaged with a ubiquitous CAG promoter driving expression of a green fluorescent protein (GFP) trans gene. Barcodes identifying unique AAV variants were included following the GFPPage 78 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOtransgene. 30-60 days following injection, single-cell RNA-Seq was used to quantify the expression of GFP as a metric of the performance of variants in the pool. A wild-type AAV8 (SEQ ID NO: 17) was included in the mixture as a benchmarking control in the screen. The performance of the capsid comprising SEQ ID NO: 17 with SEQ ID NO: 9 inserted between positions 590 and 591 of SEQ ID NO: 17 was quantified according to the number of cells expressing the transgene. As shown in Table 6, SEQ ID NO: 9 (SEQ ID NO: 5 flanked by LA- and A- linkers, respectively) outperformed the parental wild-type AAV8 serotype across retinal cells in all non-human primates.

[0136] SEQ ID NO: 17 denotes VP1 of AAV8 MAADGYLPDWLEDNLSEGIREWWALKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQ PARKRLNFGQTGDSESVPDPQPLGEPPAAPSGVGPNTMAAGGGAPMADNNEGADG VGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGATNDNTYFG YSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLSFKLFNIQVKEVTQNEGTKT IANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGR SSFYCLEYFPSQMLRTGNNFQFTYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSR TQTTGGTANTQTLGFSQGGPNTMANQAKNWLPGPCYRQQRVSTTTGQNNNSNFAW TAGTKYHLNGRNSLANPGIAMATHKDDEERFFPSNGILIFGKQNAARDNADYSDVM LTSEEEIKTTNPVATEEYGIVADNLQQQNTAPQIGTVNSQGALPGMVWQNRDVYLQ GPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQSKLNSFITQYS TGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTSVDFAVNTEGVYSEPRPIGTRYL TRNL (SEQ ID NO: 17)Table 6: Exemplary amino acid sequence of SEQ ID NO: 5 was inserted into an AAV capsid polypeptide at position 590. The nucleic acid sequence of SEQ ID NO: 20 encodes the amino acid sequence of SEQ ID NO: 5. Activity level denoting the performance of the exemplary amino acid sequence as compared to AAV8 (SEQ ID NO: 17) is provided in the “Activity Level” column.Amino Acid Sequence of Nucleic Acid Sequence encoding the Activity Capsid (SEQ ID NO:) Amino Acid Sequence (SEQ ID NO:) Level*SEQ ID NO: 17 with insert CGGGCCACCGGCAAGGTGRATGKV (SEQ ID NO: 20)(SEQ ID NO: 5) betweenposition 590 and 591 +++AAV8 (SEQ ID NO: 17) - - * Each + sign denotes that the modified AAV8 vector had a performance that increased by 0.51ogl0 in terms of number of retinal cells expressing transgene as compared to wild-type AAV8. “-“indicates the “baseline” to which AAV8 and exemplary amino acid sequence were compared.Page 79 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOExample 2: Construction of AAV vectors comprising exemplary variant capsid polypeptides.

[0137] A low-throughput method was used to create AAV vectors with mutated capsid polypeptides (capsid polypeptides of amino acid sequences comprising SEQ ID NOs: 17, 18, or 19 with an insert of 6 or 8 amino acids, as set forth in table 3B, and flanked by an “LA” linker on the N-tenninus of the insert and an “A” linker on the C -terminus of the insert). A screen was performed on those created AAV vectors for particular AAV vectors having the ability to exhibit high efficiency and / or specificity for infecting retinal cells. Briefly, a set of AAV variants were cloned and packaged individually, then pooled together. The AAV variants were pooled and injected into the eyes of cynomolgus macaques non-human primates (n=2) via intravitreal injection. The AAVs were packaged with a ubiquitous CAG promoter driving expression of a green fluorescent protein (GFP) transgene. Barcodes identifying unique AAV variants were included following the GFP transgene. 30-60 days following injection, singlecell RNA-Seq was used to quantify the expression of GFP as a metric of the performance of variants in the pool. The performance of each variant was quantified according to the number of cells expressing the transgene, as shown in Table 7. Performance was binned into quarters (top 14 performers (++++), top-middle 14 performers (+++), bottom-middle 14 performers (++), and bottom 'A performers (+)).Table 7: Exemplary amino acid sequences that can be inserted into an AAV capsid polypeptide with an exemplary linker. Respective nucleic acid sequences encoding the amino acid sequences are also provided. _ _ _ _ _ Activity Amino Acid SEQ ID Activity Amino Acid Sequence SEQ Level* Sequence NO: Level* ID NO: AAV8 Based Vector (SEQ ID NOs: 20-94) AAV9 Based Vector(SEQ ID NOs: 95-109)+++-1- RATGKV 5 +++ SSSGQKAS 95 +++ NTKMIR 20 +++ WPRQDG 96 +++ VRSNMQ 21 +++ VTKILP 97 +++ NSTSRE 22 +++ TTSNTRMG 98 +++ LNVAKP 23 +++ SNQKNL 99 +++ HNTTKT 24 4-4- NPSDVS 100 +++ DVRGNK 25 ++ QNSYHA 101 +++ TAGARG 26 ++ VYQGEY 102 +++ FIKAPS 27 4-4- QQNSVR 103 +++ TKKNIE 28 4-4- VTNLHM 104 +++ TMAGFS 29 ++ HKSRED 105 +++ ENASRK 30 ++ GSDHRSSS 106+++ YTRPKD 31 + LPSTQD 107Page 80 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOActivity Amino Acid SEQ ID Activity Amino Acid Sequence SEQ Level* Sequence NO: Level* ID NO:+++ SAHRSN 32 + KTDHIE 108 +++ DTRPQR 33 + HSIEHK 109 +++ MNGVKA 34 AAVrhlO Based Vector+++ NNRGTS 35 (SEQ ID NOs: 110-162)+++ YQTSKT 36 +++ YNKTRE 110 +++ ETKTRW 37 +++ NVTRHQ 111 +++ LNNTRA 38 +++ NNMVRN 112 +++ GNRLPS 39 +++ NTRKDW 113 ++ NQVGRF 40 +++ WTGKPM 114 4-4- STRPLT 41 +++ QNQTKW 115 4-4- EKATRS 42 +++ STRQHM 116 ++ TGHKGS 43 +++ SNHARQ 117 ++ TKGQGV 44 +++ ARPAQS 118 4-4- EAKGWS 45 +++ NKPAFS 119 4-4- HFTGEI 46 +++ INSVKG 120 ++ PNGVRY 47 +++ NNRIPG 121 4-4- TTNATR 48 +++ NRIKAD 122 4-4- RAPT AM 49 +++ NRTNAG 123 4-4- NGTKQW 50 +++ KGDKGW 124 ++ DTKARW 51 +++ NVNYTR 125 4-4- SNQIMR 52 +++ STKHQY 126 4-4- ANFTKQ 53 +++ NRVSVQ 127 ++ IQLGKS 54 +++ VNLVKQ 128 ++ NHTARQ 55 +++ TNLTRM 129 4-4- FTKKQE 56 +++ RTSSFG 130 4-4- HTRSSP 57 +++ NRVPRD 131 ++ NSVKMA 58 ++ NMTRNN 132 ++ NRTDWK 59 ++ NNSAKQ 133 4-4- NFTKGS 60 4-4- NVKPVT 134 4-4- NNIKAG 61 4-4- NKVGQY 135 ++ NSTSFK 62 ++ TNITKP 136 4-4- NRTSGG 63 ++ NNVGRL 137 4-4- NNIKGN 64 4-4- NRVPHQ 138 4-4- DNRMHG 65 ++ NNRIPA 139 ++ INKTKD 66 ++ NNRMPG 140 4-4- ERLGKQ 67 ++ YVKPGT 141 + QFGAGK 68 ++ GNNTRG 142 + NSKARD 69 ++ NKVPYS 143 + QKNNME 70 ++ NQIRMT 144+ FNNTKL 71 + NNIRAA 145Page 81 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOActivity Amino Acid SEQ ID Activity Amino Acid Sequence SEQ Level* Sequence NO: Level* ID NO:+ YENKIK 72 + GNTTRM 146 + HNSTHY 73 + VNAVTR 147 + NTKLSN 74 + NTVQRQ 148 + THLSIG 75 + HNTVKQ 149 + DHGRAS 76 + NSIKPA 150 + NKVKQD 77 + NQVKST 151 + PNGVRH 78 + LAKVAG 152 + NASKPH 79 + SPEYRG 153 + PNNTRY 80 + NMRGPV 154 + NRTDYK 81 + QNSTRM 155 + YEMKTS 82 + GNAVRL 156 + TTKPSP 83 + DNRLPG 157 + VNHIKT 84 + HTAAMM 158 + TTKEYK 85 + GNNTKA 159 + GNHTKD 86 + NNQIPA 160 + NHTKAG 87 + ILAEAQ 161 + GQKKES 88 + IDLTKA 162 + NGTKPL 89+ HNQTKS 90+ NFTKTN 91+ GLPKSQ 92+ GNKISP 93+ ARGDHY 94* ++++ denotes that the modified vectors had a performance that placed them within the top 1 / 4 of the rescued AAV vectors; +++ denotes that the modified AAV vectors had a performance that placed them within the top-middle 1 / 4 of the rescued AAV vectors, ++ denotes that the modified AAV vectors had a performance that placed them within the bottom-middle 1 / 4 of the rescued AAV vectors; and + denotes that the modified vectors had a performance that placed them within the bottom 1 / 4 of the rescued AAV vectors.Example 3: Efficient transduction of retinal pigment epithelium cells following suprachoroidal delivery.

[0138] An amino acid sequence insert of SEQ ID NO: 5 was inserted into an AAV capsid polypeptide of SEQ ID NO: 17 between positions 590 and 591 and was packaged with a CAG-mGL transgene. A total of 1.74E+11 vg was administered to a single eye of a cynomolgus macaque via suprachoroidal injection using microneedles. Injections were performed 3.5-4.0 mm posterior to the sclerocorneal limbus and consisted of two 75-p. L injections delivered 180° degrees apart. Four weeks post-injection, the eye globe was enucleated and dissected. The retinal pigment epithelium (RPE) layer was isolated, flat-mounted, and imaged. TransfectedPage 82 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcells were visualized with the fluorescent label and demonstrated efficient transduction of RPE cells using the capsid with the insert of SEQ ID NO: 5 following suprachoroidal delivery (data not shown).EQUIVALENTS

[0139] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.OTHER EMBODIMENTS

[0140] It is to be understood that while any claimed invention or inventions has / have been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of any invention disclosed herein, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.Page 83 of 108IPTS / 200323529 1

Claims

Attorney Docket No.: AVI-006WOWHAT IS CLAIMED IS:

1. An adeno-associated virus (AAV) vector comprising an AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162.

2. An adeno-associated virus (AAV) vector comprising an AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

3. An adeno-associated virus (AAV) vector comprising an AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 5 (RATGKV).

4. The AAV vector of any one of the preceding claims, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

5. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.Page 84 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO6. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

7. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-94.

8. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from positions corresponding to positions 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

9. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

10. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

11. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from positions corresponding to positions 586 to 591 ofPage 85 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOany one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 95-109.

12. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from positions corresponding to positions 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with the amino acid sequence comprising any one of SEQ ID NOs: 5-9.

13. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

14. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

15. The AAV vector of any one of claims 1-4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 110-162.

16. The AAV vector of any one of claims 1 -4, wherein the AAV capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.Page 86 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO17. The AAV vector of any one of the preceding claims, wherein the vector is any one of an AAV2 vector, an AAV8 vector, an AAV9 vector, and an AAVrhlO vector.

18. The AAV vector of any one of the preceding claims, wherein the vector is an AAV2 vector.

19. The AAV vector of any one of the preceding claims, wherein the vector is an AAV8 vector.

20. The AAV vector of any one of the preceding claims, wherein the vector is an AAV9 vector.

21. The AAV vector of any one of the preceding claims, wherein the vector is an AAVrhlO vector.

22. The AAV vector of any one of the preceding claims, wherein the vector further comprises an exogenous nucleic acid encoding an RNA or a therapeutic polypeptide.

23. The AAV vector of claim 22, wherein the exogenous nucleic acid encodes an RNA.

24. The AAV vector of claim 23, wherein the RNA is an siRNA or microRNA.

25. The AAV vector of claim 22, wherein the exogenous nucleic acid encodes a therapeutic polypeptide.

26. The AAV vector of claim 25, wherein the therapeutic polypeptide is a VEGF polypeptide, a RSI polypeptide, a PRPF31 polypeptide, an ABCA4 polypeptide, a CRB1 polypeptide, an NPHP5 polypeptide, or an NR2E3 polypeptide.

27. The AAV vector of any one of claims 1-26, wherein AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17.Page 87 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO28. The AAV vector of claim 27, wherein AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17.

29. The AAV vector of any one of claims 1-26, wherein AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18.

30. The AAV vector of claim 29, wherein AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18.

31. The AAV vector of any one of claims 1-26, wherein AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19.

32. The AAV vector of claim 31, wherein AAV capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19.

33. An AAV capsid polypeptide having an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162.

34. An AAV capsid polypeptide having an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

35. The AAV capsid polypeptide of claim 33 or 34, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584Page 88 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOand 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

36. The polypeptide of any one of claims 33-35, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

37. The polypeptide of claim 36, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

38. The polypeptide of any one of claims 33-35, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-94.

39. The polypeptide of claim 38, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

40. The polypeptide of any one of claims 33-35, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between aminoPage 89 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOacid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4. 17, 18, and 19.

41. The polypeptide of claim 40, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

42. The polypeptide of any one of claims 33-35, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 95-109.

43. The polypeptide of claim 42, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

44. The polypeptide of any one of claims 33-35, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

45. The polypeptide of claim 44, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

46. The polypeptide of any one of claims 33-35, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 110-162.Page 90 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO47. The polypeptide of claim 46, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

48. The polypeptide of any one of claims 33-47, wherein the polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17.

49. The polypeptide of claim 48, wherein the polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17.

50. The polypeptide of any one of claims 33-47, wherein the polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18.

51. The polypeptide of claim 50, wherein the polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18.

52. The polypeptide of any one of claims 33-47, wherein the polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19.

53. The polypeptide of claim 53, wherein the polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19.Page 91 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO54. A nucleic acid molecule encoding the AAV vector of any one of claims 1-32, or the polypeptide of any one of claims 33-53.

55. The nucleic acid molecule of claim 54, wherein the nucleic acid molecule is DNA.

56. A host cell comprising the nucleic acid molecule of claim 54 or 55.

57. The host cell of claim 56, wherein the host cell expresses the AAV vector of any one of claims 1-32.

58. The host cell of claim 56, wherein the host cell expresses the polypeptide of any one of claims 33-53.

59. A host cell comprising the AAV vector of any one of claims 1-32 or the polypeptide of any one of claims 33-53.

60. The host cell of any one of claims 56-59, wherein the host cell is a retinal cell.

61. A composition comprising the vector of any one of claims 1-32, and a pharmaceutically acceptable excipient.

62. The composition of claim 61, wherein the composition comprises from about 1 x 107vector genomes / mL (vg / mL) to about 1 x 1014vg / mL of the vector.

63. The composition of claim 61 or 62, wherein the pharmaceutically acceptable excipient comprises one or more of: phosphate buffered saline, Hank’s Balanced Salt Solution, and Pluronic F68.

64. A method for delivering an exogenous nucleic acid sequence to a retinal cell of a mammal, wherein the method comprises contacting the retinal cell with an AAV vector comprising an AAV capsid polypeptide and the exogenous nucleic acid sequence, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9Page 92 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOor 20-162, wherein the AAV vector infects the retinal cell, thereby delivering the exogenous nucleic acid sequence to the retinal cell.

65. The method of claim 64, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 591 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

68. The method of claim 64, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-94.

69. The method of 64 or 68, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

70. The method of claim 64, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

71. The method of claim 64 or 70, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

72. The method of claim 64, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acidsPage 93 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOfrom position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 95-109.

73. The method of claim 64 or 72, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

74. The method of claim 64, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

75. The method of claim 64 or 74, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

76. The method of 64 or 75, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 110-162.

77. A method for delivering an exogenous nucleic acid sequence to a retinal cell of a mammal, wherein the method comprises contacting the retinal cell with an AAV vector comprising an AAV capsid polypeptide and the exogenous nucleic acid sequence, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9, wherein the AAV vector infects the retinal cell, thereby delivering the exogenous nucleic acid sequence to the retinal cell.

78. The method of claim 77, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 591 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.Page 94 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO79. The method of any one of claims 64-78, wherein the mammal is a human.

80. The method of any one of claims 64-79, wherein the vector is an AAV2 vector.

81. The method of any one of claims 64-79, wherein the vector is an AAV8 vector.

2. The method of any one of claims 64-79, wherein the vector is an AAV9 vector.

83. The method of any one of claims 64-79, wherein the vector is an AAVrhlO vector.

84. The method of any one of claims 64-83, wherein the exogenous nucleic acid sequence encodes an RNA or a polypeptide.

85. The method of claim 84, wherein the exogenous nucleic acid encodes an RNA.

86. The method of claim 85, wherein the RNA is an siRNA or microRNA.

87. The method of claim 84, wherein the exogenous nucleic acid encodes a polypeptide.

88. The method of claim 87, wherein the polypeptide is a VEGF polypeptide, a RSI polypeptide, a PRPF31 polypeptide, an ABCA4 polypeptide, a CRB1 polypeptide, an NPHP5 polypeptide, or an NR2E3 polypeptide.

89. The method of any one of claims 64-88, wherein the method comprises intravitreally administering a composition comprising the vector to the mammal, thereby contacting the retinal cell with the vector.Page 95 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO90. The method of claim 89, wherein the composition comprises from about 1 x 107vector genomes / mL (vg / mL) to about 1 x 1014vg / mL of the vector.

91. A method for treating a retinal condition in a mammal in need thereof, wherein the method comprises contacting a retinal cell of a mammal having the retinal condition with a therapeutically effective amount of an AAV vector comprising an AAV capsid polypeptide and an exogenous nucleic acid sequence, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162, wherein the AAV vector infects the retinal cell and drive expression of the exogenous nucleic acid sequence within the retinal cell, thereby treating the retinal condition.

92. A method for treating a retinal condition in a mammal in need thereof, wherein the method comprises contacting a retinal cell of a mammal having the retinal condition with a therapeutically effective amount of an AAV vector comprising an AAV capsid polypeptide and an exogenous nucleic acid sequence, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9, wherein the AAV vector infects the retinal cell and drive expression of the exogenous nucleic acid sequence within the retinal cell, thereby treating the retinal condition.

93. The method of claim 91 or 92, wherein the mammal is a human.

94. The method of any one of claims 91-93, wherein the retinal condition is selected from the group consisting of cone dystrophy, cone / rod dystrophy, retinitis pigmentosa, macular degeneration, achromatopsia, blue cone monochromacy, and color blindness.

95. The method of any one of claims 91-94, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-162 is located between amino acid positions corresponding to positions 581 and 582, between amino acid 582 and 583, between positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positionsPage 96 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOcorresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

96. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

97. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

98. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-94.

99. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

100. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.Page 97 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO101. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

102. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 95-109.

103. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 586 to 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

104. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

105. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19.

106. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that the amino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 110-162.

107. The method of any one of claims 91-95, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 except that thePage 98 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOamino acids from position 588 to 593 of any one of SEQ ID NOs: 1-4, 17, 18, and 19 are replaced with an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

108. The method of any one of claims 91-107, wherein the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17.

109. The method of any one of claims 91-107, wherein the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 17 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 17.

110. The method of any one of claims 91-107, wherein the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18.

111. The method of any one of claims 91-107, wherein the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 18 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 588 and 589 of SEQ ID NO: 18.

112. The method of any one of claims 91-107, wherein the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19.

113. The method of any one of claims 91-107, wherein the capsid polypeptide has an amino acid sequence comprising SEQ ID NO: 19 except that the amino acid sequence of any one of SEQ ID NOs: 5-9 is located between amino acid positions corresponding to positions 590 and 591 of SEQ ID NO: 19.Page 99 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO114. The method of any one of claims 91-113, wherein the vector is an AAV2 vector.

115. The method of any one of claims 91-113, wherein the vector is an AAV8 vector.

116. The method of any one of claims 91-113, wherein the vector is an AAV9 vector.

117. The method of any one of claims 91-113, wherein the vector is an AAVrhlO vector.

118. The method of any one of claims 91-113, wherein the exogenous nucleic acid sequence encodes an RNA.

119. The method of claim 118, wherein the RNA is an siRNA or a microRNA.

120. The method of any one of claims 91-113, wherein the exogenous nucleic acid encodes a polypeptide.

121. The method of claim 120, wherein the polypeptide is a VEGF polypeptide, a RSI polypeptide, a PRPF31 polypeptide, an ABCA4 polypeptide, a CRB1 polypeptide, an NPHP5 polypeptide, or an NR2E3 polypeptide.

122. The method of any one of claims 90-121, wherein the method comprises intravitreally administering a composition comprising the vector to the mammal, thereby contacting the retinal cell with the vector.

123. The method of claim 122, wherein the composition comprises from about 1 x 107vector genomes / mL (vg / mL) to about 1 x 1014vg / mL of the vectors.

124. A non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid Page 100 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOpositions corresponding to positions 581 and 582, between amino acid positions corresponding to positions 582 and 583, between amino acid positions corresponding to positions 583 and 584, between amino acid positions corresponding to positions 584 and 585, between amino acid positions corresponding to positions 585 and 586, between amino acid positions corresponding to positions 586 and 587, between amino acid positions corresponding to positions 587 and 588, between amino acid positions corresponding to positions 588 and 589, between amino acid positions corresponding to positions 589 and 590, between amino acid positions corresponding to positions 590 and 591, between amino acid positions corresponding to positions 591 and 592, between amino acid positions corresponding to positions 592 and 593, or between amino acid positions corresponding to positions 593 and 594 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-Li-[6-mer or 8-mer polypeptide]-L2-,wherein the Li and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 6-mer or 8-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162.

125. A non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 20-94.

126. A non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:Page 101 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9.

127. A non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 95-109.

128. A non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 588 and 589 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9.

129. A non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,Page 102 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOwherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9 or 110-162.

130. A non-naturally occurring AAV capsid polypeptide, wherein the capsid polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 1-4, 17, 18, and 19 comprising an amino acid sequence insert of Formula A located between amino acid positions corresponding to positions 590 and 591 of any one of SEQ ID NOs: 1-4, 17, 18, and 19, wherein the Formula A is:-L1-INSERT-L2-,wherein the Li and the L2 are each independently optional amino acid linkers having one, two, or three amino acids, and wherein INSERT represents the amino acid sequence of any one of SEQ ID NOs: 5-9.

131. The capsid polypeptide of any one of claims 124-130, wherein the Li is one amino acid Xi.

132. The capsid polypeptide of claim 131, wherein the Xi is selected from the group of amino acid residues consisting of A, V, I, and L.

133. The capsid polypeptide of claim 131, wherein the Xi is A.

134. The capsid polypeptide of any one of claims 124-130, wherein the Li is two amino acids X2-X1.

135. The capsid polypeptide of claim 134, wherein the Xi is selected from the group of amino acid residues consisting of A, V, I, and L.

136. The capsid polypeptide of claim 135, wherein the Xi is A.

137. The capsid polypeptide of any one of claims 134-361, wherein the X2 is selected from the group of amino acid residues consisting of A, V, I, and L.Page 103 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO138. The capsid polypeptide of claim 137, wherein the X2 is L.

139. The capsid polypeptide of claim 134, wherein the X2-X1 is LA.

140. The capsid polypeptide of any one of claims 124-129, wherein the Li is three amino acids X3-X2-X1.

141. The capsid polypeptide of claim 140, wherein the Xi is selected from the group of amino acid residues consisting of A, V, I, and L.

142. The capsid polypeptide of claim 141, wherein the Xi is A.

143. The capsid polypeptide of any one of claims 140-142, wherein the X2 is selected from the group of amino acid residues consisting of A, V, I, and L.

144. The capsid polypeptide of claim 143, wherein the X2 is L.

145. The capsid polypeptide of claim 140, wherein the X2-X1 is LA.

146. The capsid polypeptide of any one of claims 140-145, wherein the X3 is selected from the group of amino acid residues consisting of A, V, I, and L.

147. The capsid polypeptide of any one of claims 134-130, wherein the Li is absent.

148. The capsid polypeptide of any one of claims 124-147, wherein the L2 is one amino acid Zi.

149. The capsid polypeptide of claim 148, wherein the Zi is selected from the group of amino acid residues consisting of A, V, I, and L.

150. The capsid polypeptide of claim 149, wherein the Zi is A.Page 104 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO151. The capsid polypeptide of any one of claims 124-147, wherein the L2 is two amino acids Z1-Z2.

152. The capsid polypeptide of claim 151, wherein the Zi is selected from the group of amino acid residues consisting of A, V, I, and L.

153. The capsid polypeptide of claim 152, wherein the Zi is A.

154. The capsid polypeptide of any one of claims 151-153, wherein the Z2 is selected from the group of amino acid residues consisting of A, V, I, and L.

155. The capsid polypeptide of claim 154, wherein the Z2 is L.

156. The capsid polypeptide of claim 151, wherein the Z1-Z2 is AL.

157. The capsid polypeptide of any one of claims 124-147, wherein the L2 is three amino acids Z1-Z2-Z3.

158. The capsid polypeptide of claim 157, wherein the Zi is selected from the group of amino acid residues consisting of A, V, I, and L.

159. The capsid polypeptide of claim 158, wherein the Zi is A.

160. The capsid polypeptide of any one of claims 157- 159-, wherein the Z2 is selected from the group of amino acid residues consisting of A, V, I, and L.

161. The capsid polypeptide of claim 160, wherein the Z2 is L.

162. The capsid polypeptide of claim 157, wherein the Z1-Z2 is AL.

163. The capsid polypeptide of any one of claims 157-162, wherein the Z3 is selected from the group of amino acid residues consisting of A, V, I, and L.Page 105 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WO164. The capsid polypeptide of any one of claims 124-147, wherein the L2 is absent.

165. A non-naturally occurring adeno-associated virus (AAV) vector comprising an AAV capsid polypeptide according to any one of claims 124-164.

166. A viral particle comprising a capsid polypeptide of any one of claims 124-164.

167. A method for administering an exogenous nucleic acid sequence to a mammal in need thereof, wherein the method comprises administering an effective amount of a vector of claim 165 to the mammal, wherein the vector comprising the exogenous nucleic acid sequence.

168. The method of claim 167, wherein the mammal is a human.

169. The method of claim 167 or 168, wherein the administering comprises administering the effective amount to an eye of the mammal.

170. The method of any one of claims 167-169, wherein the administering is sufficient to allow for expression of the exogenous nucleic acid sequence in a cell of the mammal.

171. The method of any one of claims 166-170, wherein the exogenous nucleic acid sequence encodes a therapeutic polypeptide.

172. A method of treating a retinal disorder in a patient in need thereof, comprising administering to the patient’s eye an effective amount of an AAV vector, wherein the AAV vector comprises an AAV capsid polypeptide and an exogenous nucleic acid sequence, wherein the AAV capsid polypeptide is represented by Formula A.

173. A method of treating a retinal disorder in a patient in need thereof, comprising administering to the patient’s eye an effective amount of an AAV vector, wherein the AAV vector comprises an AAV capsid polypeptide and an exogenous nucleic acid sequence,Page 106 of 108IPTS / 200323529 1Attorney Docket No.: AVI-006WOwherein the AAV capsid polypeptide comprises an amino acid sequence insert of Formula A, wherein the Formula A is:-Li-[6-mer polypeptide] -L2-,wherein the Li and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 6-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9 or 20-162.

174. A method of treating a retinal disorder in a patient in need thereof, comprising administering to the patient’s eye an effective amount of an AAV vector, wherein the AAV vector comprises an AAV capsid polypeptide and an exogenous nucleic acid sequence, wherein the AAV capsid polypeptide comprises an amino acid sequence insert of Formula A, wherein the Formula A is:-Li-[6-mer polypeptide] -L2-,wherein the Li and the L2 are each, independently, optional amino acid linkers, each having one, two, or three amino acids, and wherein the 6-mer polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 5-9.

175. A method of treating a retinal disorder in a patient in need thereof, comprising administering to the patient’s eye an effective amount of an AAV vector, wherein the AAV vector comprises an AAV capsid polypeptide of any one of claims 5-9 or 85-122 and an exogenous nucleic acid sequence.

176. A method of treating a retinal disorder in a patient in need thereof, comprising administering to the patient’s eye an effective amount of an AAV vector, wherein the AAV vector comprises an AAV capsid polypeptide of any one of claims 5-9 and an exogenous nucleic acid sequence.Page 107 of 108IPTS / 200323529 1

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