AAV VARIANTS FOR TREATMENT OF COMPLEMENT DISORDERS

1 . A recombinant adeno-associated virus (rAAV) comprising (i) a variant AAV capsid protein comprising a heterologous peptide with a length of 7, 8, 9, 10 or 11 amino acids covalently inserted in the GH-loop of the capsid protein relative to a corresponding parental AAV capsid protein, wherein the peptide insertion comprises the amino acid sequence ISDQTKH (SEQ ID NO:1) and (ii) a heterologous nucleic acid comprising a nucleotide sequence encoding a complement regulator factor H (CFH) protein or a fragment thereof.

2 . The rAAV according to claim 1 , wherein the insertion peptide is LAISDQTKHA (SEQ ID NO:2).

3 . The rAAV according to claim 1 , wherein the insertion site is located between amino acids corresponding to amino acids 587 and 588 of VP1 of AAV2 (SEQ ID NO:47) or the corresponding position in the capsid protein of another AAV serotype.

4 . (canceled)

5 . The rAAV according to claim 1 , wherein the capsid protein comprises a P34A amino acid substitution relative to VP1 of AAV2 and comprises an amino acid sequence at least 95% identical to the entire length of the amino acid sequence set forth as SEQ ID NO:42, preferably wherein the capsid protein consists of the amino acid sequence set forth as SEQ ID NO:42.

6 . (canceled)

7 . The rAAV according to claim 1 , wherein the variant AAV capsid protein comprises an amino acid sequence with 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:42.

8 . The rAAV according to claim 1 , wherein the rAAV comprises a heterologous acid comprising from 5′ to 3′: (a) an inverted terminal repeat (b) a promoter (c) a nucleotide sequence encoding the CFH protein or a fragment thereof (d) a polyadenylation sequence and/or a WPRE sequence and (e) an inverted terminal repeat.

9 . (canceled)

10 . (canceled)

11 . The rAAV according to claim 1 , wherein the CFH protein fragment consists of SCRs: 1, 2, 3, 4, 19, 20 and one or more of SCR 7, 17 and/or 18, and a leader sequence and one or more linker sequences.

12 . The rAAV according to claim 1 , wherein the CFH protein fragment consists of SCRs: 1, 2, 3, 4, 19, 20 and one or more of SCR 7, 17 and/or 18 and one or more of SCR5, SCR6, SCR8, SCR16, and a leader sequence and one or more linker sequences.

13 . (canceled)

14 . The rAAV according to claim 1 , wherein the CFH protein fragment consists of a combination of SCR domains selected from one or more of:

(a) SCR1, 2, 3, 4, 7, and 19-20;

(b) SCR1-4, 6, 7, and 19-20;

(c) SCR1-4, 7, 8, and 19-20;

(d) SCR1-4, 6, 7, 8, and 19-20;

(e) SCR1-4, 17, 19-20;

(f) SCR1-4, and 18-20;

(g) SCR1-4, and 17-20;

(h) SCR1-4, 7, and 18-20;

(i) SCR1-4, 6, 7, and 18-20;

(j) SCR1-4, 7, 8, and 18-20;

(k) SCR1-4, 6-8, and 18-20,

(l) SCR1-4, 7, and 17-20;

(m) SCR1-4, 6, 7, and 17-20;

(n) SCR1-4, 7, 8, and 17-20; or

(o) SCR1-4, 6-8, and 17-20,

and a leader sequence and one or more linker sequences.

15 . The rAAV according to claim 14 , wherein the CFH protein fragment comprises SCR1-4, 6-8, and 17-20 and wherein the CFH protein fragment does not comprise SCR5 and SCR9-16.

16 . The rAAV according to claim 15 , wherein the CFH protein fragment comprises at least a linker of 1 to about 18 amino acids located between one or more of the SCRs.

17 . The rAAV according to claim 16 , wherein the CFH protein fragment comprises SCR1-(L1)-SCR2-(L2)-SCR3-(L3)-SCR4-(L4)-(SCR6-(L4′))-SCR7-(L5)-(SCR8-(L5′))-(SCR16-(L5″))-(SCR17-(L5″′))-(SCR1 8-(L5″″))-SCR19-(L6)-SCR20, wherein the ( ) indicate optional component(s), “L” refers to a linker, and each of L1, L2, L3, L4, L4′, L5, L5?, L5″, L5″′, L5″″ and L6 may be absent or independently selected from an amino acid sequence of about 1 to about 12 to about 18 amino acids.

18 . (canceled)

19 . (canceled)

20 . The rAAV according to claim 17 , wherein the CFH protein fragment comprises an amino acid sequence with at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:34.

21 . The rAAV according to claim 17 , wherein the CFH protein fragment comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:34.

22 . The rAAV according to claim 17 , wherein the CFH protein fragment comprises at least one glycosylation site in one or more of the SCRs.

23 . (canceled)

24 . The rAAV according to claim 22 , wherein the glycosylation site is engineered into one or more of SCR17 and/or SCR18.

25 . (canceled)

26 . The rAAV according to claim 22 , wherein the CFH protein fragment comprises SCR1-4, 6-8, and 17-20 and wherein the glycosylation site is engineered into SCR 17 and SCR18, and wherein the CFH protein fragment does not comprise SCR5 and SCR9-16.

27 . The rAAV according to claim 26 , wherein the CFH protein fragment comprises an amino acid sequence with 100% sequence identity to the sequence set forth in SEQ ID NO:34 and wherein the glycosylation site is engineered into SCR17 and SCR18.

28 . The rAAV according to claim 1 , wherein the promoter is a ubiquitous promoter, optionally a CAG promoter.

29 . (canceled)

30 . (canceled)

31 . The rAAV according to claim 28 , wherein the rAAV comprises a heterologous nucleic acid comprising a nucleotide sequence with at least 95% sequence identity to the nucleotide sequence set forth in any one of SEQ ID NOs:43-46.

32 . (canceled)

33 . (canceled)

34 . The rAAV according to claim 28 , wherein the rAAV comprises a heterologous nucleic acid comprising the nucleotide sequence set forth in any one of SEQ ID NOs:43-46.

35 . A host cell comprising the rAAV according to claim 34 .

36 . A pharmaceutical composition comprising the rAAV according to claim 31 and a pharmaceutically acceptable carrier, diluent, excipient or buffer.

37 . A method for treating dry age-related macular disorder (dry AMD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 36 by intravitreal, suprachoroidal or subretinal administration.

38 . (canceled)

39 . (canceled)

40 . A method for treating geographic atrophy (GA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 36 by periocular, intravitreal, suprachoroidal or subretinal administration.

41 . (canceled)

42 . (canceled)

43 . (canceled)

44 . (canceled)