Clinical parameters by expression of factor VIII

Patent metadata

Field	Value
Publication number	US-12497632-B2
Application number	US-201917265750-A
Country	US
Kind code	B2
Filing date	Aug 2, 2019
Priority date	Aug 3, 2018
Publication date	Dec 16, 2025
Grant date	Dec 16, 2025

Abstract

Described herein are constructs used for liver-specific expression of a transgene.

First claim

What is claimed is:

1 . A method of increasing Factor VIII (FVIII) protein in a human subject, comprising intravenously administering to the human subject a dose of 1×10 13 to 5×10 13 vg/kg of an Adenovirus-Associated Virus serotype 6 (AAV6) vector that encodes a FVIII protein, wherein administration of the AAV6 vector results in a clinically relevant 20% to 172% increase in the level of circulating FVIII activity, and wherein the AAV6 vector comprises an expression cassette that comprises
a first insulator sequence comprising nucleotides 14-32 of SEQ ID NO:5,
an enhancer sequence of SEQ ID NO:2,
a promoter sequence of SEQ ID NO:3,
a coding sequence that encodes an FVIII protein of SEQ ID NO:1, and
a second insulator sequence comprising nucleotides 4869-4885 of SEQ ID NO:5.

2 . The method of claim 1 , wherein administration of the AAV6 vector results in one or zero occurrences of spontaneous bleeding episodes in the human subject between 3-12 months after administration.

3 . The method of claim 1 , comprising administering a dose of 1×10 13 vg/kg to 3×10 13 vg/kg of the AAV6 vector.

4 . The method of claim 1 , comprising administering a dose of 2×10 13 vg/kg to 4×10 13 vg/kg of the AAV6 vector.

5 . The method of claim 1 , comprising administering a dose of 3×10 13 vg/kg of the AAV6 vector.

6 . The method of claim 1 , wherein the clinically relevant increase is a 20% to 150% increase.

7 . The method of claim 1 , wherein the AAV6 vector comprises an AAV2 5′ inverted terminal repeat (ITR) sequence and an AAV2 3′ ITR sequence that flank the expression cassette.

8 . The method of claim 7 , wherein the AAV2 5′ ITR comprises the nucleotide sequence of SEQ ID NO:12 and/or the AAV2 3′ ITR comprises the nucleotide sequence of SEQ ID NO:13.

9 . The method of claim 1 , wherein the expression cassette comprises the nucleotide sequence of SEQ ID NO:5.

10 . The method of claim 1 , wherein the human subject has hemophilia.

11 . A method of decreasing spontaneous bleeding episodes in a human subject receiving FVIII therapy, comprising intravenously administering to the human subject a dose of 1×10 13 to 5×10 13 vg/kg of an Adenovirus-Associated Virus serotype 6 (AAV6) vector that encodes a FVIII protein, wherein no more than one spontaneous bleeding episode occurs from 3 to 12 months after the intravenous administration, and wherein the AAV6 vector comprises an expression cassette that comprises
a first insulator sequence comprising nucleotides 14-32 of SEQ ID NO:5,
an enhancer sequence of SEQ ID NO:2,
a promoter sequence of SEQ ID NO:3,
a coding sequence that encodes an FVIII protein of SEQ ID NO:1, and
a second insulator sequence comprising nucleotides 4869-4885 of SEQ ID NO:5.

12 . The method of claim 11 , wherein the human subject does not receive any FVIII treatments 3-12 months after administration.

13 . The method of claim 11 , comprising administering a dose of 1×10 13 vg/kg to 3×10 13 vg/kg of the AAV6 vector.

14 . The method of claim 11 , comprising administering a dose of 2×10 13 vg/kg to 4×10 13 vg/kg of the AAV6 vector.

15 . The method of claim 11 , comprising administering a dose of 3×10 13 vg/kg of the AAV6 vector.

16 . The method of claim 11 , wherein the human subject does not receive any FVIII treatments 2, 5, or 10 years after administration.

17 . The method of claim 11 , wherein the AAV6 vector comprises an AAV2 5′ ITR sequence and an AAV2 3′ ITR sequence that flank the expression cassette.

18 . The method of claim 17 , wherein the AAV2 5′ ITR comprises the nucleotide sequence of SEQ ID NO:12 and/or the AAV2 3′ ITR comprises the nucleotide sequence of SEQ ID NO:13.

19 . The method of claim 12 , wherein the human subject has hemophilia and wherein the expression cassette comprises the nucleotide sequence of SEQ ID NO:5.

Assignees

• Sangamo Therapeutics Inc

Inventors

• Conner Edward R
• Riley Brigit E
• Rouy Didier

Classifications

• C12N15/86 Primary

  Viral vectors · CPC title

• C12N2750/14071

  Demonstrated in vivo effect · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title

• C12N2750/14043

  viral genome or elements thereof as genetic vector · CPC title