IP Library › Granted Patent US 12,692,512
Granted Patent B2
US 12,692,512 · App. 17/311,869 · Granted Jul 28, 2026

Methods and compositions for treating glycogen storage diseases

Inventors: Christopher Tipper (Cambridge, MA); Kelly Reed Clark (Westerville, OH); Samuel Wadsworth (Shrewsbury, MA)
Assignee: Ultragenyx Pharmaceutical Inc.
C12N15/86C12N9/16C12N15/11C12Y301/03009A61K38/00C12N2320/35C12N2750/14143C12N2830/34C12N2830/42C12N2830/50
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Quick Facts
Patent No.
US 12,692,512
App. No.
17/311,869
Filed
Jun 8, 2021
Granted
Jul 28, 2026
Kind
B2
Art Unit
1638
USPC
424/93.2
Abstract

This invention provides a variety of novel adeno-associated virus (AAV) vectors for gene therapy applications in the treatment of glycogen storage disease type 1 a (GSD-Ia). Disclosed herein are a number of recombinant nucleic acid molecules, vectors and recombinant AAV that incorporate a modified G6PC promoter/enhancer sequence. Utilization of the modified G6PC promoter/enhancer sequence results in enhanced AAV yield and quality when expressed from various host cell platforms. Also provided herein are compositions comprising the novel AAV of the invention and methods of treating GSD-Ia using the same.

Claims (20)

1 . A recombinant nucleic acid molecule comprising a modified G6PC promoter/enhancer (GPE) sequence, wherein the modified GPE sequence has a deletion of one or more Alu element(s) selected from the group consisting of Alu-1, Alu-2, and Alu-3, wherein:

the modified GPE sequence comprises the nucleic acid sequence of contiguous nucleotides 146-2123 of SEQ ID NO: 1, or the nucleic acid sequence of SEQ ID NO: 7, 8, 9, 10, 11, or 12.

2 . The recombinant nucleic acid molecule of claim 1 further comprising a glucose-6-phosphatase-alpha (G6Pase-α) coding sequence.

3 . The recombinant nucleic acid molecule of claim 2 , wherein the G6Pase-α coding sequence comprises a sequence identical to SEQ ID NO: 3 or SEQ ID NO: 4.

4 . The recombinant nucleic acid molecule of claim 2 , wherein the recombinant nucleic acid molecule further comprises a polyadenylation (polyA) signal sequence and/or an intron.

5 . The recombinant nucleic acid molecule of claim 2 , wherein the recombinant nucleic acid molecule comprises SEQ ID NO: 1 or SEQ ID NO: 2.

6 . A recombinant vector comprising the recombinant nucleic acid molecule of claim 2 .

7 . The recombinant vector of claim 6 , wherein the recombinant vector is an adeno-associated virus (AAV) vector.

8 . The recombinant vector of claim 7 , wherein the AAV vector is an AAV serotype 8 (AAV8) vector.

9 . An isolated host cell comprising the recombinant nucleic acid molecule of claim 2 .

10 . A method of increasing recombinant AAV (rAAV) yield, comprising delivering the recombinant vector of claim 7 to a eukaryotic host cell culture and harvesting the rAAV from the eukaryotic host cell culture.

11 . A composition comprising the recombinant vector of claim 7 and a pharmaceutically acceptable carrier.

12 . A recombinant adeno-associated virus (rAAV) for the treatment of glycogen storage disease type Ia (GSD-Ia), said rAAV comprising an AAV capsid and a vector genome packaged therein, said vector genome comprising:

(a) an AAV 5′ inverted terminal repeat sequence (ITR) sequence;

(b) a promoter/enhancer sequence comprising the contiguous nucleotides 146-2123 of SEQ ID NO: 1;

(c) a coding sequence encoding a glucose-6-phosphatase alpha (G6Pase-α); and

(d) an AAV 3′ ITR.

13 . The rAAV of claim 12 , wherein the G6Pase-α comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5 and/or the coding sequence encoding the G6Pase-α is at least 90% identical to SEQ ID NO: 3 or SEQ ID NO: 4.

14 . The rAAV of claim 13 , wherein the AAV capsid is an AAV8 capsid.

15 . The recombinant nucleic acid molecule of claim 2 , wherein the G6Pase-α coding sequence is at least 95% identical to the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4.

Continuity (2)
Provisional Application 62781380 · Dec 18, 2018
Related Publication 20220017922A1 · Jan 20, 2022
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