Granted Patent
B2
US 12,350,311 · App. 18/616,511 · Granted Jul 8, 2025
Gene therapy for neurodegenerative disorders
Inventors:
Marco A. Passini (Northborough, MA); Lamya Shihabuddin (Brighton, MA); Seng H. Cheng (Natick, MA)
Assignee:
Genzyme Corporation
A61K38/1709A61K31/7088A61K48/00A61K48/0008A61K48/005A61K48/0075C07K14/4702C12N7/00C12N15/86C12N2750/14121C12N2750/14133C12N2750/14143C12N2750/14171
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Abstract
Compositions and methods for treating disorders affecting motor function, such as motor function affected by disease or injury to the brain and/or spinal cord, are disclosed.
Claims (26)
1. A method of modulating motor function in a subject with spinal muscular atrophy (SMA) comprising administering to a subject in need thereof a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) virion comprising a self-complementary adeno-associated virus (scAAV) vector comprising a heterologous nucleic acid construct, wherein the heterologous nucleic acid construct comprises:
a. a first AAV2 inverted terminal repeat (ITR);
b. a cytomegalovirus enhancer/chicken-β actin (CBA) promoter;
c. a polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 2; and
d. a second AAV2 ITR,
wherein the rAAV virion comprises an AAV8 or AAV9 capsid, and wherein the rAAV virion is administered (i) via direct spinal cord injection, and/or (ii) via intrathecal injection.
2. The method of claim 1 , wherein the polynucleotide encodes a SMN protein comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 2.
3. The method of claim 1 , wherein the polynucleotide encodes a SMN protein comprising an amino acid sequence that is identical to SEQ ID NO: 2.
4. The method of claim 1 , wherein the first or the second ITR is mutated.
5. The method of claim 4 , wherein the first or the second ITR comprises a mutation in a terminal resolution sequence.
6. The method of claim 4 , wherein the mutation comprises a deletion at the terminal resolution site of the first or the second ITR.
7. The method of claim 1 , wherein a single dose of the rAAV virion is administered.
8. The method of claim 1 , wherein about 10 6 to about 10 15 rAAV virions are administered.
9. The method of claim 1 , wherein the scAAV virion is administered via direct spinal cord injection.
10. The method of claim 1 , wherein the scAAV virion is administered via intrathecal injection.
11. A method of treating spinal muscular atrophy (SMA) comprising administering to a subject in need thereof a therapeutically effective amount of recombinant AAV (rAAV) virions, wherein the rAAV virions comprise a self-complementary heterologous nucleic acid construct comprising, in 5′ to 3′ order, a first AAV2 ITR; a cytomegalovirus enhancer/chicken-β actin (CBA) promoter; a polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 2; a second AAV2 ITR; an inverted polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 2; an inverted cytomegalovirus enhancer/chicken-β actin (CBA) promoter; and an inverted AAV2 ITR, wherein the rAAV virions comprise an AAV8 or AAV9 capsid, and wherein the rAAV virions are administered via intrathecal injection.
12. The method of claim 11 , wherein the first or the second ITR is mutated.
13. The method of claim 12 , wherein the first or the second ITR comprises a mutation in a terminal resolution sequence.
14. A method of increasing survival of a subject, comprising administering to a subject in need thereof a therapeutically effective amount of recombinant AAV (rAAV) virions, wherein the subject has spinal muscular atrophy (SMA), wherein the rAAV virions comprise a self-complementary heterologous nucleic acid construct comprising, in 5′ to 3′ order, a first AAV2 ITR; a cytomegalovirus enhancer/chicken-β actin (CBA) promoter; a polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 2; a second AAV2 ITR; an inverted polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 2; an inverted cytomegalovirus enhancer/chicken-β actin (CBA) promoter; and an inverted AAV2 ITR, wherein the rAAV virions comprise an AAV8 or AAV9 capsid, and wherein the rAAV virions are administered via intrathecal injection.
15. The method of claim 14 , wherein the first or the second ITR is mutated.
16. The method of claim 15 , wherein the first or the second ITR comprises a mutation in a terminal resolution sequence.
17. A method of expressing a survival motor neuron (SMN) protein in motor neurons of the spinal cord, comprising administering to a subject in need thereof a therapeutically effective amount of recombinant AAV (rAAV) virions, wherein the subject has spinal muscular atrophy (SMA), wherein the rAAV virions comprise a self-complementary heterologous nucleic acid construct comprising, in 5′ to 3′ order, a first AAV2 ITR; a cytomegalovirus enhancer/chicken-β actin (CBA) promoter; a polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 2; a second AAV2 ITR; an inverted polynucleotide encoding a survival motor neuron (SMN) protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 2; an inverted cytomegalovirus enhancer/chicken-β actin (CBA) promoter; and an inverted AAV2 ITR, wherein the rAAV virions comprise an AAV8 or AAV9 capsid, and wherein the rAAV virions are administered via intrathecal injection.
18. The method of claim 17 , wherein the first or the second ITR is mutated.
19. The method of claim 18 , wherein the first or the second ITR comprises a mutation in a terminal resolution sequence.
20. The method of claim 17 , wherein the motor neurons of the spinal cord are in the dorsal and ventral horns of the spinal cord.
21. The method of claim 17 , wherein the motor neurons of the spinal cord are in the lumbar, thoracic and/or cervical segments of the spinal cord.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 27, 2024
From: PASSINI, MARCO; SHIHABUDDIN, LAMYA; CHENG, SENG
To: GENZYME CORPORATION
Reel/Frame 066920/0028 →
Continuity (9)
Continuation
16449221
· Jun 21, 2019
Continuation
PCTUS2010001239
· Apr 27, 2010
Provisional Application
61268059
· Jun 8, 2009
Provisional Application
61174982
· May 2, 2009
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