Method and composition for treating neuronal hyper-excitabtiity

Patent metadata

Field	Value
Publication number	US-11472859-B2
Application number	US-201716084912-A
Country	US
Kind code	B2
Filing date	Mar 27, 2017
Priority date	Mar 28, 2016
Publication date	Oct 18, 2022
Grant date	Oct 18, 2022

Abstract

The present invention provides a therapy for treating loss of GABA-mediated pre-synaptic inhibition after spinal injury. The therapeutic regimen includes spinal segment-specific upregulation of GAD65 (glutamate decarboxylase) and VGAT (vesicular GABA transporter) to modulate chronic spasticity in patients after spinal traumatic or ischemic injury.

First claim

What is claimed is:

1. A method of treating spasticity in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a vector comprising a polynucleotide encoding glutamate decarboxylase (GAD65) and vesicular GABA transporter (VGAT), wherein:
the vector is administered directly into the subpial space of the subject, GAD 65 and VGAT are expressed and upregulated, and
the expression and upregulation of GAD65 and VGAT generate spinal interneurons with a mixed inhibitory-excitatory neurotransmitter phenotype, thereby treating spasticity in the subject.

2. The method of claim 1 , wherein the GAD65 and VGAT are overexpressed.

3. The method of claim 1 , wherein the vector is a lentiviral vector, an AV, an AAV, or a recombinant AAV.

4. The method of claim 3 , wherein the vector is a lentiviral vector.

5. The method of claim 3 , wherein the vector is an AAV.

6. The method of claim 5 , wherein the AAV is AAV9.

7. The method of claim 1 , further comprising directly administering the vector into the spinal parenchyma of the subject, into the intrathecal space of the subject, or into a peripheral spastic muscle of the subject.

8. The method of claim 3 , wherein the vector is a recombinant AAV9 comprising a GA65 polynucleotide and a VGAT polynucleotide.

9. The method of claim 8 , wherein the recombinant AAV9 is AAV9-UBI-GAD65+VGAT.

10. A method for treating a subject having a spinal cord injury comprising administering a vector comprising a polynucleotide encoding glutamate decarboxylase (GAD65) and vesicular GABA transporter (VGAT), wherein:
the vector is administered directly into the subpial space of the subject, GAD65 and VGAT are expressed and upregulated, and
the expression and upregulation of GAD65 and VGAT generate spinal interneurons with a mixed inhibitory-excitatory neurotransmitter phenotype, thereby treating the spinal cord injury.

11. The method of claim 10 , wherein the GAD65 and VGAT are overexpressed.

12. The method of claim 10 , wherein the vector is a lentiviral vector, an AV, an AAV, or a recombinant AAV.

13. The method of claim 12 , wherein the vector is a lentiviral vector.

14. The method of claim 12 , wherein the vector is an AAV.

15. The method of claim 14 , wherein the AAV is AAV9.

16. The method of claim 10 , further comprising directly administering the vector into the spinal parenchyma of the subject, into the intrathecal space of the subject, or into a peripheral spastic muscle of the subject.

17. A vector comprising a promoter functionally linked to a polynucleotide encoding GAD65 and VGAT to express and upregulate GAD65 and VGAT, wherein:
the vector is administered directly into the subpial space of the subject,
the expression and upregulation of GAD65 and VGAT generate spinal interneurons with a mixed inhibitory-excitatory neurotransmitter phenotype, and
the vector is used in a method of treating spasticity or a treatment regimen for treating a subject having a spinal cord injury.

18. The vector of claim 17 , wherein the vector is a viral vector selected from the group consisting of a lentiviral, adenoviral, and AAV vector.

19. The vector of claim 18 , wherein the vector is AAV9-UBI-GAD65+VGAT.

20. An isolated mammalian host cell containing the vector according to claim 17 .

Assignees

• Univ California

Inventors

• Marsala Martin

Classifications

• C07C233/69

  of an acyclic saturated carbon skeleton · CPC title

• C07C235/42

  having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton · CPC title

• C12N9/88

  Lyases (4.) · CPC title

• A61K48/005 Primary

  characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered · CPC title

• C12N2710/00

  dsDNA viruses · CPC title