Methods of treating or preventing amyotrophic lateral sclerosis

Patent metadata

Field	Value
Publication number	US-12508327-B2
Application number	US-201917270553-A
Country	US
Kind code	B2
Filing date	Aug 30, 2019
Priority date	Aug 30, 2018
Publication date	Dec 30, 2025
Grant date	Dec 30, 2025

Abstract

This disclosure provides methods for treating, ameliorating, or reversing at least one symptom of amyotrophic lateral sclerosis (ALS) in a subject by increasing the amount of neuronal aspartate in spinal cord through administration of a therapeutically effective amount of a composition comprising a nucleic acid encoding ASPA or a functional fragment thereof.

First claim

What is claimed is:

1 . A method of increasing the amount of neuronal aspartate in the brain and spinal cord or increasing the N-acetylaspartate (NAA) catabolism in the brain or spinal cord to facilitate mitochondrial function in a subject at risk of developing amyotrophic lateral sclerosis (ALS) or suffering from ALS comprising identifying said subject by screening the subject for ALS and administering to the subject a therapeutically effective amount of a composition, wherein the composition comprises a nucleic acid encoding aspartoacylase (ASPA) or a functional fragment thereof, wherein the ASPA or functional fragment thereof comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO:1 carried on a recombinant adeno-associated virus (rAAV) vector, and wherein the ASPA or functional fragment thereof has the enzymatic activity of aspartoacylase.

2 . The method of claim 1 , wherein the administration of the composition increases the NAA catabolism in brain or spinal tissue and enhances motor-neuron survival in the subject.

3 . The method of claim 1 , further comprising administering to the subject a second therapeutic agent.

4 . The method of claim 3 , wherein the second therapeutic agent is Riluzole, Edaravone, or a salt or solvate thereof or a combination thereof.

5 . A method of treating, ameliorating, or reversing at least one symptom of amyotrophic lateral sclerosis (ALS) in a subject having ALS, comprising the steps of:
a) identifying a patient in need of an increase in intracellular aspartate level; and b) administering to the subject a therapeutically effective amount of a composition that increases a level or activity of aspartoacylase (ASPA) in motor neurons of the subject.

6 . The method of claim 5 , wherein the composition comprises a gene therapy composition.

7 . The method of claim 5 , wherein the composition comprises a nucleic acid encoding ASPA or a functional fragment thereof, wherein the ASPA or functional fragment thereof comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO: 1.

8 . The method of claim 7 , wherein the nucleic acid encoding ASPA or a fragment thereof, comprises an amino acid sequence of SEQ ID NO: 1.

9 . The method of claim 7 , comprising introducing the nucleic acid to the at least one cell of the subject by viral transduction.

10 . The method of claim 9 , wherein the composition is provided a virus or a virus-like particle comprising the nucleic acid.

11 . The method of claim 10 , wherein the nucleic acid is carried on a recombinant adeno-associated virus (rAAV) vector.

12 . The method of claim 1 , comprising administering the composition to at least a portion of the brain and spinal cord of the subject.

13 . The method of claim 1 , wherein the composition is administered by a route selected from oral, parenteral, transdermal, pulmonary, intranasal, buccal, intrathecal, and intravenous.

14 . The method of claim 13 , wherein the composition is administered by an intrathecal route.

15 . The method of claim 1 , wherein the subject is a mammal.

16 . The method of claim 15 , wherein the mammal is a human.

17 . The method of claim 5 , wherein the at least one symptom of ALS is mitochondrial dysfunction.

18 . A kit for increasing a level or activity of ASPA in a cell of a subject comprising a rAAV1 vector or a virus-like particle, wherein the virus or the virus-like particle comprises a nucleic acid encoding ASPA or a functional fragment thereof, wherein the ASPA or functional fragment thereof comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO: 1, and wherein the ASPA or functional fragment thereof has the enzymatic activity of aspartoacylase.

19 . The method of claim 1 , wherein the administration of the composition delivers said composition to motor neurons.

20 . The method of claim 7 , wherein the administering step delivers the composition to said motor neurons.

Assignees

• Univ Rowan

Inventors

• Francis Jeremy
• Leone Paola

Classifications

• C12Y305/01015

  Aspartoacylase (3.5.1.15) · CPC title

• C12N2750/14171

  Demonstrated in vivo effect · CPC title

• C12N2750/14143

  viral genome or elements thereof as genetic vector · CPC title

• C12N15/86

  Viral vectors · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title