Metabolic therapy for oxidative stress in the brain through targeted neuronal catabolism of N-acetyl-aspartic acid
The present invention provides a novel method of treatment for treating brain disorders that manifest oxidative stress by providing targeted populations of neurons with the ability to catabolize the acetylated amino acid derivative, N-acetylaspatic acid (NAA) and further supply extraphysiological levels of ATP to neurons via the targeted expression of the NAA catabolic enzyme aspartoacylase (ASPA) in neurons and astrocytes.
1. A method of reducing oxidative stress in a subject suffering from Parkinson's disease, the method comprising:
(a) identifying a subject suffering from Parkinson's disease; and
(b) administering to the subject an effective amount of a formulation comprising an isolated nucleic acid comprising a first sequence that encodes aspartoacylase (ASPA) under conditions whereby the nucleic acid is expressed in a host cell of the subject and whereby expression of ASPA leads to enhanced catabolism of NAA, increased concentration of AcCoA, and reduced oxidative stress.
2. The method of claim 1 , wherein the host cell is a nerve cell selected from the group consisting of oligodendrocytes, neurons, astrocytes, and any combination thereof.
3. The method of claim 1 , further comprising administration of a secondary therapeutic product selected from the group consisting of an antibody, a cultured cell, an active substance and a diagnostic agent.
4. The method of claim 1 , wherein the formulation further comprises a pharmaceutically acceptable carrier.
5. The method of claim 1 , further comprising a step of administering an adjunct immunotherapy, a dietary regime, or combinations thereof.
6. The method of claim 1 , wherein the isolated nucleic acid is in a vector and operatively linked to a promoter.
7. The method of claim 6 , wherein the vector is an AAV vector comprising a regulatory element.
8. The method of claim 7 , wherein the AAV vector is an AAV 2 vector.
9. The method of claim 8 , wherein the AAV2 vector further comprises bovine growth hormone polyA, the promoter is neuron specific enolase, and the regulatory element is woodchuck hepatitis virus post-translational regulatory element.
10. The method of claim 1 , wherein the first sequence that encodes ASPA is SEQ ID NO: 1.
11. A method for improving the disease phenotype of a subject suffering Parkinson's disease, the method comprising administering to the subject an effective amount of a formulation comprising an isolated nucleic acid comprising a first sequence that encodes ASPA under conditions whereby the nucleic acid is expressed in a host cell of the subject and whereby expression of ASPA leads to enhanced catabolism of NAA, increased concentration of AcCoA, and reduced oxidative stress, wherein the formulation is administered to a tissue afflicted by the disease.
12. The method of claim 11 , wherein the isolated nucleic acid further comprises a second sequence that encodes a tag and is fused in frame with the first sequence.
13. The method of claim 11 , wherein the tissue is selected from the group consisting of cerebral cortex, intracranial white matter, basal ganglia, thalamus, hypothalamus, brain stem, and cerebellum.
14. The method of claim 11 , wherein the first sequence that encodes ASPA is SEQ ID NO: 1.