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 increasing the intracellular concentration of acetyl coenzyme A (AcCoA) in a subject, the method comprising administering to the subject an effective amount of a delivery construct comprising an isolated nucleic acid comprising the nucleotide sequence of SEQ ID NO: 1 under conditions whereby the nucleic acid is expressed in a host cell of the subject.
2. The method of claim 1 , wherein the delivery construct comprises a viral vector or a non-viral vector.
3. The method of claim 2 , wherein the viral vector is selected from the group consisting of an AAV1 vector, an AAV2 vector, an AAV3 vector, an AAV4 vector, an AAV5 vector, an AAV6 vector, an AAV7 vector, an AAV8 vector, an AAV9 vector, an AAV10 vector, an AAV 11 vector, a retroviral vector, an alphaviral vector, a vaccinia viral vector, an adenoviral vector, and an herpes simplex viral vector.
4. The method of claim 3 , wherein the viral vector is an AAV2 viral vector.
5. The method of claim 2 , wherein the delivery non-viral vector is a lipid, a poly-lysine, a synthetic polyamino polymer, or a plasmid.
6. The method of claim 2 , wherein the delivery construct further comprises a pharmaceutically acceptable carrier.
7. The method of claim 1 , further comprising administering to the subject a secondary therapeutic agent selected from the group consisting of an antibody, a cultured cell population, a tag or a targeting agent, an active substance and a diagnostic agent.
8. The method of claim 1 , wherein the host cell is a nerve cell selected from the group consisting of oligodendrocytes, neurons, astrocytes, and any combinations thereof.
9. A recombinant cell transfected or transformed with at least one isolated nucleic acid comprising the nucleotide sequence of SEQ ID NO:1.
10. The cell of claim 9 , wherein the nucleic acid is operatively linked to a promoter.
11. The cell of claim 9 , wherein the cell is a mammalian cell.
12. The cell of claim 11 , wherein the mammalian cell is a human neuron, a human astrocyte, or a human oligodendrocyte.
13. A gene delivery construct comprising a vector and a nucleic acid comprising the nucleotide sequence of SEQ ID NO:1.
14. The construct of claim 13 , wherein the vector is a viral vector or a non-viral vector.
15. The construct of claim 14 , wherein the viral vector is selected from the group consisting an AAV1 vector, an AAV2 vector, an AAV3 vector, an AAV4 vector, an AAV5 vector, an AAV6 vector, an AAV7 vector, an AAV8 vector, an AAV9 vector, an AAV10 vector, an AAV 11 vector, a retroviral vector, an alphaviral vector, a vaccinia viral vector, an adenoviral vector, and an herpes simplex viral vector.
16. The method of claim 14 , wherein the non-viral vector is a lipid, a poly-lysine, a synthetic polyamino polymer, or a plasmid.