Methods and gene therapy constructs for treating GM2 gangliosidoses
View Patent ↗Disclosed are novel gene therapy constructs containing both HEXA and HEXB genes to treat GM2 gangliosidoses, including Sandhoff disease and Tay-Sach's disease. Also described are co-treatments using chaperone and anti-inflammatory agents to enhance the effects of gene therapy.
1. A method for enhancing β-hexosaminidase A (HexA) enzyme activity in a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of a composition comprising
an AAV9 vector produced by expressing a construct in a cell, wherein said construct comprises a nucleotide sequence encoding from a 5′ end to a 3′ end a first ITR, a CAG promoter, a human HEXB gene, a self-cleaving P2A linker of 57 nucleotides, a human HEXA gene, and a second ITR;
wherein the self-cleaving P2A linker of 57 nucleotides links the HEXB gene and the HEXA gene;
wherein the nucleotide sequence from the beginning of the first ITR through the end of the second ITR consists of nucleotides 1 to 4792 of SEQ ID NO: 1.
2. The method of claim 1 , wherein the subject is predisposed to having, suspected of having, or diagnosed as having a lysosomal storage disorder characterized by a deficiency in HexA expression or activity.
3. The method of claim 2 , wherein the HexA deficiency comprises a partial or complete loss of endogenous expression or function of α-subunit of HexA encoded by the HEXA gene, β-subunit of HexA encoded by the HEXB gene, or both.
4. The method of claim 2 , wherein the HexA deficiency is Tay-Sach's disease or Sandhoff disease.
5. The method of claim 4 , comprising treating, reducing the severity of, or delaying the onset of Tay-Sach's disease and/or Sandhoff disease.
6. The method of claim 1 , comprising administering the composition to the subject systemically.
7. The method of claim 6 , comprising administering the composition to the subject intravenously.
8. The method of claim 1 , wherein the subject is human.
9. The method of claim 1 , comprising administering the composition to the subject intrathecally.
10. The method of claim 1 , comprising further administering a therapeutically effective amount of at least one anti-inflammatory agent, or at least one pharmaceutical chaperone agent, or a combination thereof.
11. The method of claim 10 , wherein the at least one anti-inflammatory agent comprises at least one agent selected from the group consisting of indomethacin and ITF2357.
12. The method of claim 10 , wherein the at least one pharmaceutical chaperone agent comprises pyrimethamine.