Bicistronic aav vectors encoding hexosaminidase alpha and beta-subunits and uses thereof

A technology of hexosaminidase and encoding, applied in the field of bicistronic AAV vector encoding hexosaminidase alpha and beta subunits and its application

Inactive Publication Date: 2021-01-08
UNIV OF MASSACHUSETTS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there are no available treatments for these disorders, collectively known as GM2 gangliosidosis

Method used

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  • Bicistronic aav vectors encoding hexosaminidase alpha and beta-subunits and uses thereof
  • Bicistronic aav vectors encoding hexosaminidase alpha and beta-subunits and uses thereof
  • Bicistronic aav vectors encoding hexosaminidase alpha and beta-subunits and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1: Behavioral performance of AAV-treated SD mice remains stable over time

[0128] Behavioral performance of AAV-treated SD and control (KO) mice was assessed at 60, 90, 105, 120 and 149 days of age using the rotarod and inverted screen tests. The motor coordination and performance of AAV-treated SD mice in accelerating rotarod ( Figure 2A ) and the inverted sieve test ( Figure 2B-2C ) test until the last time point of 149 days of age was still comparable to the normal control group. The performance of untreated SD mice declined over time and no animals survived at the last time point.

Embodiment 2

[0129] Example 2: Systemic AAV Treatment Reduces GM2 Ganglioside Content in the Whole Central Nervous System of SD Mice

[0130] 150-day-old AAV-treated SD mice (high dose) had significantly lower levels of GM2 gangliosides in the brain, cerebellum, brainstem, and spinal cord than untreated SD mice at the humane endpoint, and at AAV9-Bic and two AAV-PHP.B treatment groups were barely detected ( image 3 ). In AAV9-P2I-treated animals, GM2 levels remained above background.

Embodiment 3

[0131] Example 3: Increased hexosaminidase activity in the brain and liver of AAV-treated SD mice

[0132] Hexosaminidase activity in the cerebrum and cerebellum ( Figures 4A-4D) is consistent with the findings for GM2 ganglioside content. Enzyme activity in the brains of AAV9-P2I-treated mice was consistently lower than in the other groups, but despite this, restoration of about 10% of normal HexA activity appeared to be sufficient to significantly reduce GM2 ganglioside levels in the brain ( image 3 ). As in AAV9-Bic treated animals ( Figure 4A ), restoring HexA activity in the brain to about 20% appears to be sufficient to largely eliminate GM2 ganglioside storage ( image 3 ). Total hexosaminidase (HexA, HexB, HexS) activity in the liver was also assessed following systemic administration of AAV-PHP.Bic using the artificial substrate MUG ( Figure 5 ). In the liver, total hexosaminidase activity returned to 15% of normal.

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Abstract

Aspects of the disclosure relate to bicistronic AAV nucleic acid constructs comprising a transgene encoding hexosaminidase A ( HEXA ) and hexosaminidase (HEXB) proteins. In some embodiments, the disclosure provides methods for treating or preventing lysosomal storage disorders, such as Tay-Sachs disease and Sandhoff disease, using bicistronic nucleic acid constructs described by the disclosure.

Description

[0001] related application [0002] This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 62 / 657,243, filed April 13, 2018, under 35 U.S.C. § 119(e), the entire contents of which are incorporated herein by reference. [0003] Federally Sponsored Research [0004] This invention was made with support under National Grant No. NS093941 awarded by the National Institutes of Health. The government has certain rights in this invention. [0005] Background of the invention [0006] Tay-Sachs disease (TSD) and Sandhoff disease (SD) are autosomal recessive disorders caused by hexosaminidase A (HexA) deficiency caused by mutations in the HEXA or HEXB genes, respectively Lysosomal storage disease (LSD). HexA deficiency results in GM2 ganglioside storage in the central nervous system (CNS) and progressively worsens neurological function, developmental regression and ultimately premature death. Currently, there are no available treatments for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00
CPCC12N15/86C12N2750/14143C12N2830/205C12N9/2402A61K48/005A61K48/0075A61P25/00A61K48/00C12N2830/50C12Y302/01052
Inventor M.S.埃斯特维斯D.戈尔比奥夫斯基
Owner UNIV OF MASSACHUSETTS
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