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Life-Limiting Peripheral Organ Dysfunction in Feline Sandhoff Disease Emerges after Effective CNS Gene Therapy

Aime K Johnson1, Victoria J McCurdy2,3, Heather L Gray-Edwards2

  • 1Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.

Annals of Neurology
|August 1, 2023
PubMed

Insights

Adeno-associated virus (AAV) gene therapy successfully treated feline Sandhoff disease, significantly extending lifespan and clearing neurological ganglioside storage. Whole-body targeting is crucial for future treatments.

Area of Science:

  • Neuroscience
  • Genetics
  • Biotechnology

Background:

  • GM2 gangliosidosis, including Tay-Sachs and Sandhoff diseases, is a fatal neurodegenerative disorder with no current effective treatments.
  • Children with GM2 gangliosidosis typically succumb by age five after a prolonged period of neurodegeneration.

Purpose of the Study:

  • To advance adeno-associated virus (AAV) gene therapy for potential human translation in treating GM2 gangliosidosis.
  • To evaluate the efficacy of AAV-mediated gene therapy in a feline model of Sandhoff disease.

Main Methods:

  • Feline models of Sandhoff disease received intracranial injections of vectors encoding feline β-N-acetylhexosaminidase.
  • Hexosaminidase activity and ganglioside storage were assessed in the central nervous system and throughout the body post-treatment.

Main Results:

  • AAV gene therapy normalized hexosaminidase activity and significantly reduced ganglioside storage in the brain and spinal cord.
  • Treated cats showed a marked increase in lifespan, from 4.4 months to 19.1 months, with some surviving over 21 months.
  • While central nervous system pathology was corrected, peripheral tissues, particularly the enteric nervous system, remained inadequately treated, leading to secondary complications.

Conclusions:

  • AAV gene therapy effectively addresses neuropathology in feline Sandhoff disease, offering a promising therapeutic strategy.
  • The study highlights the need for whole-body targeting in future gene therapy approaches to fully address systemic manifestations of GM2 gangliosidosis.
Abstract

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