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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
Summary
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.
