Open AccessTherapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease
Author(s) -
Victoria J. McCurdy,
Aime K. Johnson,
Heather L. GrayEdwards,
Ashley N. Randle,
Allison M. Bradbury,
Nancy E. Morrison,
Misako Hwang,
Henry J. Baker,
Nancy R. Cox,
Miguel SenaEsteves,
Douglas R. Martin
Publication year - 2020
Publication title -
gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.332
H-Index - 159
eISSN - 1476-5462
pISSN - 0969-7128
DOI - 10.1038/s41434-020-00190-1
Subject(s) - sandhoff disease , genetic enhancement , lysosomal storage disease , cats , disease , medicine , neurodegeneration , ganglioside , gangliosidosis , thalamus , central nervous system disease , pathology , biology , gene , neuroscience , genetics
Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside. Hex deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neurodegeneration and death, typically in infancy. No effective treatment exists for human patients. Adeno-associated virus (AAV) gene therapy led to improved clinical outcome and survival of SD cats treated before the onset of disease symptoms. Most human patients are diagnosed after clinical disease onset, so it is imperative to test AAV-gene therapy in symptomatic SD cats to provide a realistic indication of therapeutic benefits that can be expected in humans. In this study, AAVrh8 vectors injected into the thalamus and deep cerebellar nuclei of symptomatic SD cats resulted in widespread central nervous system enzyme distribution, although a substantial burden of storage material remained. Cats treated in the early symptomatic phase showed delayed disease progression and a significant survival increase versus untreated cats. Treatment was less effective when administered later in the disease course, although therapeutic benefit was still possible. Results are encouraging for the treatment of human patients and provide support for the development AAV-gene therapy for human SD.