Gene Transfer Corrects Acute GM2 Gangliosidosis—Potential Therapeutic Contribution of Perivascular Enzyme Flow

Abstract

The GM2 gangliosidoses are fatal lysosomal storage diseases principally affecting the brain. Absence of β-hexosaminidase A and B activities in the Sandhoff mouse causes neurological dysfunction and recapitulates the acute Tay-Sachs (TSD) and Sandhoff diseases (SD) in infants. Intracranial coinjection of recombinant adeno-associated viral vectors (rAAV), serotype 2/1, expressing human β-hexosaminidase α (HEXA) and β (HEXB) subunits into 1-month-old Sandhoff mice gave unprecedented survival to 2 years and prevented disease throughout the brain and spinal cord. Classical manifestations of disease, including spasticity-as opposed to tremor-ataxia-were resolved by localized gene transfer to the striatum or cerebellum, respectively. Abundant biosynthesis of β-hexosaminidase isozymes and their global distribution via axonal, perivascular, and cerebrospinal fluid (CSF) spaces, as well as diffusion, account for the sustained phenotypic rescue-long-term protein expression by transduced brain parenchyma, choroid plexus epithelium, and dorsal root ganglia neurons supplies the corrective enzyme. Prolonged survival permitted expression of cryptic disease in organs not accessed by intracranial vector delivery. We contend that infusion of rAAV into CSF space and intraparenchymal administration by convection-enhanced delivery at a few strategic sites will optimally treat neurodegeneration in many diseases affecting the nervous system.

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

“…85 In the case of large transgenes that exceed the carrying capacity of AAV, methods have been developed to facilitate packaging and delivery of these longer genes as demonstrated by emerging therapies for Duchenne's muscular dystrophy, dysferlinopathies, hemophilia A, Usher 1B, and Tay-Sachs disease. [86][87][88][89][90][91] In most cases these vectors are manufactured separately and combined before dosing. In the present study, two vectors are similarly necessary to achieve efficacy.…”

Therapeutic opportunities for lysosomal diseases affecting the brain

“…The expressed enzymes seem to be appropriately processed for local diffusion, with dissemination and functional complementation throughout the brain. Given at the appropriate time, this intervention has shown remarkable effects on neurological function and survival in challenging acute neurodegenerative models [11][12] (see Fig 1 and Ref 11 and accompanying data). Transduced animals were injected with rAAV at the age of four weeks.…”

“…11,12 Future development will be predicated on experimental medicine as revealed by challenging safety and efficacy trials as a critical part of the orthodox clinical testing pathway now dignified by the term translational medical research.…”

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…While investigating brain fatal diseases like GM2 gangliosidoses, intracranial co-injection into month-old Sandhoff mice of recombinant adeno-associated viral vectors (rAAV) expressing human β-hexosaminidase α (HEXA) and β (HEXB) prevented disease throughout the brain and spinal cord [50]. Gene transfer confined to the striatum or cerebellum prevented typical symptoms of disease.…”