Gene Transfer Corrects Acute GM2 Gangliosidosis--potential Therapeutic Contribution of Perivascular Enzyme Flow

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2012 Mar 29

PMID 22453766

Citations 40

Authors

M Begona Cachon-Gonzalez

Susan Z Wang

Rosamund McNair

Josephine Bradley

David Lunn

Robin Ziegler

Seng H Cheng

Timothy M Cox

Affiliations

Soon will be listed here.

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.

Citing Articles

Tay-Sachs and Sandhoff Diseases: Diffusion tensor imaging and correlational fiber tractography findings differentiate late-onset GM2 Gangliosidosis.

Lewis C, Chipman S, Johnston J, Acosta M, Toro C, Tifft C medRxiv. 2025; .

PMID: 39802759 PMC: 11722463. DOI: 10.1101/2024.12.13.24318793.

Intravenous gene therapy improves lifespan and clinical outcomes in feline Sandhoff Disease.

Maguire A, Ta L, Gross A, Osterhoudt D, Cannon J, Hall P bioRxiv. 2024; .

PMID: 39605340 PMC: 11601349. DOI: 10.1101/2024.11.15.623838.

Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease.

Tsourmas K, Butler C, Kwang N, Sloane Z, Dykman K, Maloof G bioRxiv. 2024; .

PMID: 39484433 PMC: 11526954. DOI: 10.1101/2024.10.21.619538.

Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.

Metovic J, Li Y, Gong Y, Eichler F Neurotherapeutics. 2024; 21(4):e00443.

PMID: 39276676 PMC: 11418141. DOI: 10.1016/j.neurot.2024.e00443.

Treating late-onset Tay Sachs disease: Brain delivery with a dual trojan horse protein.

Osher E, Anis Y, Singer-Shapiro R, Urshanski N, Unger T, Albeck S Mol Ther Methods Clin Dev. 2024; 32(3):101300.

PMID: 39211733 PMC: 11357852. DOI: 10.1016/j.omtm.2024.101300.

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