A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay–Sachs disease

Abstract

Therapy for neurodegenerative lysosomal Tay-Sachs (TS) disease requires active hexosaminidase (Hex) A production in the central nervous system and an efficient therapeutic approach that can act faster than human disease progression. We combined the efficacy of a non-replicating Herpes simplex vector encoding for the Hex A alpha-subunit (HSV-T0alphaHex) and the anatomic structure of the brain internal capsule to distribute the missing enzyme optimally. With this gene transfer strategy, for the first time, we re-established the Hex A activity and totally removed the GM2 ganglioside storage in both injected and controlateral hemispheres, in the cerebellum and spinal cord of TS animal model in the span of one month's treatment. In our studies, no adverse effects were observed due to the viral vector, injection site or gene expression and on the basis of these results, we feel confident that the same approach could be applied to similar diseases involving an enzyme defect.

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

“…16 In this study, the feasibility of administering a replicationselective HSV-1 vector by CED into normal brain was therefore examined in detail. In spite of the large number of preclinical studies that have involved the direct intracranial administration of HSV-based vectors, 17,18,[20][21][22][23][24][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] remarkably this represents the first published study to evaluate the distribution properties of an HSV-1 vector using appropriate infusion parameters in both gray and white matter, as well as evaluation of strategies to improve vector distribution.…”

“…16 Clearly this has the potential to make the effective intracranial administration of HSV-1-based vectors unachievable. Nevertheless, in addition to the aforementioned clinical trials, [6][7][8][9] HSV vectors have been administered by stereotactic injection into normal mouse, [17][18][19] rat [20][21][22][23][24][25][26] and primate brains, [20][21][22][23][24][25][26][27][28] animal models of high-grade glioma, [29][30][31][32][33][34][35] mucopolysaccharidosis type VII, 36 GM2 gangliosidosis 37 and Parkinson's disease, [37][38][39] as well as being administered by CED into a glioma rat model. 40 In view of there being this large number of studies, it is surprising that to date no attempt has been made to systematically evaluate and optimize the delivery of these vectors directly into the brain.…”

HSV as a vector in vaccine development and gene therapy

“…17,21,[144][145][146][147] Non-replicative HSV vectors have been tested in many different gene therapy animal models of various neuropathies, Parkinson's disease, [148][149][150] Alzheimer's disease, 151 chronic pain 152,153 or lysosomal storage disorders with neurological involvement. 154 Therapy of lysosomal storage disorders with neurological involvement such as Tay-Sachs (TS) disease requires production and distribution of the missing enzyme into the CNS. Several therapeutic approaches allow restoring the enzymatic activity in many key tissues (kidney, liver, spleen, etc.)…”

Specific Determination of β-Galactocerebrosidase Activity via Competitive Inhibition of β-Galactosidase

“…Adult twi mice and wild-type (wt) littermates were killed by CO 2 exposure and decapitated (19 ). Brains were either isolated and quickly frozen in liquid nitrogen or immediately treated to obtain extracts for biochemical analyses.…”