Prenatal Diagnosis and Fetal Pathology of Tay-Sachs Disease

Higami, Shinobu; Nishizawa, Koji; Omura, Kiyoshi; Sugimoto, Koichi; Isshiki, Gen; Tada, Keiya; Kamoshita, Shigehiko

doi:10.1620/tjem.118.323

Cited by 4 publications

(2 citation statements)

References 6 publications

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“…Low levels of GM2 storage may affect developing neurons and glial cells, greatly restricting the time window available for effective therapeutic interventions. Indeed, neurodevelopmental defects have been described in GM2 gangliosidosis [38][39][40] as well as other infantile neurodegenerative LSDs; e.g., mucopolysaccharidosis type 1 (MPSI), Nieman-Pick disease 41,42 and globoid cell leukodystrophy (GLD) 43,44 . In addition to the timing of the intervention, the threshold concentration of enzyme needed for a therapeutic effect is a central issue for consideration.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

Sala

Ornaghi

Morena

et al. 2022

Molecular Therapy - Methods & Clinical Development

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Section: Introductionmentioning

confidence: 99%

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

Sala

Ornaghi

Morena

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…Low levels of GM2 storage may affect developing neurons and glial cells, greatly restricting the time window available for effective therapeutic interventions. Indeed, neurodevelopmental defects have been described in GM2 gangliosidosis (37)(38)(39) as well as other infantile neurodegenerative LSDs, e.g., Mucopolysaccharidosis type 1 (MPSI) and Nieman-Pick (40,41), and globoid cell leukodystrophy (GLD) (42,43). Further to the timing of the intervention, the threshold concentration of enzyme needed for therapeutic effect is a central issue for consideration.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

Sala

Ornaghi

Morena

et al. 2021

Preprint

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The GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease (SD) are respectively caused by mutations in the HEXA and HEXB genes encoding the α and β subunits of β-N-acetylhexosaminidase (Hex). The consequential accumulation of ganglioside in the brain leads to severe and progressive neurological impairment. There are currently no approved therapies to counteract or reverse the effects of GM2 gangliosidosis. Adeno-associated vector (AAV)-based investigational gene therapy (GT) products have raised expectations but come with safety and efficacy issues that need to be addressed. Thus, there is an urgent need to develop novel therapies targeting the CNS and other affected tissues that are appropriately timed to ensure pervasive metabolic correction and counteract disease progression. In this report, we show that the sequential administration of lentiviral vector (LV)-mediated intracerebral (IC) GT and bone marrow transplantation (BMT) in pre-symptomatic SD mice provide a timely and long-lasting source of the Hex enzyme in the central and peripheral nervous systems and peripheral tissues, leading to global rescue of the disease phenotype. Combined therapy showed a clear therapeutic advantage compared to individual treatments in terms of lifespan extension and normalization of the neuroinflammatory and neurodegenerative phenotypes of the SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in the brain tissues that single treatments failed to achieve. Our results highlight the complementary and synergic mode of action of LV-mediated IC GT and BMT, clarify the relative contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of enzymatic activity that is required to achieve a significant therapeutic benefit, with important implications for the monitoring and interpretation of ongoing experimental therapies, and for the design of more effective treatment strategies for GM2 gangliosidosis.

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