Intravenous administration of scAAV9-Hexb normalizes lifespan and prevents pathology in sandhoff disease mice

Natalia Niemir, Laura Rouvière, Aurore Besse, Marie T. Vanier, Jasmin Dmytrus, Thibaut Marais, Stéphanie Astord, Jean Philippe Puech, Ganna Panasyuk, Jonathan D. Cooper, Martine Barkats, Catherine Caillaud

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Sandhoff disease (SD) is a rare inherited disorder caused by a deficiency of β-hexosaminidase activity which is fatal because no effective treatment is available. A mouse model of Hexb deficiency reproduces the key pathognomonic features of SD patients with severe ubiquitous lysosomal dysfunction, GM2 accumulation, neuroinflammation and neurodegeneration, culminating in death at 4 months. Here, we show that a single intravenous neonatal administration of a self-complementary adeno-associated virus 9 vector (scAAV9) expressing the Hexb cDNA in SD mice is safe and sufficient to prevent disease development. Importantly, we demonstrate for the first time that this treatment results in a normal lifespan (over 700 days) and normalizes motor function assessed by a battery of behavioral tests, with scAAV9-treated SD mice being indistinguishable from wild-type littermates. Biochemical analyses in multiple tissues showed a significant increase in hexosaminidase A activity, which reached 10?15% of normal levels. AAV9 treatment was sufficient to prevent GM2 and GA2 storage almost completely in the cerebrum (less so in the cerebellum), as well as thalamic reactive gliosis and thalamocortical neuron loss in treated Hexb -/- mice. In summary, this study demonstrated a widespread protective effect throughout the entire CNS after a single intravenous administration of the scAAV9-Hexb vector to neonatal SD mice.

Original languageEnglish
Pages (from-to)954-968
Number of pages15
JournalHuman molecular genetics
Issue number6
StatePublished - Mar 15 2018


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