Gene transfer in a murine model of Sandhoff disease using a specific AAV9 vector
Dr Catherine Caillaud
Institut Necker Enfants Malades
Dr. Catherine Caillaud, took part in a study carried out about the gene transfer though an adeno associated virus in Sandhoff mice for the correction of brain and cerebellum using a combined way of administration.
The team explored a gene transfer approach in SD based on the use of an AAV9 vector, known to cross the BBB after intravenous administration. A vector was intravenously administered in neonatal Sandhoff mice. Animals treated had a survival similar to normal mice for more than 700 days, with no neurological sign by comparison with naive Sandhoff mice.
At 4 months post-treatment, lipid analyses showed that GM2 storage was absent in brain, but it is only decreased in cerebellum of treated mice. Even if no symptom was associated with this residual storage in mice at 2 years, the team wondered if it could possibly be pathogenic at longer-term if extrapolated to patients.
Therefore, they tested an intravenous and intracerebroventricular combined way of administration using the same vector with the same final dose. Two groups of mice were injected using different doses in both compartments and treatment efficacy was evaluated at short- and long-term. Treated mice had more than one year and they had no neurological sign. In both groups, hexosaminidases activities at short-term were around 30% of normal in treated mice brain. In cerebellum, a significant increase of enzymatic activity (around 20%) was obtained with the highest dose in the ICV compartment. In both groups, it was showed that GM2 storage was absent in normal as well as in AAV9-treated Sandhoff
mice by comparison with naive mice.
However, the highest ICV dose was needed to obtain a complete cure of the cerebellum. Neuroinflammation and autophagy dysfunction presented in the cerebrum of Sandhoff mice were corrected in both groups after treatment. Short-term analyses were also performed on liver. Enzymatic activity was less than 10 % and gangliosides remained in treated mice. However, liver hypertrophy presented in Sandhoff mice was significantly reduced in treated animals as well as lysosomal expansion. The results showed that a minimal dose is required not only in ICV to obtain a prevention of GM2 accumulation in cerebellum but also in IV to completely correct liver.