AAV-mediated gene therapy ameliorates disease in Niemann-Pick type C2 mice

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Researchers demonstrate the therapeutic potential of adeno-associated virus serotype 10-mediated gene therapy in improving the motor deficits, behavioral abnormalities and lifespan of mice with Niemann-Pick type C2 (NPC2) disease.

NPC2 disease is an autosomal recessive neurodegenerative, lysosomal storage disorder caused by abnormality in lysosomes, resulting in the accumulation of unesterified cholesterol and other lipids in these organelles to form cellular inclusions. It is caused by mutations in the NPC2 gene and is characterized by hepatosplenomegaly, liver dysfunction and progressive neuronal degeneration resulting in disability and premature death.

In the present study published in Experimental Neurology, a research team led by Dr Dolan Sondhi of Weill Cornell Medical College investigated the therapeutic potential of AAV serotype rh.10-mediated NPC2 gene delivery for the treatment of NPC2 in mice. The team constructed an AAV serotype rh.10 vector encoding the expression cassette of mouse NPC2 gene and injected it intracisternally into 6 week old Npc2 knockout (Npc2-/-) mice. Results showed that Npc2-/- mice that received AAV10-NPC2 displayed high expression of NPC2 protein in the brain and other organs.

AAV10-NPC2 treatment effectively ameliorated disease pathology in the brain, reduced lysosomal storage, reduced Purkinje cell death, decreased gliosis, and improved behavioral performance in Npc2−/− mice. More importantly, the treatment significantly extended its life span. These findings demonstrate the benefit of a one-time intracisternal administration of AAVrh.10-NPC2 as a promising treatment strategy to treat NPC2 disease.

Source: Markmann S et al., Attenuation of the Niemann-Pick type C2 disease phenotype by intracisternal administration of an AAVrh.10 vector expressing Npc2. Experimental Neurology, April 2018. DOI