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

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Researchers demonstrate the therapeutic potential of adeno-associated virus serotype 9 (AAV9)-mediated gene therapy in improving the motor deficits, behavioral abnormalities and lifespan of mice with Niemann-Pick type C (NPC) disease.

NPC disease is an autosomal recessive neurodegenerative, lysosomal storage disorder caused by abnormality in lysosomes, resulting in the accumulation of macromolecules in these organelles to form cellular inclusions. 95% of NPC results from a mutation in the NPC1 gene and 5% is caused my mutations in the NPC2 gene. These genes encode for lysosomal lipid transport proteins. NPC disease is characterized by a progressive neuronal degeneration resulting in disability and premature death.

In the present study published in the Journal of Lipid Research, a research team led by Dr Bao-Liang Song of Wuhan University, China, investigated the therapeutic potential of AAV9-mediated NPC1 gene delivery for the treatment of NPC. The team constructed an AAV9 vector encoding the expression cassette of human NPC1 gene and injected it systemically into Npc1 knockout (Npc1-/-) mice at postnatal day 4 (P4). Results showed that Npc1-/- mice that received AAV9-NPC1 displayed high expression of NPC1 protein in the brain, lung, heart and other peripheral tissues.

Purkinje cell (neurons of the cerebellum involved in motor coordination) loss is a hallmark of NPC disease and in mice it initiates from 49 days of age and becomes pronounced by 9 weeks of age. To evaluate the effect of AAV9-NPC1 injection on Purkinje cell survival, the team systemically injected AAV9-NPC1 into Npc1-/- mice at P4 and analyzed cerebellar Purkinje cells 2 months post-injection. Results showed that Purkinje cell number was significantly increased upon the injection of AAV9-NPC1. AAV9-NPC1 treatment also effectively ameliorated the locomotor activity, motor coordination, behavioral abnormalities and lifespan in Npc1-/- mice.

Thus, these findings propose AAV-mediated gene therapy as a promising strategy to treat NPC disease.

Source: Intracardiac injection of AAV9-NPC1 significantly ameliorates Purkinje cell death and behavioral abnormalities in mouse Niemann-Pick type C disease. Xie C et al., Journal of Lipid Research January 2017. DOI