NIH scientists demonstrate the therapeutic potential of adeno-associated virus serotype 9 (AAV9)-mediated gene therapy in improving the lifespan of mice with Niemann-Pick disease, type C1 (NPC1).
NPC1 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 NPC1 results from a mutation in the NPC1 gene which encodes a lysosomal lipid transport protein. The disease is characterized by the progressive neuronal degeneration which leads to disability and premature death.
In the present study published in Human Molecular Genetics, a research team led by Prof. Charles Venditti of NIH’s National Human Genome Research Institute investigated the therapeutic potential of AAV-madiated gene therapy for NPC1. The team constructed AAV9 vectors encoding human NPC1 gene under the transcriptional control of either a neuronal-specific (CamKll) promoter or a ubiquitous (EF1a) promoter and injected them into Npc1-/- mice at either the neonatal stage or at weaning.
Results showed that the Npc1-/- mice that received a single dose of AAV9-CamKII-NPC1 (at neonatal or weaning) and the mice that received a single dose of AAV9-EF1a-NPC1 at weaning, exhibited an increased life span. The survival rates increased significantly from 69 days to 97 and >166 days respectively. Interestingly, cholesterol storage and Purkinje neuron loss were also reduced in the central nervous system of AAV9 treated Npc1-/- mice.
Thus, these findings clearly demonstrate that gene therapy may represent a therapeutic option for NPC1 patients and suggest that extraneuronal NPC1 expression can further augment the lifespan of the Npc1-/- mice after systemic AAV gene delivery.
Source: Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1. Chandler RJ et al., Human Molecular Genetics October 2016; DOI