An adeno-associated viral approach to prevent Huntington disease – SAVEHD

Huntington disease (HD) is a devastating adult-onset dominantly inherited neurological disorder. Unmet medical needs: There is currently no treatment to delay or prevent appearance of the symptoms. Patients are heterozygous for the mutation, an abnormal CAG expansion in the HTT gene, and thus produce one dose of wild type HTT (wtHTT) and one of mutant polyglutamine-containing (mHTT) protein. Disease onset is associated to the length of the CAG repeat and to the balance between wtHTT and mHTT levels. The past therapeutic strategies focusing on inhibiting the toxic gain-of-function of mHTT have failed so far. The current approaches, aimed to reduce mHTT via non-allele-selective silencing approaches have also been stopped due to high risk/benefit ratio in patients. Novel hypothesis: wtHTT has neuroprotective function during brain development and by promoting the axonal transport of the neurotrophic factor BDNF. We propose that restoration of HTT function in vitro in HD brain-on-a-chip through the modification of wt and mHTT levels delays or prevents pathophysiology and behavioral alterations of HD mice. Aim1: Due to the large size of the protein, we will identify and validate the most relevant wtHTT fragments (miniHTT) that restore axonal transport and the functioning of HD brain-on-a-chip. We will combine expression of HTT with silencing of the wild-type and/or mutant alleles. Aim2: We will use adeno-associated virus (AAV)-vector-based gene therapies to demonstrate their efficacy in vivo in HD mice and to determine the best treatment approach. Impact: We will provide the ground breaking proof-of-concept that restoring wtHTT function influences adulthood behavior and degenerative processes in mouse. We will identify the most efficient window of treatment. Feasibility: The combination of our unique expertise in state-of-the-art microfluidic devices to investigate HTT function in HD brain-on-a-chips and in the in vivo evaluation of HTT biology during brain development and degeneration put our consortium in a unique position to fulfill this ambitious program.