Using AAV-mediated gene silencing to explore DYT1 dystonia pathogenesis and therapeutics

Children'S Hosp Of Philadelphia, Philadelphia PA

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Abstract

ABSTRACT The long-term research objective of our laboratory is to develop curative or preventive interventions for dystonia. Dystonia is a neurological syndrome characterized by prolonged twisting involuntary movements that are frequently repetitive and stereotyped. Several genetic forms of dystonia have been described, DYT1 being among the most common. DYT1 is an incurable disease caused by a single mutation in the TOR1A gene which encodes for the protein torsinA. Experimental evidence suggests that lowering levels of the mutant protein in the right area of the brain and at the right time should be therapeutically beneficial. However, what the right time and right location are remain unknown. The main goal of the experiments proposed here is to determine if widespread neuronal reduction in levels of mutant torsinA in the neonatal stage prevents motor and synaptic dysfunction in rodent models of DYT1 dystonia. To do that, we will use AAV vectors encoding a microRNA targeting specifically mutant torsinA or a control vector. We will transduce the entire brain of neonatal animals and measure the consequences of these interventions on motor function, synaptic plasticity, cerebellar histology and protein levels, also evaluating for potential signs of toxicity. If successful, these experiments could yield a candidate therapeutic approach for DYT1 dystonia.