RNAI for DYT1 Dystonia

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DYT1 dystonia is a devastating neurological disorder, producing disabling, sustained abnormal involuntary movements for which reliably effective treatments do not exist. DYT1 dystonia is caused by a three base-pair in-frame GAG mutation in the TOR1A gene that encodes torsinA (TA), an endoplasmic reticulum (ER) glycoprotein belonging to the AAA (ATPases Associated with various cellular Activities) protein family. Using patient tissue, we recently discovered that this mutation causes TA to abnormally relocalize to the nuclear envelope (NE). Furthermore, our data suggest that DYT1 mutant TA (mutTA) acts through a dominant-negative or dominant-toxic effect, by recruiting wild type TA (wtTA) to the NE. Based on these observations, we hypothesize that allele-specific suppression of mutTA will ameliorate the disease. The ability to achieve allele-specific silencing of TA would also be a valuable tool for further characterizing the pathophysiology of DYT1 dystonia. We have already demonstrated that potent allele-specific suppression of TA with RNAi is possible in vitro, and our current proposal represents an attempt to selectively silence TA alleles in vivo. Our main goal is to explore the utility of this strategy as a potential therapy for DYT1 dystonia, but these studies may also uncover important molecular events in disease pathogenesis. We have already generated neural cell lines and transgenic animal models of DYT1 dystonia and the various experimental tools required to achieve allele-specific suppression of TA in vitro and in vivo. These diverse reagents and the complementary skills and commitment of our laboratories to the study and treatment of DYT1 dystonia present us with a unique opportunity to begin to tackle this disease.