Silencing mutant SOD1 in vivo for treatment of ALS

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DESCRIPTION (provided by applicant): Many human diseases are caused by dominant, gain-of-function gene mutations. Among these are some neurodegenerative diseases. A well established example is amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease with middle to old age onset. ALS is progressive disease-after onset, patients' muscles progressively weaken and eventually become paralyzed. Paralysis is caused by a relentless progression of motor neuron death in the spinal cord and motor cortex. Fifty percent of patients die in 3 years after diagnosis and 90% in 5 years. At present, there is no cure. Ninety percent of ALS cases are sporadic; ten percent are familial. Mutations in the Cu, Zn superoxide dismutase (SOD1) gene cause approximately 25% of familial ALS. More than 100 different mutations have been identified that cause ALS (www.alsod.org). By expressing the disease-causing mutant SOD1 in different systems, numerous in vitro and in vivo models have overwhelmingly demonstrated that mutant SOD1 causes motoneuron degeneration by a gain of toxic property. These findings explain why heterozygotes bearing one mutant and one wild-type copy of SOD1 nevertheless develop ALS. The ideal therapy for ALS caused by a gain-of-function SOD1 mutation would be to eliminate the mutant protein while retaining expression of the wild-type copy of SOD1. This may be achieved by RNAi, which is capable of directing sequence-specific destruction of RNA. RNAi against mutant SOD1 can be induced by introducing short hairpin RNA (shRNA) with sequences homologous to SOD1 mRNA. We propose to test an RNAi therapy strategy, in which the shRNA is delivered to motor neurons in transgenic mice that express mutant SOD1 by recombinant adenovirus. Because these mice develop ALS similar to humans, we will observe whether this therapeutic strategy can lower mutant SOD1 levels in motor neurons, delay disease onset and prolong the survival of these mice. If successful, these experiments will provide impetus for further human trials of this therapeutic strategy.