The cause of Huntington?s disease is an increase in the trinucleotide CAG repeat from under 36 repeats to 36 or greater repeats. The mode for the number of repeats is 42, and most patients have between 40 and 45. The disease generally starts between ages 30 and 40, with onset and progression of impaired cognition, depression, and aberrant movement. The genetics is autosomal dominant. Lowering mutant huntingtin in HD animal models delays onset of disease or mitigates the severity of disease. We use advanced, modified, di- branched siRNA to lower mutant huntingtin, by invoking RNA interference in brain. Our advanced siRNA achieves therapeutic advantages: spread throughout the brain in non- human primate and long-term huntingtin lowering after a single administration into the cerebrospinal fluid. The siRNA will be optimized in structure for safety and preliminary results will be secured. The goal of this CREATE proposal is to set the stage for promising therapeutics for treatment of Huntington?s disease. Similar treatments could be applicable to other autosomal dominant neurological disorders.
(Public Health Relevance Statement): Huntingtin?s disease (HD) is based on a mutation in a gene called huntingtin. Huntington?s disease is inherited as autosomal dominant, which means that an affected parent would have a 50:50 chance of passing the gene to a child. All who inherit the mutation will eventually develop the disease, with impaired cognition (dementia), depression and apathy, and abnormal movements. Patients will need to receive long-term skilled nursing for many years. We discovered an advanced, modified small interfering RNA that can lower the mutant huntingtin that causes HD, setting the stage for this CREATE proposal. Advantages of this therapeutic are long-term activity (about six months) to lower huntingtin after a single injection into cerebrospinal fluid and, critically, widespread distribution and neuronal uptake over the entire non-human primate brain. Our discoveries will set the stage for a new paradigm of therapeutics for an array of neurological diseases, including those with increased numbers of repeats of sequences in genes, such as HD, other CAG repeat expansions, and brain diseases with dementia and movement problems (C9ORF based amyotrophic lateral sclerosis and frontal-temporal dementia). Our program has public health relevance. Diseases marked by dementia and severe movement limitations are expensive to society, by requiring high level nursing care. Patients are removed from the active work force, thus lowering their earning capacity. These diseases reduce the gross national product. The stress on public health for HD is that the disease affects individuals in the prime of their lives ? magnifying the economic burden while intensifying family hardship. Reversing HD or delaying its onset will have economic as well as health benefits.