RNA-directed therapy for Huntington’s disease

Huntington’s disease (HD) is a genetic neurodegenerative disease that can occur from childhood to middle age followed by inexorable disease progression and death within 15-20 years after diagnosis. HD is caused by a repeat sequence expansion in the Huntingtin (HTT) gene: while unaffected individuals harbor fewer than 35 repeats of a sequence consisting of three DNA bases (C-A-G. encoding glutamine) in both gene copies, in HD patients one of the two copies has up to 120. Since the repeat expansion is in a protein coding portion of the gene, the protein product of mutant HTT contains a poly-glutamine stretch that is toxic to neurons, in particular those in the striatum of the brain important for motor control. Recent research also suggests that the mutant messenger RNA (mRNAs) itself is toxic to the cells. Currently, available treatments only temporarily relieve clinical symptoms and no disease-modifying treatments have been identified for HD patients. In this project we have successfully tested a novel biologic as a therapeutic candidate for HD. This biologic is based on so-called small nuclear RNAs (snRNAs) that in cells normally binds pre-mRNAs to regulate their splicing. We have engineered one such snRNA to bind the toxic mutant HTT mRNA , causing its degradation. We show that our engineered snRNAs, when delivered using viral vectors (adeno-associated virus used in several approved therapeutics) to striatal organoids (cell assemblies that mimic the human striatum) derived from HD patient induced pluripotent stem cells, potently decrease levels of mutant HTT mRNA. We also introduced engineered snRNAs into mice that harbor the human mutant HTT gene as a disease model and observed improvements in motor function and lifespan. Based on these positive results, we plan to progress this candidate therapeutic to preclinical studies, hopefully under CIRM's translational funding mechanisms, that if successful will enable an FDA investigational new drug (IND) application.