Huntington’s disease (HD) is a fatal neurodegenerative condition with no current treatment. This significant neurodegenerative disease, whose relatively simple and unique known genetic cause, a CAG expansion in the HD gene correlated with severity and onset of clinical symptoms, makes it particularly suited to therapeutic development. The Huntington’s disease (HD) iPS cell consortium, funded with NIH and CIRM support, brings together leading groups in stem cell and HD research to establish whether newly created iPS cell lines show HD related (i.e., CAG length-dependent) phenotypes. Human iPSC technology can be used to generate specific neuronal and glial cell types, permitting investigation of the effects of the genetic lesion in the susceptible human cell types in the context of HD. The monogenic nature of HD and the existence of allelic series of iPSCs with a range of CAG repeat lengths confer tremendous power to model HD. Through CIRM support this consortium has capitalized on new technologies to use non-integrating approaches for reprogramming and promising phenotypes in current HD iPS lines to develop robust and validated assays for drug development for HD.
Significant progress has been made through CIRM-funded support of this proposal. Notably, the Cedars-Sinai Medical Center’s Board of iPSC core housed in the Board of Governors Regenerative Medicine Institute has taken skin cells from HD patients with a wide range of CAG repeats (43 to 180), and unaffected healthy controls (21 to 33) and reprogrammed then to pluripotency using the latest non-integrating iPS cell technology. So far 18 well-characterized patient-specific iPSC lines have been generated. These new iPSC lines have been rigorously characterized by our iPSC core and available to HD research community throughout California and the world. The Svendsen lab and the other HD iPSC Consortium laboratories have already used these lines and differentiated into relevant neuronal cell types to study the disease mechanisms as well develop new treatment.
These cell lines will be an essential resource for academic groups and pharmaceutical companies for studying pathogenesis and for testing experimental therapeutics for HD. The ultimate goal is to develop and validate methods and assays using >96 well format for CAG repeat length-dependent phenotypes that are amenable to high content/throughput screening methods. Assays developed using these patient-specific iPSC lines and their neuronal derivatives will allow academic groups and pharmaceutical companies to study pathogenesis and test experimental therapeutics for HD, which will significantly advance both our understanding of HD and potential treatments for this devastating and currently untreatable disease.