Induced Pluripotent Stem Cells in Huntington's Disease: Disease Modeling and the Potential for Cell-Based Therapy

Abstract

Huntington's disease (HD) is an incurable neurodegenerative disorder that is characterized by motor dysfunction, cognitive impairment, and behavioral abnormalities. It is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene, resulting in progressive neuronal loss predominately in the striatum and cortex. Despite the discovery of the causative gene in 1993, the exact mechanisms underlying HD pathogenesis have yet to be elucidated. Treatments that slow or halt the disease process are currently unavailable. Recent advances in induced pluripotent stem cell (iPSC) technologies have transformed our ability to study disease in human neural cells. Here, we firstly review the progress made to model HD in vitro using patient-derived iPSCs, which reveal unique insights into illuminating molecular mechanisms and provide a novel human cell-based platform for drug discovery. We then highlight the promises and challenges for pluripotent stem cells that might be used as a therapeutic source for cell replacement therapy of the lost neurons in HD brains.

Keywords: Cell replacement therapy; Drug discovery; Huntington’s disease; Induced pluripotent stem cells; Stem cell models.

Fig. 1

The generation and application of iPSCs in HD research. HD patient-specific iPSCs can be obtained by reprogramming of skin fibroblasts. Established iPSCs can be used as a tool for better understanding the molecular basis of HD. iPSC technology can also be coupled with high-throughput screening that provides a more efficacious platform to assess novel drug candidates aimed at stopping or slowing disease process. Moreover, HD-iPSCs can be differentiated into specific cell types predominantly affected in the disease (striatal MSNs). Emerging gene therapies make the genetic correction of HD-iPSCs become feasible, paving the way for autologous transplantation strategies of healthy iPSCs or iPSC-derived neural cells