Stem cell therapy and cellular engineering for treatment of neuronal dysfunction in Huntington's disease

Huntington's disease (HD) is a fatal inherited neurodegenerative disorder characterized by progressive loss of neurons in the striatum, a sub‐cortical region of the forebrain. The sub‐cortical region of the forebrain is associated with the control of movement and behavior, thus HD initially presents with coordination difficulty and cognitive decline. Recent reprogramming technologies, including induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs), have created opportunities to understand the pathological cascades that underlie HD and to develop new treatments for this currently incurable neurological disease. The ultimate objectives of stem cell‐based therapies for HD are to replace lost neurons and to prevent neuronal dysfunction and death. In this review, we examine the current understanding of the molecular and pathological mechanisms involved in HD. We discuss disease modeling with HD‐iPSCs derived from the somatic cells of patients, which could provide an invaluable platform for understanding HD pathogenesis. We speculate about the benefits and drawbacks of using iNSCs as an alternative stem cell source for HD treatment. Finally, we discuss cell culture and engineering systems that promote the directed differentiation of pluripotent stem cell‐derived NSCs into a striatal DARPP32+ GABAergic MSN phenotype for HD. In conclusion, this review summarizes the potentials of cell reprogramming and engineering technologies relevant to the development of cell‐based therapies for HD. Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expanded CAG trinucleotide repeats in the huntingtin gene. Reprogramming technology has been used to convert HD patient fibroblasts into pluripotent or multipotent stem cells, which can be differentiated into striatal medium spiny neurons in vitro. In this article, the authors describe the current understanding of pathological mechanisms in HD and suggest alternative stem cell sources that could be used in HD therapies in the near future.