Abstract
Transplantation of stem cells for the treatment of Huntington’s disease (HD) garnered much attention prior to the turn of the century. Several studies using mesenchymal stem cells (MSCs) have indicated that these cells have enormous therapeutic potential in HD and other disorders. Advantages of using MSCs for cell therapies include their ease of isolation, rapid propagation in culture, and favorable immunomodulatory profiles. However, the lack of consistent neuronal differentiation of transplanted MSCs has limited their therapeutic efficacy to slowing the progression of HD-like symptoms in animal models of HD. The use of MSCs which have been genetically altered to overexpress brain derived neurotrophic factor to enhance support of surviving cells in a rodent model of HD provides proof-of-principle that these cells may provide such prophylactic benefits. New techniques that may prove useful for cell replacement therapies in HD include the use of genetically altering fate-restricted cells to produce induced pluripotent stem cells (iPSCs). These iPSCs appear to have certain advantages over the use of embryonic stem cells, including being readily available, easy to obtain, less evidence of tumor formation, and a reduced immune response following their transplantation. Recently, transplants of iPSCs have shown to differentiate into region-specific neurons in an animal model of HD. The overall successes of using genetically altered stem cells for reducing neuropathological and behavioral deficits in rodent models of HD suggest that these approaches have considerable potential for clinical use. However, the choice of what type of genetically altered stem cell to use for transplantation is dependent on the stage of HD and whether the end-goal is preserving endogenous neurons in early-stage HD, or replacing the lost neurons in late-stage HD. This review will discuss the current state of stem cell technology for treating the different stages of HD and possible future directions for stem-cell therapy in HD.
Highlights
Huntington’s disease (HD) is a genetically inherited neurodegenerative disorder caused by a mutation to the huntingtin (HTT) gene
Various hypotheses have emerged: loss of trophic support, glutamate excitotoxicity, mitochondrial dysfunction, and autophagy. Each of these hypotheses is valid with respect to the function of mutant HTT, yet no single hypothesis unifies the distinct pathology of HD
An increase of parvalbumin expressing interneurons was observed following an injection of an adeno-associated virus (AAV) vector, which increased the release of glial derived neurotrophic factor (GDNF) [19]. These findings suggest that multiple NTFs are more efficacious in protecting multiple cell types
Summary
Huntington’s disease (HD) is a genetically inherited neurodegenerative disorder caused by a mutation to the huntingtin (HTT) gene. Various hypotheses have emerged: loss of trophic support, glutamate excitotoxicity, mitochondrial dysfunction, and autophagy Each of these hypotheses is valid with respect to the function of mutant HTT (mHTT), yet no single hypothesis unifies the distinct pathology of HD. In 2008, the USDA approved tetrabenazine to treat the motor symptoms of HD, while anti-psychotics and anti-depressants have been prescribed to treat other movement as well as cognitive and emotional disturbances [7,8]. These treatments are only palliative and not always effective. This review will explore new techniques in modification of stem cells, including alterations that increase trophic factor release in mesenchymal stem cells (MSCs), MSC-mediated gene therapies, and induced pluripotent stem cells for the treatment of HD
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