Huntington’s disease (HD) is one of the most debilitating neurological disorders. HD is an autosomal dominant disorder characterized by uncontrolled ballistic movements and by extensive neuronal degeneration, especially of the medium spiny neurons (MSNs) in the striatum. Although it is known that the pathology of HD is the result of a trinucleotide CAG repeat mutation (The Huntington’s Disease Collaborative Research Group, 1993), the mechanisms responsible for the onset of neuronal degeneration and the characteristic motor and cognitive dysfunction have not been elucidated. The only FDA-approved treatment for HD is Tetrabenazine, a drug which depletes monoamine concentrations, but provides only palliative motor benefits and produces adverse side effects which limit its usefulness (Huntington Study Group, 2006). Thus, no current therapies exist that can reduce the constellation of cognitive, motor and psychiatric symptoms, or slow the unrelenting progression of this fatal disorder.
One of the most promising strategies for treating HD has emerged with the advent of cellular therapies. Transplantations of embryonic cells in HD have shown some success, but rejection of these cells and their limited engraftment into the host tissue have mitigated the efficacy of this approach. Although other cell replacement approaches are being developed, transplantation of mesenchymal adult stem cells (MSCs) has gained considerable attention because of their ability to produce and release anti-inflammatory cytokines and neurotrophic factors. Our strategy of transplanting genetically altered MSCs that overexpress a critical neurotrophin, brain derived neurotrophic factor (BDNF), has been targeted for clinical trials, funded by a $17 million grant from the California Institute of Regenerative Medicine to University of California, Davis. Although we believe this strategy is currently one of the most promising therapeutic approaches for slowing the relentless progression of HD, we believe that the efficacy of MSCs for treating HD can be further enhanced by co-transplanting them with induced-pluripotent stem cells (iPSCS), when either or both of these cell population are genetically altered to overexpress BDNF.