An overlapping but distinct set of concerns exists in regards to stem cell-based treatment of Huntington’s disease. While medium spiny neurons (MSNs) are among the first cell types lost in adult HD, the disease ultimately affects all central neuronal populations, and patients typically suffer profound cortical as well as striatal neuronal loss with disease progression, manifesting as personality changes, psychoses and ultimately dementia. Thus, while current approaches to MSN production and replacement from hESCs and hiPSCs have progressed significantly, the clinical utility of MSN addition is necessarily limited: a strategy focused on striatal neuronal replacement alone may temporize and delay, but not halt, disease progression. This concern was borne out by early clinical trials of striatal tissue and cell transplantation in patients with HD, which largely failed to achieve significant or durable benefit (reviewed in (Benraiss and Goldman, 2011). Indeed, even in experimental models, transplanting hESC and hiPSC-derived MSNs into the adult striatum has proven challenging, with little dispersal of donor MSNs into the host striatum, and thus little evidence of architecturally-appropriate neuronal integration, much less circuit reconstruction, despite MSN-appropriate
