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 antigenic expression (Arber et al., 2015). As a result, recent efforts for designing cell-based treatment approaches to HD have focused on using gene therapeutic strategies to trigger the local production of new MSNs, from endogenous subependymal neural stem cells (Chmielnicki et al., 2004). These newly generated neurons integrate into the diseased striatum and restore normal basal ganglia circuitry, and their addition is associated with the substantially prolonged survival of transgenic HD mice (Benraiss et al., 2013; Cho et al., 2007). Yet despite the development of this approach to striatal neuronal replacement, no effective strategy for inducing functional cortical neuronal replacement has yet been established, without which any treatment strategies focused solely on the striatum will be necessarily limited in efficacy.
