I033 Reprogrammed human lateral ganglionic eminence precursors generate striatal neurons and restore motor function in a rat model of Huntington’s disease

<h3></h3> Cell replacement therapy is a potential option for the treatment of Huntington’s disease. Our lab developed a direct reprogramming protocol that generates lateral ganglionic eminence precursors (hiLGEPs) from human dermal fibroblasts by transient overexpression of chemically modified SOX2 and PAX6 mRNA. This potentially provides a clinically viable cell source for cell replacement therapy for HD. We investigated the potential for hiLGEPs to survive and generate functionally integrated MSNs following transplantation into the quinolinic acid (QA) lesion rat model of HD. Three weeks following QA lesioning, hiLGEPs were transplanted into the lesioned rat striatum (n = 15). Control animals were injected with sterile saline (n = 15). Motor function was assessed up to 14 weeks post transplantation using the cylinder test. The rats were killed 14 weeks following transplantation and the survival and maturation of transplanted hiLGEPs determined by immunohistochemistry. hiLGEPs expressed the human-specific marker STEM121 and co-expressed the neuronal marker MAP2 (76.8% ± 9.6) and the MSN specific marker DARPP32 (80.7% ± 5.4). STEM121+ cells also co-expressed the enzyme GAD65/67 (18.2% ± 6.8) and GABA (24.36% ± 6.3). Furthermore, STEM121+ cells did not co-express GFAP indicating transplanted hiLGEPs did not generate astrocytes. At 14 weeks post-transplant, transplanted rats demonstrated restoration of motor function with no difference in ipsilateral forelimb use compared to baseline (p = 0.8). In contrast, saline treated rats retained significant increase in ipsilateral forepaw use compared to baseline (p = 0.02). This study demonstrates the therapeutic potential of directly reprogrammed hiLGEPs for cell replacement therapy for HD.