Alleviation of mutant TDP-43-mediated neuropathology by inducible stem cells in monkeys

Abnormal cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43) is a common pathological feature of TDP-43 proteinopathies. Since non-human primate models can better recapitulate this neuropathology than rodents, we used a monkey model to evaluate the therapeutic potential of stem cells for TDP-43-mediated neuropathology. We established a cynomolgus monkey model by expressing mutant TDP-43 (M337V) in the monkey striatum through AAV injection. This model exhibited motor dysfunction and abnormal cytoplasmic TDP-43 accumulation. Using multi-gene modified stem cells (NILB-hiPSCs) that can be induced to differentiate in vivo with doxycycline treatment, we found that transplanted NILB-hiPSCs improved the limb movements of the TDP-43-injected monkeys, differentiated into mature neurons, and were integrated with neural circuit activity in the monkey brain. Furthermore, NILB-hiPSC therapy reduced reactive gliosis and diminished the abnormal cytoplasmic localization of mutant TDP-43. These results highlight the potential of in vivo inducible stem cells for the treatment of TDP-43 proteinopathies.