Engineered microglia for the treatment of Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a neurodegenerative disease that is caused by a mutation in the colony stimulating factor-1 receptor gene, leading to microglia dysfunction and loss, cognitive and behavioral decline, and impaired motor activity. ALSP is a rare disease with accumulating evidence that it is underdiagnosed, owing to its similarities to other neurodegenerative disease. The standard of care for ALSP is limited to supportive care; it is 100% fatal and there are no effective treatments. The NovoGlia technology platform uniquely uses induced human pluripotent stem cells to produce human microglial cells, called iMGL. The transplantation of wild-type iMGL into a mouse brain results in robust engraftment of iMGL that acquires transcriptional and functional profiles mirroring those of endogenous human microglia. Transplanted iMGL can both prevent and reduce ALSP-related pathologies in a mouse model of the disease. To build on these proof-of-concept studies, the proposed work is focused on validating an ex vivo gene correction strategy and ensuring the safety, therapeutic efficacy, and delivery of an autologous cell replacement therapy. The project encompasses validating a gene corrected protocol, demonstrating the safety and tolerability of the iMGL product, and completing the development of a custom-designed cannula device suitable for intraparenchymal cell delivery to the CNS. These efforts aim to provide the necessary preclinical data to support an Investigational New Drug (IND) application, with the potential to significantly improve treatment for ALSP and extend patient survival.