Enhancing the Engraftment of Microglia for the Treatment of Neurological Disease

There are no effective treatments for microgliopathies, a class of neurodegenerative disorders that are caused
by the absence or misfunction of specialized cells in the brain, called microglia. One potential strategy to treat
patients with a microgliopathy is to replace their diseased microglia with new cells. The NovoGlia technology
platform uses induced pluripotent stem cells to generate new microglia cells at high scale and with high purity.
NovoGlia cells can be safely and effectively transplanted into the brains of young mice, in which endogenous
microglia are still developing, yet strategies that enable high levels of microglial chimerism within adult brains
with a fully occupied niche have yet to be developed. The objective of this proposal is to demonstrate the
feasibility of a novel approach that combines the depletion of endogenous microglia using a commercially
available drug with the transplantation of NovoGlia cells that are engineered to be resistant to the small molecule
inhibitor. NovoGlia developed two novel cell lines that bear mutations making them resistant to the drug, and
demonstrated their viability in cell-based experiments, confirmed their microglia transcriptomic profile, and
demonstrated drug resistance in cell-based assay. Aim 1 will confirm the in vivo transcriptomic and functional
preservation of the novel cell lines. Aim 2 will measure the success NovoGlia cell replacement in the presence
of variable doses of inhibitor in vivo, and Aim 3 will optimize the NovoGlia cell replacement strategy. Successful
completion of these Aims is a necessary first step in developing new commercial therapeutics for the treatment
of microgliopathies and potentially other neurodegenerative diseases. Phase I results will provide proof-of-
concept data to support the continued development of NovoGlia therapies for microgliopathies and other
neurodegenerative diseases.