Ready-to-use iPSC-derived microglia progenitors for the treatment of CNS disease in mouse models of neuropathic mucopolysaccharidoses
Panagiotis Douvaras, Diego F. Buenaventura, Bruce Sun, Ashley E. Lepack, Liz Baker, Elizabeth Simpson, Mark E. Ebel, Gregory Lallos, Deven LoSchiavo, Nicholas Stitt, Nathaniel Adams, C. McAuliffe, Ana Forton‐Juarez, Brian Kosmyna, Elizabeth Pereira, Benjamin Burnett, David Dilworth, Stephanie Fisher, Jing Wang, Peter J. Tonge, Mark Tomishima, Carlos A. Paladini, Dan Wilkinson, Chew-Li Soh, Maya Srinivas, Christoph Patsch, Stefan Irion
Abstract
Mucopolysaccharidoses are inherited metabolic disorders caused by the deficiency in lysosomal enzymes required to break down glycosaminoglycans. Accumulation of glycosaminoglycans leads to progressive, systemic degenerative disease. The central nervous system is particularly affected, resulting in developmental delays, neurological regression, and early mortality. Current treatments fail to adequately address neurological defects. Here we explore the potential of human induced pluripotent stem cell (hiPSC)-derived microglia progenitors as a one-time, allogeneic off-the-shelf cell therapy for several mucopolysaccharidoses (MPS). We show that hiPSC-derived microglia progenitors, possessing normal levels of lysosomal enzymes, can deliver functional enzymes into four subtypes of MPS knockout cell lines through mannose-6-phosphate receptor-mediated endocytosis in vitro. Additionally, our findings indicate that a single administration of hiPSC-derived microglia progenitors can reduce toxic glycosaminoglycan accumulation and prevent behavioral deficits in two different animal models of MPS. Durable efficacy is observed for eight months after transplantation. These results suggest a potential avenue for treating MPS with hiPSC-derived microglia progenitors. Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by enzyme deficiencies leading to glycosaminoglycan accumulation and systemic degenerative disease. Here, the authors show that iPSC-derived microglia progenitors can reduce glycosaminoglycan accumulation and prevent behavioral deficits in MPS mouse models.