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 Lepack, Elizabeth Baker, Elizabeth Simpson, Mark Ebel, Gregory Lallos, Deven LoSchiavo, Nicholas Stitt, Nathaniel Adams, Conor McAuliffe, Ana Forton-Juarez, Brian Kosmyna, Elizabeth Pereira, Benjamin Burnett, David Dilworth, Stephanie Fisher, Jing Wang, Peter Tonge, Mark Tomishima, Carlos Paladini, Dan Wilkinson, Chew-Li Soh, Maya Srinivas, Christoph Patsch () and Stefan Irion ()
Additional contact information
Panagiotis Douvaras: BlueRock Therapeutics
Diego F. Buenaventura: BlueRock Therapeutics
Bruce Sun: BlueRock Therapeutics
Ashley Lepack: BlueRock Therapeutics
Elizabeth Baker: BlueRock Therapeutics
Elizabeth Simpson: BlueRock Therapeutics
Mark Ebel: BlueRock Therapeutics
Gregory Lallos: BlueRock Therapeutics
Deven LoSchiavo: BlueRock Therapeutics
Nicholas Stitt: BlueRock Therapeutics
Nathaniel Adams: BlueRock Therapeutics
Conor McAuliffe: BlueRock Therapeutics
Ana Forton-Juarez: BlueRock Therapeutics
Brian Kosmyna: BlueRock Therapeutics
Elizabeth Pereira: BlueRock Therapeutics
Benjamin Burnett: BlueRock Therapeutics
David Dilworth: BlueRock Therapeutics
Stephanie Fisher: BlueRock Therapeutics
Jing Wang: BlueRock Therapeutics
Peter Tonge: BlueRock Therapeutics
Mark Tomishima: BlueRock Therapeutics
Carlos Paladini: BlueRock Therapeutics
Dan Wilkinson: BlueRock Therapeutics
Chew-Li Soh: BlueRock Therapeutics
Maya Srinivas: BlueRock Therapeutics
Christoph Patsch: BlueRock Therapeutics
Stefan Irion: BlueRock Therapeutics

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52400-8

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