Ready-to-use iPSC-derived microglia progenitors for the treatment of CNS disease in mouse models of neuropathic mucopolysaccharidoses
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.
Authors
- Benjamin Burnett
- Stefan Irion (ORCID: https://orcid.org/0000-0002-0482-714X)
- Peter J. Tonge (ORCID: https://orcid.org/0000-0003-1606-3471)
- Panagiotis Douvaras (ORCID: https://orcid.org/0000-0002-4430-997X)
- Christoph Patsch (ORCID: https://orcid.org/0000-0003-4224-3249)
- Carlos A. Paladini (ORCID: https://orcid.org/0000-0002-2329-1213)
- Deven LoSchiavo
- Chew-Li Soh
- Elizabeth Simpson (ORCID: https://orcid.org/0000-0002-2118-3139)
- Elizabeth Pereira (ORCID: https://orcid.org/0000-0003-1762-3717)
- Diego F. Buenaventura (ORCID: https://orcid.org/0000-0002-5430-1357)
- Mark Tomishima
- Gregory Lallos
- Maya Srinivas
- Bruce Sun (ORCID: https://orcid.org/0000-0002-1714-0208)
- David Dilworth (ORCID: https://orcid.org/0000-0001-5557-9476)
- Nathaniel Adams
- Jing Wang (ORCID: https://orcid.org/0009-0005-9474-3538)
- Mark E. Ebel (ORCID: https://orcid.org/0000-0001-8833-7115)
- C. McAuliffe
- Liz Baker (ORCID: https://orcid.org/0000-0001-8165-1136)
- Dan Wilkinson
- Brian Kosmyna
- Ana Forton‐Juarez
- Nicholas Stitt
- Stephanie Fisher
- Ashley Lepack
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Merck KGaA, Darmstadt (Germany) (DE)
- Winrock International (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1038/s41467-024-52400-8
- Citations
- 12
- Primary Topic
- Lysosomal Storage Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 3.92
Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences
- Common Fund