Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy.

ALSP CRISPR correction CSF1R FIRE axonal spheroids chimera humanized leukoencephalopathy microglia

Journal

Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320

Informations de publication

Date de publication:
12 Jun 2024
Historique:
received: 15 11 2023
revised: 18 04 2024
accepted: 22 05 2024
medline: 20 6 2024
pubmed: 20 6 2024
entrez: 19 6 2024
Statut: aheadofprint

Résumé

Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.

Identifiants

DOI: 10.1016/j.neuron.2024.05.023 PMID: 38897209
pubmed: 38897209
pii: S0896-6273(24)00370-2
doi: 10.1016/j.neuron.2024.05.023
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests J.P.C., J.H., R.C.S., S.G. H.D., and M.B.-J. are co-inventors on patent applications filed by the University of California Regents (US 63/169,578) related to genetic modification of cells to confer resistance to CSF1R antagonists and (US 63/388,766) related to transplantation of stem-cell-derived microglia to treat leukodystrophies. M.B.-J. is a co-inventor of patent application WO/2018/160496, related to the differentiation of human pluripotent stem cells into microglia. M.B.-J., S.G., and R.C.S. are co-founders of NovoGlia Inc. Z.K.W. serves as principal investigator (PI) or co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206) and Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high-field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research; as an external advisory board member for Vigil Neuroscience, Inc.; and as a consultant on neurodegenerative medical research for Eli Lilli & Company.

Auteurs

Jean Paul Chadarevian (JP)

Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

Jonathan Hasselmann (J)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

Alina Lahian (A)

Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

Joia K Capocchi (JK)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.

Adrian Escobar (A)

Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

Tau En Lim (TE)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

Lauren Le (L)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.

Christina Tu (C)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

Jasmine Nguyen (J)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.

Sepideh Kiani Shabestari (S)

Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

William Carlen-Jones (W)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.

Sunil Gandhi (S)

Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.

Guojun Bu (G)

Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China.

David A Hume (DA)

Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.

Clare Pridans (C)

University of Edinburgh, University of Edinburgh Center for Inflammation Research, Edinburgh, UK.

Zbigniew K Wszolek (ZK)

Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.

Robert C Spitale (RC)

Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.

Hayk Davtyan (H)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA. Electronic address: hdavtyan@uci.edu.

Mathew Blurton-Jones (M)

Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA. Electronic address: mblurton@uci.edu.

Classifications MeSH