163738 20230915090534.0 pmc:PMC9618306 pmc 10.1126/scitranslmed.abl9945 doi pmid:35294256 pmid 1946-6234 ISSN 1946-6242 ISSN altmetric:124752153 altmetric DZNE-2022-00477 English 500 Shibuya, Yohei 0000-0002-8825-5440 0 Treatment of a genetic brain disease by CNS-wide microglia replacement. Washington, DC 2022 AAAS article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1650554305_20569 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases. 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Animals MeSH Bone Marrow Cells MeSH Brain MeSH Brain Diseases MeSH Central Nervous System MeSH Hematopoietic Stem Cell Transplantation MeSH Mice MeSH Microglia MeSH Kumar, Kevin K 0000-0002-0704-1492 1 Mader, Marius Marc-Daniel 0000-0002-7467-9672 2 Yoo, Yongjin 3 Ayala, Luis Angel 0000-0002-6272-3314 4 Zhou, Mu 0000-0001-5326-4884 5 Mohr, Manuel Alexander 0000-0002-5189-541X 6 Neumayer, Gernot 7 Kumar, Ishan 0000-0001-6847-9706 8 Yamamoto, Ryo 9 Marcoux, Paul 10 Liou, Benjamin 11 Bennett, F Chris 12 Nakauchi, Hiromitsu 0000-0002-9841-6973 13 Sun, Ying 14 Chen, Xiaoke 0000-0001-9032-9093 15 Heppner, Frank P:(DE-2719)2812386 16 dzne Wyss-Coray, Tony 0000-0001-5893-0831 17 Südhof, Thomas C 0000-0003-3361-9275 18 Wernig, Marius 0000-0002-5309-515X 19 10.1126/scitranslmed.abl9945 Vol. 14, no. 636, p. eabl9945 PERI:(DE-600)2518839-2 636 eabl9945 Science translational medicine 14 2022 1946-6234 oai:pub.dzne.de:163738 VDB Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 16 P:(DE-2719)2812386 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-353 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Clinical and Health Care Research 0 2022 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-30 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-01-30 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-30 JCR StatID:(DE-HGF)0100 StatID SCI TRANSL MED : 2021 2022-11-16 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-16 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-16 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-16 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-16 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-16 IF >= 15 StatID:(DE-HGF)9915 StatID SCI TRANSL MED : 2021 2022-11-16 I:(DE-2719)1810007 AG Heppner Neuroimmunology 0 journal VDB I:(DE-2719)1810007 UNRESTRICTED