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Treatment of a genetic brain disease by CNS-wide microglia replacement

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Treatment of a genetic brain disease by CNS-wide microglia replacement. / Shibuya, Yohei; Kumar, Kevin K; Mader, Marius Marc-Daniel; Yoo, Yongjin; Ayala, Luis Angel; Zhou, Mu; Mohr, Manuel Alexander; Neumayer, Gernot; Kumar, Ishan; Yamamoto, Ryo; Marcoux, Paul; Liou, Benjamin; Bennett, F Chris; Nakauchi, Hiromitsu; Sun, Ying; Chen, Xiaoke; Heppner, Frank L; Wyss-Coray, Tony; Südhof, Thomas C; Wernig, Marius.

in: SCI TRANSL MED, Jahrgang 14, Nr. 636, eabl9945, 16.03.2022.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Shibuya, Y, Kumar, KK, Mader, MM-D, Yoo, Y, Ayala, LA, Zhou, M, Mohr, MA, Neumayer, G, Kumar, I, Yamamoto, R, Marcoux, P, Liou, B, Bennett, FC, Nakauchi, H, Sun, Y, Chen, X, Heppner, FL, Wyss-Coray, T, Südhof, TC & Wernig, M 2022, 'Treatment of a genetic brain disease by CNS-wide microglia replacement', SCI TRANSL MED, Jg. 14, Nr. 636, eabl9945. https://doi.org/10.1126/scitranslmed.abl9945

APA

Shibuya, Y., Kumar, K. K., Mader, M. M-D., Yoo, Y., Ayala, L. A., Zhou, M., Mohr, M. A., Neumayer, G., Kumar, I., Yamamoto, R., Marcoux, P., Liou, B., Bennett, F. C., Nakauchi, H., Sun, Y., Chen, X., Heppner, F. L., Wyss-Coray, T., Südhof, T. C., & Wernig, M. (2022). Treatment of a genetic brain disease by CNS-wide microglia replacement. SCI TRANSL MED, 14(636), [eabl9945]. https://doi.org/10.1126/scitranslmed.abl9945

Vancouver

Shibuya Y, Kumar KK, Mader MM-D, Yoo Y, Ayala LA, Zhou M et al. Treatment of a genetic brain disease by CNS-wide microglia replacement. SCI TRANSL MED. 2022 Mär 16;14(636). eabl9945. https://doi.org/10.1126/scitranslmed.abl9945

Bibtex

@article{ba3674c219e64af5ab566b347969a043,
title = "Treatment of a genetic brain disease by CNS-wide microglia replacement",
abstract = "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.",
keywords = "Animals, Bone Marrow Cells, Brain, Brain Diseases, Central Nervous System, Hematopoietic Stem Cell Transplantation, Mice, Microglia",
author = "Yohei Shibuya and Kumar, {Kevin K} and Mader, {Marius Marc-Daniel} and Yongjin Yoo and Ayala, {Luis Angel} and Mu Zhou and Mohr, {Manuel Alexander} and Gernot Neumayer and Ishan Kumar and Ryo Yamamoto and Paul Marcoux and Benjamin Liou and Bennett, {F Chris} and Hiromitsu Nakauchi and Ying Sun and Xiaoke Chen and Heppner, {Frank L} and Tony Wyss-Coray and S{\"u}dhof, {Thomas C} and Marius Wernig",
year = "2022",
month = mar,
day = "16",
doi = "10.1126/scitranslmed.abl9945",
language = "English",
volume = "14",
journal = "SCI TRANSL MED",
issn = "1946-6234",
publisher = "AMER ASSOC ADVANCEMENT SCIENCE",
number = "636",

}

RIS

TY - JOUR

T1 - Treatment of a genetic brain disease by CNS-wide microglia replacement

AU - Shibuya, Yohei

AU - Kumar, Kevin K

AU - Mader, Marius Marc-Daniel

AU - Yoo, Yongjin

AU - Ayala, Luis Angel

AU - Zhou, Mu

AU - Mohr, Manuel Alexander

AU - Neumayer, Gernot

AU - Kumar, Ishan

AU - Yamamoto, Ryo

AU - Marcoux, Paul

AU - Liou, Benjamin

AU - Bennett, F Chris

AU - Nakauchi, Hiromitsu

AU - Sun, Ying

AU - Chen, Xiaoke

AU - Heppner, Frank L

AU - Wyss-Coray, Tony

AU - Südhof, Thomas C

AU - Wernig, Marius

PY - 2022/3/16

Y1 - 2022/3/16

N2 - 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.

AB - 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.

KW - Animals

KW - Bone Marrow Cells

KW - Brain

KW - Brain Diseases

KW - Central Nervous System

KW - Hematopoietic Stem Cell Transplantation

KW - Mice

KW - Microglia

U2 - 10.1126/scitranslmed.abl9945

DO - 10.1126/scitranslmed.abl9945

M3 - SCORING: Journal article

C2 - 35294256

VL - 14

JO - SCI TRANSL MED

JF - SCI TRANSL MED

SN - 1946-6234

IS - 636

M1 - eabl9945

ER -