hematopoietic stem cell transplantation (HSCT) in Krabbe disease
In this study, researchers used a preclinical model to directly insert therapeutic cells in the brain, replacing GLD-associated microglia. They also created a large single-cell sequencing (scSeq) atlas of microglia before and after symptoms appeared, with and without replacement for comparison.
In the model with GLD, researchers observed relatively normal microglial maturation, followed by an early immune response which progressed to significant disruption of the normal functioning and regulation of microglia. The researchers noted a prominent transcriptional signature found in damaged white matter along with a molecular signature of globoid cells (GC).
The researchers subsequently transplanted GALC expressing monocytes, a type of white blood cell involved in the response to injury and infection, directly into the CNS of the mice. This approach replaced more than 80% of microglia with healthy monocytes, virtually eliminating the GCs, protecting against damage, and extending survival.
Additionally, the researchers noted that a companion paper, "Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide Sall1+ microglia," led by the Mohavedi Lab in Brussels, Belgium and published today in Immunity, complements their work and highlights key next steps toward developing new therapies. Frederick Christian Bennett, MD, an Assistant Professor of Psychiatry in the Perelman School of Medicine and a co-senior and corresponding author, also contributed to the companion paper.
"We are eager to spotlight the power of microglia replacement," said Bennett. "Our findings support building on our research to better understand microglia's formation and origin, allowing us to unlock their role in disease and develop more precision therapies."
The research was supported by the Penn Metabolomics Core (RRID:SCR_022381), the Penn Cardiovascular Institute and, in part, by NCI (P30 CA016520) and NIH (P30DK050306), NIH (5T32MH019112) and (5T32MH014654). Additional funding was provided by Partners for Krabbe Research (P4KR), the University of Pittsburgh Brain Institute internal funding, NIH (DP5OD036159), NIH (R01-NS-120960), Klingenstein-Simons Fellowship in Neuroscience, the Paul Allen Frontiers Group and Children's Hospital of Philadelphia K readiness award. The research was also supported by the Alzheimer's Research UK Senior Fellowship (ARUK-SRF2022A-006), the NIHR Newcastle Biomedical Research Centre (BRC), a partnership between Newcastle Hospitals NHS Foundation Trust, Newcastle University, and Cumbria, Northumberland and Tyne and Wear NHS Foundation Trust and the National Institute for Health and Care Research (NIHR).
In the model with GLD, researchers observed relatively normal microglial maturation, followed by an early immune response which progressed to significant disruption of the normal functioning and regulation of microglia. The researchers noted a prominent transcriptional signature found in damaged white matter along with a molecular signature of globoid cells (GC).
The researchers subsequently transplanted GALC expressing monocytes, a type of white blood cell involved in the response to injury and infection, directly into the CNS of the mice. This approach replaced more than 80% of microglia with healthy monocytes, virtually eliminating the GCs, protecting against damage, and extending survival.
Additionally, the researchers noted that a companion paper, "Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide Sall1+ microglia," led by the Mohavedi Lab in Brussels, Belgium and published today in Immunity, complements their work and highlights key next steps toward developing new therapies. Frederick Christian Bennett, MD, an Assistant Professor of Psychiatry in the Perelman School of Medicine and a co-senior and corresponding author, also contributed to the companion paper.
"We are eager to spotlight the power of microglia replacement," said Bennett. "Our findings support building on our research to better understand microglia's formation and origin, allowing us to unlock their role in disease and develop more precision therapies."
The research was supported by the Penn Metabolomics Core (RRID:SCR_022381), the Penn Cardiovascular Institute and, in part, by NCI (P30 CA016520) and NIH (P30DK050306), NIH (5T32MH019112) and (5T32MH014654). Additional funding was provided by Partners for Krabbe Research (P4KR), the University of Pittsburgh Brain Institute internal funding, NIH (DP5OD036159), NIH (R01-NS-120960), Klingenstein-Simons Fellowship in Neuroscience, the Paul Allen Frontiers Group and Children's Hospital of Philadelphia K readiness award. The research was also supported by the Alzheimer's Research UK Senior Fellowship (ARUK-SRF2022A-006), the NIHR Newcastle Biomedical Research Centre (BRC), a partnership between Newcastle Hospitals NHS Foundation Trust, Newcastle University, and Cumbria, Northumberland and Tyne and Wear NHS Foundation Trust and the National Institute for Health and Care Research (NIHR).
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