Preclinical Study from Children's Hospital of Philadelphia Highlights Innovative Approach to Replacing Brain Cells in the Treatment of Leukodystrophies

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Apr 30, 2025, 13:10 ET

Research shows potential for brain-specific replacement over Hematopoietic Stem Cell Transplantation, which impacts the entire immune system

PHILADELPHIA, April 30, 2025 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania announced the first ever direct approach to the depletion and replacement of microglia, the native immune cells of the central nervous system (CNS). The approach leverages microglial replacement in Krabbe disease to demonstrate its broader therapeutic potential across other neurological conditions. The preclinical findings were published in the journal Immunity.

Microglia provide an essential function to the nervous system, acting like tiny cleaners responding to the site of an injury or infection by removing germs or damaged cells to help protect the CNS and keep it healthy. Unfortunately, specific diseases cause microglia dysfunction, which can lead to issues like impaired development, increased susceptibility to infections and difficulties in repairing brain injuries. However, enthusiasm for therapeutically treating microglia is rapidly growing among researchers and clinicians as more research validates the key role they play in disease.

In recent research, clinicians indirectly targeted microglia with hematopoietic stem cell transplantation (HSCT) in Krabbe disease, also named Globoid Cell Leukodystrophy (GLD). This severe leukodystrophy, caused by galactosylceramidase (GALC) mutations, primarily affects infants and young children, causing symptoms such as irritability, feeding difficulties, seizures, muscle stiffness and developmental delays. As the disease progresses, it leads to severe neurological decline, including loss of vision, hearing and motor skills. CHOP and Penn researchers have taken a different approach – seeking to directly target microglia in the brains of a GLD preclinical model.

"For the first time, we're excited to show that brain-specific microglia replacement provides significant therapeutic benefits in a disease that affects the brain and peripheral nervous system," said Mariko Bennett, MD, PhD, a co-senior author and a neurologist within the Division of Neurology at CHOP. "We found we could maintain CNS health, as well as provide a survival benefit. This does not rule out the therapeutic contributions of HSCT, but it does lend definitive support for potentially new microglia replacement approaches in leukodystrophies."

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).

Aisenberg et al. "Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease." Immunity. Online April 30, 2025. DOI: 10.1016/j.immuni.2025.03.019.

About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu .