Children's Hospital of Philadelphia (CHOP) and the Perelman

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.

Description

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).

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