Unfortunately CRNO caused by galactosylceramidase (GALC)

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.

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