Bone Marrow Transplants Stop ALSP Progress in Mice, Humans

Using newly developed mouse models and a microglia replacement strategy, researchers show that bone marrow transplantation could be used as an effective therapy for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare and fatal neurodegenerative disease, according to a new study. ALSP is caused by mutations in CSF1R, a gene expressed primarily in microglia, which are the brain's resident immune cells. Currently, there is no cure for ALSP and a lack of suitable animal models has greatly limited research on this disease. To address this, Jingying Wu and colleagues developed a pair of mouse models carrying human disease-linked CSF1R mutations. These models exhibited hallmark ALSP symptoms, including widespread microglial loss, brain calcification, myelin abnormalities, axonal damage, motor dysfunction, and cognitive decline. To evaluate therapeutic strategies, Wu et al. used a bone marrow transplantation-based strategy called Mr BMT, which combines traditional bone marrow transplantation (tBMT) with pharmacological depletion of "resident" microglia. The authors found that gene correction via Mr BMT effectively improves ALSP symptoms in mouse models. While tBMT alone yields minimal microglia replacement under normal conditions due to cellular competition, the inherent CSF1R deficiency in ALSP mimics pharmacological inhibition, allowing tBMT to achieve high replacement efficiency. Wu et al. further evaluated these findings in a clinical cohort of 8 ALSP patients and found that tBMT successfully corrected CSF1R mutations and halted disease progression over a two-year follow-up, suggesting that microglia replacement could be a promising therapeutic strategy for ASLP and potentially other microglia-driven neurological disorders. "Although microglial replacement strategies hold therapeutic potential, several key questions remain," write Siling Du and Jonathan Kipnis in a related Perspective. "Future strategies must strike a balance between replacement efficiency, systemic toxicity, and the functional competence of engrafted cells."