Scientists from Fudan University have halted the progression of ALSP, a rare and fatal brain disease, using a pioneering microglia replacement therapy – marking the first effective clinical approach to tackling the disease.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a devastating neurodegenerative disease that typically strikes in midlife and is fatal within a few years. Anew study, published in Science, by researchers at Fudan University offers a new method by replacing faulty brain microglia – which could be the first effective treatment for ALSP.
A fatal diagnosis with no cure
ALSP is caused by mutations in a gene called CSF1R, which is crucial for the health and function of microglia – the central nervous system’s immune cells. Without properly functioning microglia, patients with ALSP develop widespread brain damage characterised by myelin loss, axonal swelling and neurological decline. Symptoms typically begin around age 43, with death usually occurring within three to five years.
ALSP is caused by mutations in a gene called CSF1R, which is crucial for the health and function of microglia
“ALSP is a fatal disease with no current curative treatment,” said Bo Peng, a professor at Fudan University in Shanghai and senior author of the study. “Since pathogenic mutations in microglia-specific gene CSF1R are the cause of ALSP, we reasoned that replacing CSF1R-deficient microglia with wild-type microglia would halt disease progression.”
From concept to clinic: the MISTER strategy
Peng and his team first pioneered a set of methods known as MISTER – microglia intervention strategy for therapy and enhancement by replacement – in 2020. One of these methods, termed Mr BMT (microglia replacement by bone marrow transplantation), involves replacing defective microglia with healthy ones found in donor bone marrow. This study is the first time this approach has been tested in both animal models and human patients.
“Our findings demonstrate that microglia replacement effectively corrects the pathogenic CSF1R mutations in both mice and human individuals with ALSP, halting disease progression and improving neurological function,” said Peng.
Recreating the disease in mouse models
Because ALSP is so rare, scientists had to first develop accurate animal models. Mice were genetically engineered to carry human ALSP mutations in the CSF1R gene, and researchers confirmed that the animals exhibited hallmark features of the disease, including reduced microglia, myelin degeneration, and cognitive and motor deficits.
After validating the model, scientists used Mr BMT to replace the faulty microglia with normal ones. Following treatment, 91.15 percent of the microglia in ALSP mice were successfully replaced. The intervention reversed structural brain damage and significantly improved the mice’s behaviour in cognitive and motor tests.
Clinical results: disease progression halted
Encouraged by their preclinical findings, the researchers moved to a clinical trial involving eight ALSP patients. Each received a bone marrow transplant from a healthy donor, without the need for prior CSF1R inhibition. This was because the team’s mouse studies showed this step was unnecessary in ALSP patients.
MRI scans taken 12 months after treatment revealed significant differences between patients who received the transplant and those who did not.
MRI scans taken 12 months after treatment revealed significant differences between patients who received the transplant and those who did not. Untreated individuals experienced rapid brain atrophy and worsening disease progression, while those who underwent microglia replacement showed no disease progression for at least 24 months. Their motor and cognitive functions also stabilised.
“For the first time, we have achieved microglia replacement in animal models and shown promising results in the human clinical trial,” said Peng. “This is currently the only effective clinical treatment for ALSP. Microglia replacement, which was developed in our lab in 2020, has therapeutic potential beyond ALSP for other neural diseases, too.”
A platform for other neurological conditions?
Beyond ALSP, the implications of this work could extend to other brain diseases driven by microglial dysfunction. Peng and his team hope that the techniques developed in this study will form the basis for future therapies targeting a wide range of neurological conditions.
“We previously developed efficient strategies for microglia replacement, opening up a new cell therapy strategy that has therapeutic potential for treating neural diseases,” Peng added. “Now, we demonstrated the efficacy by this first microglia replacement for clinical therapy with very good therapeutic results. Microglia replacement is the only effective clinical treatment for ALSP. We hope to utilise microglia replacement to conquer more diseases.”