Bone marrow transplant halts rare disease in eight patients

Adult leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare and fatal neurodegenerative disease. It affects adults and is caused by mutations in a gene called CSF1R, which is essential for the proper function of microglia , the cells that protect the brain. Until now, there was no cure or good models to study this disease.

But according to an innovative study published in the journal ' Science ', the disease can be stopped thanks to a bone marrow transplant that replaces the microglia.

First tested in mice, and then in a small clinical trial in six people, the therapy halted disease progression . During a 24-month follow-up, treated patients showed no disease progression, in contrast to those who did not receive the transplant, who showed brain atrophy and clinical deterioration.

ALSP is caused by mutations in the CSF1R gene, which is expressed exclusively in microglia, the brain's resident immune cells. The lack of suitable animal models has hampered the study of this disease.

To overcome this obstacle, researcher Jingying Wu and her team at Fudan University ( China) developed two mouse models carrying human mutations in CSF1R associated with the disease. These mice reproduced symptoms characteristic of ALSP, such as loss of microglia, brain calcifications, axonal damage, myelin alterations, and motor and cognitive impairment.

The team used a therapeutic strategy called Mr BMT (microglia replacement by bone marrow transplantation), which combines traditional bone marrow transplantation with pharmacological elimination of resident microglia.

In the modified mice, this technique succeeded in replacing more than 91% of microglia with healthy cells expressing normal CSF1R, significantly improving both brain structure and motor and cognitive functions.

The researchers then evaluated the treatment's efficacy in a small clinical trial involving eight human patients with ALSP. Unlike mice, these patients do not require prior pharmacological inhibition, as the CSF1R mutations themselves facilitate microglia replacement after transplantation.

“ ALSP is a devastating disease with no known cure . Our research shows that replacing mutation-carrying microglia with healthy ones can halt disease progression, both in animal models and in human patients,” explains Bo Peng of Fudan University in Shanghai, one of the study’s senior authors.

"For the first time, we have successfully replaced microglia in animal models and shown promising results in human clinical trials. This is currently the only effective clinical treatment for ALSP. Microglia replacement, which was developed in our lab in 2020, also has therapeutic potential beyond ALSP for other neuronal diseases," says Peng.

Although the results are promising, experts caution that further studies are needed. "Microglial replacement strategies have great therapeutic potential, but we still need to find a balance between replacement efficiency, systemic toxicity, and the functionality of the grafted cells," researchers Siling Du and Jonathan Kipnis noted in a commentary accompanying the study.

Scientists now hope to extend this therapeutic approach to other neurological diseases driven by microglia dysfunction.