Brain Cell Transplant Slows Rare Neurodegenerative Disease

Medscape

21-07-2025

Replacing mutant microglia with healthy donor-derived microglia has emerged as a promising treatment for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
In a small study of eight patients with ALSP, replacing dysfunctional microglia with normal microglia using traditional bone marrow transplantation (BMT) halted the progression of ALSP and improved neurologic function.
'The critical next step is to validate these results in a larger clinical trial, which is already underway,' principal investigator Bo Peng, PhD, professor, Institute for Translational Brain Research, Fudan University in Shanghai, told Medscape Medical News .
The study was published online on July 10 in Science .
From Mice to Men
ALSP is a rare, progressive neurological disease with an average age of onset of 43 years and an average life expectancy of only 3-5 years after symptoms begin. There is no cure and there are few treatments.
ALSP is caused by mutations in the colony-stimulating factor 1 receptor gene (CSF1R), which is critical to development and survival of microglia. Mutations in this gene lead to microglial dysfunction and reduced numbers of these key brain immune cells.
In earlier work, Peng and his team developed mouse models of ALSP which exhibit hallmark features of the disease including reduced numbers of microglia, myelin abnormalities, axonal swelling and motor impairments, and cognitive decline.
To test whether microglial replacement could alter disease progression in mice with ALSP, the investigators tested two approaches: traditional BMT and microglia replacement by BMT (Mr BMT), a protocol that combines pharmacological depletion of microglia with traditional BMT.
Both approaches effectively replaced mutant microglia with wild-type counterparts and successfully reversed myelin defects, axonal swellings, and motor and cognitive impairments in the animals.
To translate this to the clinic, they performed traditional BMT in eight patients with ALSP. Although traditional BMT alone typically does not achieve efficient Mr in healthy brains, the inherent CSF1R deficiency in patients with ALSP creates a 'competitive disadvantage' for the recipient's resident microglia, allowing traditional BMT to achieve effective replacement, the researchers explained in their paper.
In the 2 years following Mr, MRI and clinical evaluations indicated 'halted disease progression, preserved motor function, and stabilized cognitive abilities,' the team reported. By contrast, untreated patients with ALSP exhibited rapid worsening of brain pathology over a shorter time frame.
The findings in these eight patients also provide a 'mechanistic explanation' for a prior clinical case in which an individual with ALSP, initially misdiagnosed with adult-onset metachromatic leukodystrophy, exhibited long-term stabilization after traditional BMT.
'While the path forward is active with the ongoing trial, traditional BMT becoming a widely accessible 'clinic-ready' standard treatment for ALSP is still estimated to be several years away, contingent upon successful trial outcomes, long-term safety data, and subsequent regulatory approvals,' Peng told Medscape Medical News .
Beyond ALSP
Peng also said Mr 'holds significant theoretical promise' for treating other neurological diseases involving microglial dysfunction, including Alzheimer's disease (AD).
'Genome-wide association studies have identified TREM2 as one of the major risk genes in sporadic AD. TREM2 mutation may cause or accelerate the progression of AD. In a 2020 paper in Cell Reports , we proposed that we can replace the TREM2 -mutated microglia with TREM2 -normal cells to treat this disease,' Peng added.
In a Science perspective , Siling Du, PhD, and Jonathan Kipnis, PhD, with the Brain Immunology and Glia Center, Washington University in St Louis congratulated Peng and colleagues for demonstrating in humans that 'correcting a microglial gene defect through cell replacement can arrest disease progression.'
Du and Kipnis agreed that the potential implications of this research extend beyond ALSP.
For example, a recent study demonstrated that microglial replacement can also rescue pathology in a mouse model of Krabbe disease, a monogenic neurodegenerative disorder caused by mutations in the gene encoding galactosylceramidase.
In addition, traditional BMT has also been shown to arrest disease progression in a mouse model of Rett syndrome — a severe neurodevelopmental condition caused by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2.
'Together, these findings highlight the therapeutic potential of microglial replacement in modifying the course of monogenic neurological diseases,' Du and Kipnis said.
Looking ahead, they said it will be important to establish the optimal donor cell source to achieve 'scalable, safe, and durable microglial replacement.'
'It is also not yet clear whether the systemic toxicity caused by pretransplant conditioning can be minimized without compromising engraftment. Future strategies must strike a balance between replacement efficiency, systemic toxicity, and the functional competence of engrafted cells,' they wrote.
'Moving forward, it may ultimately become possible to reprogram the brain's immune landscape from within and find the best microglial replacement approach not only for microgliopathies but for a spectrum of neurological diseases,' Du and Kipnis concluded.