Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Dec 7;8(1):217.
doi: 10.1186/s40478-020-01093-3.

Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

Jinming Han  1 , Heela Sarlus  2 , Zbigniew K Wszolek  3 , Virginija Danylaité Karrenbauer  4   5 , Robert A Harris  2
Affiliations
Review

Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

Jinming Han et al. Acta Neuropathol Commun. .

Abstract

CSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia caused by colony stimulating factor 1 receptor (CSF1R) gene mutations. The disease has a global distribution and currently has no cure. Individuals with CSF1R-related leukoencephalopathy variably present clinical symptoms including cognitive impairment, progressive neuropsychiatric and motor symptoms. CSF1R is predominantly expressed on microglia within the central nervous system (CNS), and thus CSF1R-related leukoencephalopathy is now classified as a CNS primary microgliopathy. This urgent unmet medical need could potentially be addressed by using microglia-based immunotherapies. With the rapid recent progress in the experimental microglial research field, the replacement of an empty microglial niche following microglial depletion through either conditional genetic approaches or pharmacological therapies (CSF1R inhibitors) is being studied. Furthermore, hematopoietic stem cell transplantation offers an emerging means of exchanging dysfunctional microglia with the aim of reducing brain lesions, relieving clinical symptoms and prolonging the life of patients with CSF1R-related leukoencephalopathy. This review article introduces recent advances in microglial biology and CSF1R-related leukoencephalopathy. Potential therapeutic strategies by replacing microglia in order to improve the quality of life of CSF1R-related leukoencephalopathy patients will be presented.

Keywords: CSF1R-related leukoencephalopathy; Microglia; Microglial replacement.

PubMed Disclaimer

Conflict of interest statement

ZKW serves as PI or Co-PI on Biogen, Inc. (228PD201), Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), and Neuraly, Inc. (NLY01-PD-1) grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research.

Figures

Fig. 1
Fig. 1
Brain MRI features of CSF1R-related leukoencephalopathy. The images were obtained from a 47-year-old female with progressive cognitive and behavioral deficits, and motor impairments with an approximate 3-year disease duration. Her father died of progressive dementia. The commercial genetic testing demonstrated the presence of heterozygote CSF1R mutation, p.L786S, c.2357 T > C. a, b Restricted diffusion in the splenium and left body of corpus callosum. c Thinning of corpus callosum on the sagittal section. d T2 hyperintensities in frontal and parietal white matter on the axial section. Courtesy of Daniel F. Broderick, M.D., Mayo Clinic Florida
Fig. 2
Fig. 2
Potential scheme of microglial replacement therapy for CSF1R-related leukoencephalopathy. a Microglia lose the homeostatic phenotype and their numbers are decreased significantly in the brain tissues of patients with CSF1R-related leukoencephalopathy. Some microglia may undergo proliferation with a high proportion in selected brain regions. b The ablation of microglia using either pharmacological inhibition or genetic targeting makes the microglial niche available. Subsequently, the empty microglial niche can be repopulated (replaced) by donor monocytes-derived microglia-like cells (c) or hematopoietic stem cell transplantation (d)
See this image and copyright information in PMC

References

    1. Wider C, Wszolek ZK. Hereditary diffuse leukoencephalopathy with axonal spheroids: more than just a rare disease. Neurology. 2014;82(2):102–103. doi: 10.1212/WNL.0000000000000026. - DOI - PubMed
    1. Konno T, Kasanuki K, Ikeuchi T, Dickson DW, Wszolek ZK. CSF1R-related leukoencephalopathy: a major player in primary microgliopathies. Neurology. 2018;91(24):1092–1104. doi: 10.1212/WNL.0000000000006642. - DOI - PMC - PubMed
    1. Konno T, Yoshida K, Mizuta I, et al. Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation. Eur J Neurol. 2018;25(1):142–147. doi: 10.1111/ene.13464. - DOI - PMC - PubMed
    1. Adams SJ, Kirk A, Auer RN. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): integrating the literature on hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) J Clin Neurosci. 2018;48:42–49. doi: 10.1016/j.jocn.2017.10.060. - DOI - PubMed
    1. Axelsson R, Roytta M, Sourander P, Akesson HO, Andersen O. Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand Suppl. 1984;314:1–65. - PubMed

Publication types

MeSH terms

Substances