The path to clinical application of human microglia transplantation for the treatment of CSF1R-related disorder

ObjectiveThis poster aims to report an unregistered mutation CSF1R gene in a patient presenting young-onset dementia.Hypothesis: Novel heterozygous deletion–insertion mutation in the Colony-Stimulating Factor 1 Receptor (CSF1R) gene is linked to a case of hereditary diffuse leukoencephalopathy with spheroids (HDLS), presenting with young-onset dementia.BackgroundCSF1R mediates proliferation, differentiation, and survival of monocytes/ macrophages and microglia. Pathogenic variants in the CSF1R gene cause autosomal dominant diffuse hereditary leukoencephalopathy with spheroids characterized by variable behavioural, cognitive, and motor changes, usually presenting with young-onset dementia. The average lifespan after the start of the symptoms is often 6 years.Case reportMolecular genetic analysis of whole-exome sequencing (WES) was carried out for a 49-year-old male patient presenting with rapid cognitive decline, behavioural symptoms and impaired sphincteric control.DiscussionWES identified the heterozygous deletion–insertion variant c.2356_2357delinsAC p.(Leu786Thr) (chr5:149435867-49435868; hg19) in the CSF1R gene. To the best of our knowledge the variant has not been described in the literature so far (HGMD 2019.3). No allele frequencies in the general population have been documented.ConclusionWe believe that we have identified a novel mutation in the CSF1R gene. This mutation is likely to be linked to this patient presenting with young-onset dementia.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disorder that typically presents with early-onset cognitive decline or personality change. The disease is associated with heterozygous mutations in the colony stimulating factor-1 receptor (CSF1R) gene. CSF1R activation regulates microglial survival, proliferation, and differentiation. The different gene mutations may be related to the various clinical phenotypes. Here, we described comprehensive clinical, neuroimaging, neuropathological, and genetic analyses of a family with HDLS. A novel splicing mutation in intron 13 (c.1858+1G>T) of CSF1R was found in this family. It is located at the splice site of intron 13, resulting in a splice donor site leading to exon 13 skipping from the CSF1R mRNA. The mother and two elderly siblings of the proband had the same CSF1R mutation as the proband but showed very mild neuroimaging abnormalities and mild memory loss, which did not affect daily life, indicating very uneven penetrance and distinctly different disease progression among family members. This report provides diverse neuroimaging and clinical characteristics of a novel CSF1R mutation with different disease penetrance. The large clinical heterogeneity in the same family who all had the same mutation indicates that modifying genes and environmental factors may play a role in the pathogenesis of HDLS.

Based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we profiled the role of Colony-Stimulating Factor 1 Receptor (CSF1R) in cancer. We specifically focused on pancreatic ductal adenocarcinoma (PAAD), analysing its regulative function in cancer progression and its usefulness as a potential biomarker and therapeutic target. Using the TCGA and GEO databases, gene expression, survival prognosis, genetic abnormalities, immune infiltration, and CSF1R-related gene enrichment related to the CSF1R gene in patients with PAAD were studied. CSF1R expression appears to affect the development of PAAD; there is more CSF1R expression in the tumour tissue than in nearby normal tissues. There was no statistical difference in the overall survival or diseasefree survival of CSF1R expression. Analysis of changes in the CSF1R gene showed that PAAD samples had a low mutation frequency, and CSF1R gene amplification was the main reason. It was additionally emphasized that the impact of CSF1R on the tumor microenvironment, as evidenced by an immunological infiltration analysis, showed a strong correlation between the estimated infiltration values of cancer-associated fibroblasts and CSF1R expression in PAAD. This additional evidence was found for CSF1R expression in cancer-associated fibroblasts in PAAD. Targeting CSF1R might be a promising strategy for PAAD treatment. Inhibiting CSF1R activity or TGF-β binding to CSF1R inhibits tumour growth and immune escape. Investigating the link between CSF1R, TGF-β, and the immune system leads to new opportunities for combination therapies that integrate targeted medicine with immunotherapy. Targeting CSF1R might be a PAAD treatment. Inhibiting CSF1R activity or TGF-β binding to CSF1R inhibits tumour growth and immune escape. Investigating the link between CSF1R, TGF-β, and the immune system opens new opportunities for combining targeted medicines with immunotherapy.

Background and ObjectivesColony-stimulating factor receptor 1-related disorder (CSF1R-RD) is an underrecognized, adult-onset genetic leukodystrophy with a devastating clinical course. Disease monitoring is critical as patients with CSF1R-RD can benefit from hematopoietic stem cell transplantation. Here, we aimed to compare blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels between patients with CSF1R-RD and those with alternative diagnoses and to correlate blood biomarkers values with clinical severity.MethodsWe analyzed 22 patients with CSF1R-RD and patients with fronto-temporal lobar degeneration due to GRN pathogenic variants (GRN-FTLD, n = 22), CADASIL (N = 9), cerebral adrenoleukodystrophy (13), and primary progressive multiple sclerosis (n = 14).ResultsNfL and GFAP were elevated in CSF1R-RD and GRN-FTLD as compared with the other groups. After adjusting for age, GFAP was higher in patients with CSF1R-RD compared with those with GRN-FTLD (p = 0.035). Among CSF1R-RD patients, both NfL (p = 0.0054) and GFAP (p = 0.0065) correlated with Expanded Disability Status Scale scores. For a subset of patients with cognitive testing, GFAP correlated with the processing speed index of the Wechsler adult intelligence scale (p = 0.025) and state anxiety (p = 0.0088).DiscussionOur results show that blood NfL and GFAP are promising biomarkers of disease progression in patients with CSF1R-RD.

Background:Hormones such as prolactin, by influencing expression of the endometrial genes, play a pivotalrole in embryo implantation and development. The present study aimed to evaluate serum level of prolactin andits effect on altering expression level of colony-stimulating factor-1 (CSF-1) and colony-stimulating factor-1 receptor(CSF-1R) genes in endometrial tissue during in vitro fertilization (IVF) pregnancy in the infertile womenand recurrent pregnancy loss (RPL), compared to fertile women, who lost their pregnancies at gestational age<20 weeks.Materials and Methods:In this case-control study, 40 infertile women, 40 IVF pregnant women with RPL and 40fertile women who lost their pregnancies at <20 weeks of gestation for unknown reasons were selected. Prolactinserum level was assessed using ELISA technique and expression of CSF-1 and CSF-1R genes was determined inendometrial tissue, using quantitative reverse transcription polymerase chain reaction (qRT-PCR).Results:Mean prolactin level of the infertile group was 24.38 ± 1.43 ng/mL and it had statistically significantrelationship with the fertile group (P<0.001). Expression level of the CSF-1 and CSF-1R genes were higher in thefertile than infertile groups by 2.88 times (P<0.0001) and 2.64 times (P<0.0001), while it was respectively 2.28(P<0.0001) and 1.69 (P<0.0001) times higher compared to the RPL group. Risk factors for pregnancy loss, suchas aging, increased body mass index (BMI), smoking and diabetes caused decreasing changes in gene expression(CSF-1 and CSF-1R) and the differences were statistically significant, except in the infertile group.Conclusion:The present study showed a significant relationship of CSF-1 and CSF-1R expression levels with pregnancyloss. Risk factors such as aging, obesity, smoking and diabetes decreased both genes expression levels.

Colony stimulating factor 1 receptor (CSF1R)‐related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances.ObjectiveTo describe four cases of CSF1R‐related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter‐individual diversity of clinical presentations.MethodsThis is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein.ResultsTwo heterozygous missense mutations in the CSF1R gene were identified, c.2344C>T; p.Arg777Trp and c.2329C>T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter‐individual diversity in the loss of cognitive, motor‐neuronal, and extrapyramidal functions.ConclusionsIncluding the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow‐up for this and other leukoencephalopathies.

Colony-stimulating factor 1 receptor (CSF1R) is expressed in monocytes/macrophages and dendritic cells. These cells play important roles in the innate immune response, which is regarded as an important aspect of asthma development. Genetic alterations in the CSF1R gene may contribute to the development of asthma. We investigated whether CSF1R gene polymorphisms were associated with the risk of asthma. Through direct DNA sequencing of the CSF1R gene, we identified 28 single nucleotide polymorphisms (SNPs) and genotyped them in 303 normal controls and 498 asthmatic patients. Expression of CSF1R protein and mRNA were measured on CD14-positive monocytes and neutrophils in peripheral blood of asthmatic patients using flow cytometry and real-time PCR. Among the 28 polymorphisms, two intronic polymorphism (+20511C>T and +22693T>C) were associated with the risk of asthma by logistic regression analysis. The frequencies of the minor allele at CSF1R +20511C>T and +22693T>C were higher in asthmatic subjects than in normal controls (4.6 vs. 7.7%, p = 0.001 in co-dominant and dominant models; 16.4 vs. 25.8%, p = 0.0006 in a recessive model). CSF1R mRNA levels in neutrophils of the asthmatic patients having the +22693CC allele were higher than in those having the +22693TT allele (p = 0.026). Asthmatic patients with the +22693CC allele also showed significantly higher CSF1R expression on CD14-positive monocytes and neutrophils than did those with the +22693TT allele (p = 0.045 and p = 0.044). The +20511C>T SNP had no association with CSF1R mRNA or protein expression. In conclusion, the minor allele at CSF1R +22693T>C may have a susceptibility effect in the development of asthma, via increased CSF1R protein and mRNA expression in inflammatory cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-010-0850-3) contains supplementary material, which is available to authorized users.

BackgroundColony stimulating factor‐1 receptor (CSF1R)‐related disorder (CSF1R‐RD) is an autosomal dominant, rapidly progressive, demyelinating disease leading to death usually within a few years. Because of the central role of CSF1R in microglia functions, allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a therapy for CSF1R‐RD.ObjectivesTo report multicenter clinical (Expanded Disability Scoring Scale [EDSS]), neurocognitive), neuroimaging (Sundal score), and biological (neurofilament light chain [NfL]) outcomes after HSCT in CSF1R‐RD.MethodsWe report an international cohort of 17 adult patients (8 females/9 males, 43.3 ± 9.4 years) who were treated in seven transplant centers. Patients were evaluated for a median of 2.5 years post‐HSCT, including one patient with follow‐up of 8 years. We also report neurological outcomes of the first child transplanted to date with biallelic CSF1R variants.ResultsIn the first 6 months post‐HSCT, 2 patients died from early complications of myeloablative transplantation, and clinical and radiological severity scores worsened in most surviving adult patients. At 12 months post‐HSCT, most patients completely stabilized or improved in certain clinical domains. Radiological scores fully stabilized or slightly improved in all but one of the patients. Plasma/serum NfL sharply decreased in most patients after transplantation. Notably, 7/8 adult patients who received a reduced‐intensity conditioning regimen displayed similar neurological outcomes as patients who underwent myeloablative transplantation.ConclusionsAfter an initial clinical and radiological deterioration in the first 6 months post‐transplantation, HSCT can halt disease progression in patients with CSF1R‐RD, regardless of their presenting clinical symptoms. The possibility of reduced conditioning regimens in CSF1R‐RD opens the way to treat older patients. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare white matter degenerative disease manifesting as progressive cognitive decline, pyramidal, and extrapyramidal features resulting from mutations in the colony-stimulating factor-1 receptor (CSF1R) gene. We describe a sporadic case of a young man who developed five months history of progressive cognitive decline with predominant neuropsychiatric symptoms, suggestive of frontotemporal dementia. Brain magnetic resonance imaging (MRI) showed bilateral frontotemporal atrophy, high signal intensities in frontal and high parietal deep white matter with persistent diffusion restriction on follow-up imaging. Genetics showed a novel heterozygous mutation in CSF1R gene confirming the diagnosis of ALSP. Being a rare disease, and given its particular adult-onset presentation especially presenile cognitive impairment, it can pose a unique diagnostic challenge. The study highlights the importance of recognizing the disease early and broadens the clinical, genetic, and imaging spectrum of CSF1R gene mutation.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant disorder with high penetrance characterized by progressive cognitive and motor dysfunction. The objective of the study was to describe a new variant of the colony stimulating factor-1 receptor (CSF1R) gene causing HDLS in a Chinese family. Physical examinations, laboratory tests, structural neuroimaging studies, and whole-exome sequence analysis were carried out. Three patients in this family exhibited typical manifestations of HDLS, including progressive cognitive impairment, language and motor dysfunctions, and urinary and bowel incontinence. Genetic analysis identified a heterozygous missense mutation (c.2264T>C, p.L755P) in exon 17 of the CSF1R gene that cosegregated with the HDLS phenotype in an autosomal-dominant pattern. Brain MRI of the proband and her father showed diffuse white matter changes. The proband's 10-year-old son, a gene carrier, remains clinically asymptomatic at present. Our findings identify a novel missense mutation, p.L755P, in the CSF1R gene within a Chinese family with autosomal-dominant HDLS and broaden the genetic spectrum of CSF1R-associated HDLS.

Neurofilament light chain and glial fibrillary acidic protein as diagnostic and prognostic biomarkers in epileptic seizures and epilepsy: A systematic review.

An often rate-limiting step for cancer immunotherapy is drug development. The generation of humanized mouse models can be used to assess the clinical utility of new drugs earlier in the discovery process. Tumor-associated macrophages (TAMs) represent an emerging therapeutic target, specifically high expression of the colony-stimulating factor 1 receptor (CSF1R) protein on tumors and TAMs facilitate a tumor permissive environment. Previous reports have demonstrated that blockade of the CSF1/CSF1R pathway reduced and reprogrammed intra-tumoral CSF1R+ TAMs, altogether alleviating immune suppression. To evaluate preclinical efficacy and toxicity of CSF1R targeted therapeutic candidates, Biocytogen has successfully generated a double humanized B-hCSF1/hCSF1R mouse model. The full-length encoding sequence of mouse Csf1 and the extracellular domain of Csf1r were replaced by human CSF1 and CSF1R genes, respectively. Evaluation of CSF1 and CSF1R protein expression in homozygous B-hCSF1/hCSF1R mice (H/H) was confirmed by ELISA and flow cytometry analysis. We next performed an in vivo efficacy screening study using genetically modified hCSF1 or wild-type MC38 cells inoculated into B-hCSF1/hCSF1R (H/H) mice and observed that anti-human CSF1R antibodies or combination therapy of anti-mouse PD-L1 and anti-human CSF1R antibodies were effective in controlling tumor growth. Our combined studies illustrate that Biocytogen’s novel B-hCSF1/hCSF1R mice offer a promising model for in vivo validation of CSF1 and CSF1R antibody therapeutics. Citation Format: Ruili Lyu, Shujin Zhang, Rebecca Soto, Suman Zhao, Chonghui Liu, Luke (Zhaoxue) Yu. Evaluation of therapeutic drug candidates using a novel humanized B-hCSF1/hCSF1R mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1648.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disease clinically characterized by cognitive decline, personality changes, motor impairment, parkinsonism and seizures. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. We report clinical, neuropathological and molecular genetic findings of patients from a new family with a mutation in the CSF1R gene. Disease onset was earlier and disease progression was more rapid compared with previously reported patients. Psychiatric symptoms including personality changes, alcohol abuse and severe depression were the first symptoms in male patients. In the index, female patient, the initial symptom was cognitive decline. Magnetic resonance imaging (MRI) showed bilateral, confluent white matter lesions in the cerebrum. Stereotactic biopsy revealed loss of myelin and microglial activation as well as macrophage infiltration of the parenchyma. Numerous axonal swellings and spheroids were present. Ultrastructural analysis revealed pigment-containing macrophages. Axonal swellings were detected by electron microscopy not only in the central nervous system (CNS) but also in skin nerves. We identified a heterozygous mutation (c.2330G>A, p.R777Q) in the CSF1R gene. Through this report, we aim to enlarge the nosological spectrum of HDLS, providing new clinical descriptions as well as novel neuropathological findings from the peripheral nervous system.

The receptor tyrosine kinase type III subfamily includes the PDGF receptors (alpha and beta), c-kit and the colony stimulating factor 1 receptor (CSF1R). The similar genomic organization of the genes encoding these receptors and the observation that in mammals, the genes for PDGFR alpha and PDGFR beta are tandemly linked with the c-kit and CSF1R genes, respectively, suggest that these genes arose from an ancestral receptor tyrosine kinase gene. We have previously cloned two copies each of the PDGFR beta and CSF1R genes from the pufferfish, Fugu rubripes, and shown that they are tandemly linked. We have now cloned the Fugu PDGFR alpha and c-kit genes and show that they are also tandemly linked. The intergenic region between the two genes in the Fugu (13 kb) and humans (350 kb) contains a conserved 59 bp element, which may play a role in regulation. The Fugu PDGFR alpha gene is transcribed from two promoters giving rise to alternate transcripts.

High Incidence of Radiation-Induced Cavernous Hemangioma in Long-Term Survivors Who Underwent Hematopoietic Stem Cell Transplantation with Radiation Therapy during Childhood or Adolescence