RARE DISEASE
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
Synonyms: ALSP, Autosomal dominant leukoencephalopathy with neuroaxonal spheroids, FPSG, Familial dementia, Neumann type, Familial progressive subcortical gliosis, GPSC, HDLS, Hereditary diffuse leukoencephalopathy with spheroids, POLD, Pigmentary orthochromatic leukodystrophy, Subcortical gliosis of Neumann
Synonyms: ALSP, Autosomal dominant leukoencephalopathy with neuroaxonal spheroids, FPSG, Familial dementia, Neumann type, Familial progressive subcortical gliosis, GPSC, HDLS, Hereditary diffuse leukoencephalopathy with spheroids, POLD, Pigmentary orthochromatic leukodystrophy, Subcortical gliosis of Neumann
Synonyms: ALSP, Autosomal dominant leukoencephalopathy with neuroaxonal spheroids, FPSG, Familial dementia, Neumann type, Familial progressive subcortical gliosis, GPSC, HDLS, Hereditary diffuse leukoencephalopathy with spheroids, POLD, Pigmentary orthochromatic leukodystrophy, Subcortical gliosis of Neumann
Drug discovery
1
drug
With orphan designation
Overview
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive autosomal dominant neurodegenerative disorder caused by CSF1R gene mutations. It manifests in adulthood (mean onset ~43 years) with cognitive decline, neuropsychiatric symptoms, and motor dysfunction (parkinsonism, spasticity), progressing to severe disability and death within ~6-8 years. Diagnosis relies on MRI showing frontal-predominant white matter lesions, corpus callosum thinning, and genetic confirmation. No disease-modifying therapies exist, with care focused on symptom management [1][3][8].
Burden
Median survival: 6-8 years post-symptom onset, with late-stage patients requiring full-time care [1][8]
Caregivers report significant emotional/financial strain due to progressive cognitive/motor decline [1]
Economic burden: High hospitalization rates and loss of productivity in affected adults (prime working age) [1][8]
Therapies
Symptomatic management: Physical/occupational therapy, antidepressants, and antispasmodics [3][5]
Investigational approaches: Hematopoietic stem cell transplantation trials (preliminary data), microglia-targeted therapies in preclinical stages [5][8]
No approved disease-modifying treatments; misdiagnosis delays care in 68.5% of cases [5][8]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
49 drug discovery papers about Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
49 drug discovery papers about Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-12-15 | Case Report: A pharmacist-led precision therapy framework for managing invasive fungal infection in CSF1R-Related leukoencephalopathy post Allo-HSCT.
Hereditary diffuse leukoencephalopathy with spheroids (HDLS), caused by CSF1R mutations, is a rare autosomal dominant leukodystrophy characterized by rapid neurological decline. Hematopoietic stem cell transplantation (HSCT) is a promising treatment, but the risk of post-transplant complications such as invasive fungal disease (IFD) remains underexplored. Microglial dysfunction in CSF1R-related disorder (CRD) may further impair host immune defense. We describe a Chinese male with a non-hotspot CSF1R mutation (c.2443-1G>C) who underwent allogeneic HSCT. A multidisciplinary team (MDT), including clinical pharmacists, implemented an individualized pharmacological strategy for antifungal management, guided by immune status, infection risk, pharmacokinetics, and next-generation pathogen diagnostics. Despite prophylaxis with voriconazole and levofloxacin, the patient developed febrile neutropenia and otitis media by day +16. Empirical meropenem therapy was ineffective, prompting escalation to teicoplanin and caspofungin. Pulmonary infection developed; targeted sequencing of bronchoalveolar lavage identified Aspergillus flavus. Antifungal therapy was intensified with voriconazole, resulting in clinical resolution by day +70. Treatment was maintained with good response. This case demonstrates the complexity of managing IFD in CSF1R-related disorder patients after HSCT. The interplay between systemic immunosuppression and intrinsic microglial dysfunction may heighten infection susceptibility. Precision antifungal therapy guided by multidisciplinary team expertise and pharmacological monitoring may improve outcomes in this rare and high-risk population.
2025-06-27 | Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity.
Microglia, the brain's resident macrophages, depend on interleukin-34 and colony-stimulating factor 1 (CSF1) for their development and maintenance, engaging the CSF1 receptor (CSF1R). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disorder affecting the brain's white matter, is caused by heterozygous pathogenic mutations in the CSF1R gene. This study investigated molecular mechanisms underlying ALSP using single-nucleus RNA sequencing on postmortem brain specimens. Results showed a significant reduction in microglia in ALSP brains, with remaining cells exhibiting a unique activation signature. This reduction correlated with decreased myelinating oligodendrocytes (OLs) and increased neuropilin-2+ OLs with a stress-response and anti-apoptotic signature, driven by STAT3 and fibroblast growth factor receptor pathways. Additionally, astrocytes displayed maladaptive activation and stress responses. These findings underscore microglia's crucial role in supporting OL myelination and limiting astrocyte repair responses, suggesting therapeutic strategies balancing CSF1R, fibroblast growth factor receptor and STAT3 pathways for ALSP and other genetically caused microgliopathies.
2025-04-20 | Microglia specific Csf1r haploinsufficiency induces depressive-like behaviors by promoting NLRP6/caspase-1 signaling in mice.
Depression is an early clinical manifestation of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), although the underlying molecular mechanisms remain poorly elucidated. The objective of this study was to investigate the mechanisms underpinning depressive behavior in the context of ALSP, utilizing microglial-specific Csf1r haploinsufficient mice. Our findings indicate that these mice exhibited depressive-like behaviors, as well as microglial hyper-ramification and aberrant synaptic pruning capacity. Blockade of CSF1R signaling with PLX3397 resulted in significant amelioration of depressive symptoms and restoration of normal microglial morphology and function. RNA sequencing analysis of microglia isolated from the medial prefrontal cortex (mPFC) of the brain indicated that NLRPs signaling pathways may play a significant role in the observed alterations in microglial Csf1r haploinsufficient mice. Notably, NLRP6, rather than NLRP3, was found to be upregulated, and the expression of caspase-1 exhibited colocalization with the microglial marker Iba1. Pharmacological inhibition of caspase-1 using VX-765 improved depressive-like behaviors, as well as microglial function. Taken together, our findings delineate a causal relationship between microglial Csf1r haploinsufficiency-induced activation of the NLRP6/caspase-1 signaling pathway and the manifestation of depressive-like behaviors in ALSP mice.
2024-06-13 | The effect of a dominant kinase-deadCsf1rmutation associated with adult-onset leukoencephalopathy on brain development and neuropathology
Abstract Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Previous analysis demonstrated that heterozygous mutation ( Csf1r E631K/+ ) had a dominant inhibitory effect on CSF1R signaling in vitro and in vivo but did not recapitulate the pathology of the human disease. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the impact of heterozygous Csf1r mutation on microglial phenotype, normal postnatal brain development, age-related changes in gene expression and on two distinct pathologies in which microgliosis is a prominent feature, prion disease and experimental autoimmune encephalitis (EAE). The heterozygous Csf1r E631K/+ mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 weeks and 43 weeks of age but had no selective effect on homeostatic markers such as P2ry12 . An epistatic interaction was demonstrated between Csf1r E631K/+ and Cxc3r1 EGFP/+ genotypes leading to dysregulated microglial and neuronal gene expression in both hippocampus and striatum. Heterozygous Csf1r E631K mutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, induced expression of inflammation-associated transcripts in the hippocampus and striatum was suppressed in parallel with microglia-specific transcripts, but spinal cord demyelination was exacerbated. The results support a dominant-negative model of CSF1R-associated leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology.
2023-06-22 | Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP
Abstract CSF1R mutations cause autosomal-dominant CSF1R -related leukoencephalopathy with axonal spheroids and pigmented glia ( CSF1R -ALSP) and autosomal-recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). The former is increasingly recognized, and disease-modifying therapy was introduced; however, literature is scarce on the latter. This review analyzes BANDDOS and discusses similarities and differences with CSF1R -ALSP. We systematically retrieved and analyzed the clinical, genetic, radiological, and pathological data on the previously reported and our cases with BANDDOS. We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3). We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion. All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay. The material is heterogenous, and the presented information refers to the number of patients with sufficient data on specific symptoms, results, or performed procedures. The first symptoms occurred in the perinatal period (n = 5), infancy (n = 2), childhood (n = 5), and adulthood (n = 1). Dysmorphic features were present in 7/17 cases. Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7). Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis – Pyle disease spectrum. Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10). Three patients died in infancy, two in childhood, and one case at unspecified age. A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications. In conclusion, BANDDOS presents in the perinatal period or infancy and has a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features. There is a significant overlap in the clinical, radiological, and neuropathological aspects between BANDDOS and CSF1R -ALSP. As both disorders are on the same continuum, there is a window of opportunity to apply available therapy in CSF1R -ALSP to BANDDOS.
cell therapies
2026-05-18 | Clinical and genetic characteristics of CSF1R-related leukoencephalopathy: a retrospective analysis of three cases.
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant neurodegenerative disorder caused by CSF1R variants, which lead to microglial dysfunction and progressive white matter degeneration. This study identified CSF1R variants in three unrelated Chinese patients with HDLS. We identified heterozygous CSF1R variants (NM_001288705.3) in three unrelated Chinese patients with HDLS: c.2522 A > C/p.(Tyr841Ser), c.2442 + 1G > A/p.?, and c.2546_2548del/p.(Phe849del). While the former two variants were categorized as likely pathogenic under the American College of Medical Genetics and Genomics framework, the latter (c.2546_2548del) was classified as a variant of uncertain significance due to insufficient evidence at the time of analysis. All patients exhibited cognitive decline, personality changes, and motor symptoms. Brain MRI showed characteristic diffuse white matter hyperintensities, restricted diffusion, corpus callosum atrophy, and brain atrophy. Symptoms progressed in Patient 1 (c.2522 A > C p.(Tyr841Ser)) and Patient 3 (c.2546_2548del p.(Phe849del)) despite standard symptomatic treatments. Clinical status remained relatively stable in Patient 2 (c.2442 + 1G > A/p.?) following allogeneic hematopoietic stem cell transplantation (HSCT). These findings expand the molecular and clinical spectrum of CSF1R in Chinese populations and highlight the diagnostic value of genetic sequencing in adult-onset leukoencephalopathies. Establishing a precise molecular diagnosis is crucial, as allogeneic HSCT remains a potentially disease-modifying therapy for patients with CSF1R-related leukoencephalopathy. Further longitudinal studies are warranted to evaluate the long-term efficacy of HSCT and to explore emerging targeted therapeutic strategies.
2026-05-08 | Microglia beyond boundaries: Paradigm shifts in origin, distribution, state diversity, and therapeutic regeneration.
Microglia have undergone a fundamental redefinition, transitioning from traditional CNS-restricted scavengers to a highly dynamic and systemically distributed immune lineage. This review synthesizes recent paradigm shifts that challenge long-standing concepts in neuroimmunology. We first discuss the revision of the classical vascular extravasation model by a newly identified integrin-dependent pial surface migration route for embryonic microglial progenitors. Second, we introduce the expanded concept of the "microglial lineage," which includes transcriptionally and ontogenetically homologous cells residing not only in the CNS but also in peripheral tissues such as the skin, heart, and peripheral nervous system, suggesting broader physiological functions. Third, we highlight the transition from the obsolete M1/M2 polarization model to a microenvironment-driven, dynamic multimodal framework that captures the complex and context-dependent nature of microglial states in health and disease. Finally, we review breakthroughs in regenerative therapy, from pharmacologically induced repopulation to exogenous replacement using iPSC-derived or gene-corrected microglia, offering new hope for genetic microgliopathies such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Collectively, these advances position microglia as central mediators of neuro-immune crosstalk and open novel avenues for treating neurodegenerative, neuroinflammatory, and developmental brain disorders.
2025-10-04 | From sentinels to engineers: The future of microglia in brain regeneration.
Recent studies highlight microglial replacement as a promising therapeutic approach for neurological disease. Wu et al.1 demonstrated that transplanted bone marrow-derived cells halted ALSP progression, while Mader et al.2 introduced a strategy that avoids systemic bone marrow ablation toxicity and reduces immune rejection, collectively validating this strategy's therapeutic potential.
2025-07-10 | Microglia replacement halts the progression of microgliopathy in mice and humans.
Colony-stimulating factor 1 receptor (CSF1R) is primarily expressed in microglia. Its monoallelic mutation causes CSF1R-associated microgliopathy (CAMP), a major form of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and a fatal neurological disease without clinical cure. We developed mouse models harboring human hotspot mutations of CAMP and replaced CSF1R-deficient microglia with CSF1R-normal cells through microglia replacement by bone marrow transplantation (Mr BMT), which attenuated pathology in mice. We further demonstrated that, in the context of CSF1R deficiency, traditional bone marrow transplantation (tBMT) in ALSP functions similarly to Mr BMT, efficiently replacing microglia and reducing disease progression. We then replaced CSF1R-deficient microglia in eight patients by tBMT. The disease progression was halted during the 24-month follow-up. Together, microglia replacement corrects pathogenic mutations and halts disease progression in mice and humans.
2024-09-26 | Hematopoietic stem cell transplantation in leukodystrophies.
More than 50 leukodystrophies have been described. This group of inherited disorders affects myelin development and/or maintenance and can manifest from birth to adulthood. Neuroinflammation is a hallmark of some leukodystrophies, explaining in part the therapeutic benefit of hematopoietic stem cell transplantation (HSCT). Indeed, in addition to supplying the CNS with myelomonocyte donor cells expressing the deficient protein or enzyme, HSCT allows the restoration of normal microglia function, which may act on neuroinflammation. In this chapter, we explore the rationale, indication, and outcome of HSCT in Cerebral Adrenoleukodystrophy (CALD), Metachromatic Leukodystrophy (MLD), Krabbe Disease (KD), and Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP), which are among the most frequent leukodystrophies. For these leukodystrophies, HSCT may modify notably the natural history and improve CNS-related deficits, provided that the procedure is performed early into the disease course. In addition, we discuss the recent development of ex vivo gene therapy for CALD and MLD as a promising alternative to allograft.
antibodies
2025-04-01 | Phase 1, First-In-Human, Single-/Multiple-Ascending Dose Study of Iluzanebart in Healthy Volunteers.
To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of iluzanebart, a fully human monoclonal antibody TREM2 (triggering receptor expressed on myeloid cells 2) agonist, after single- (SAD) and multiple-ascending-dose (MAD) administration. Healthy adult volunteers (N = 136) received intravenous placebo or iluzanebart 1-60 mg/kg (SAD) or 10-60 mg/kg (MAD) followed by serial pharmacokinetics and safety assessments. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory evaluations. Pharmacokinetics were assessed through noncompartmental analysis. The study also included open-label cohorts (3, 10, 20, 40, 60 mg/kg SAD; 10, 20, 40 mg/kg MAD) for cerebrospinal fluid (CSF) collection for exploratory pharmacodynamic biomarker analysis. Iluzanebart was safe and well tolerated following single and multiple doses of up to 60 mg/kg. Most AEs were mild and resolved spontaneously. The most frequently reported AE was pruritus. No serious AEs or investigational product-related clinically meaningful changes in vital signs, electrocardiograms, or laboratory assessments were reported. Iluzanebart serum exposure was related to dose, with a 29-day half-life that is supportive of monthly dosing and confirmed central nervous system (CNS) exposure (≈0.15% CSF-to-serum ratio). Durable and dose-dependent target engagement, evidenced by marked reductions in soluble TREM2 and increased soluble CSF1R (colony-stimulating factor 1 receptor) and osteopontin/SPP1 (secreted phosphoprotein 1) levels in CSF, was observed, indicating that iluzanebart changes microglial activity following single and repeat dosing. Iluzanebart demonstrated favorable safety, tolerability, pharmacokinetics, and pharmacological activity in the CNS, supporting further clinical development for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
2025-02-18 | Use of Model-informed Drug Development and Natural History Data to Inform the Development of Iluzanebart in ALSP: A Neurological Rare Disease
Objectives: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, autosomal dominant, neurodegenerative disorder caused by a loss-of-function mutation in the colony-stimulating factor 1 receptor gene (CSF1R) resulting in disruption of intracellular signaling and primary microglial dysfunction in the central nervous system (CNS). Iluzanebart, a fully human monoclonal antibody agonist of the triggering receptor expressed on myeloid cells 2 (TREM2), is currently being investigated as a potential treatment for ALSP. TREM2 agonism by iluzanebart is hypothesized to compensate for CSF1R loss-of-function, resulting in a potential slowing of clinical decline in patients with ALSP. The objective of this analysis is to demonstrate proof-of-concept for a model-informed drug development (MIDD) approach to quantify treatment effect in a Phase 2 study (P2, NCT05677659) utilizing data from a prospective natural history study (NHS, NCT05020743) as an external control.Methods: An integrated disease progression model was constructed to simultaneously describe the longitudinal time-course of biomarker and key clinical measurements using data from the NHS: soluble CSF1R (sCSF1R), neurofilament light chain (NfL), ventricle volume (as an indicator of brain volume loss), Cortical Basal Ganglia Functional Scale (CBFS), Montreal Cognitive Assessment (MoCA). Clinical trial simulations were performed to assess study precision using the model to determine the power to detect potentially relevant treatment effects using a model-based approach. Five hundred (500) replicate P2 studies were simulated for each sample size from 5 to 50 in increments of 5. The simulated open-label treatment data were pooled with the observed data from the NHS and a model parameter was estimated for treatment effect. Precision was assessed as the proportion of trial replicates in which the 95% Confidence Interval (CI) of the parameter estimate for treatment effect fell within 60% to 140% of the true effect size.Results: A joint indirect response disease progression model was fit to all endpoints simultaneously with correlation in random effects across responses. Standard model diagnostics and visual predictive checks demonstrated that the model adequately described each endpoint. Using the MIDD approach, precise estimates of treatment effect could be achieved with the sample size in the P2 study. Conclusions: The MIDD approach evaluated in this simulation study demonstrated proof-of-concept for use as a method of quantifying iluzanebart treatment effect using NHS as an external control. Such a MIDD approach may afford greater power than traditional biostatistical methods by leveraging all available data, including NHS, to detect treatment effect, quantify the contributions of demographic and clinical factors on disease and response, and assess the correlation of markers of disease to relevant clinical outcomes in neurological rare diseases such as ALSP.Citations: none
2025-02-01 | Rescue of in vitro models of CSF1R-related adult-onset leukodystrophy by iluzanebart: mechanisms and therapeutic implications of TREM2 agonism.
Microglia dysfunction is implicated in several neurodegenerative disorders, including a rare microgliopathy; CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP). CSF1R-ALSP is caused by heterozygous loss-of-function mutations in the colony stimulating factor 1 receptor (CSF1R) gene, which encodes a receptor required for the differentiation of myeloid cells, as well as for microglial survival and proliferation. Similar functions have also been ascribed to triggering receptor expressed on myeloid cells 2 (TREM2), which shares an analogous microglia enrichment profile and converging intracellular signaling pathway mediated by spleen associated tyrosine kinase (SYK) and phosphoinositide-3-kinase (PI3K). Iluzanebart is a human monoclonal IgG1, human TREM2 (hTREM2) agonist antibody under development for the treatment of CSF1R-ALSP. To explore the therapeutic hypothesis that loss of CSF1R signaling and related microglial hypofunction can be circumvented via activation of TREM2, we evaluated the potential of iluzanebart to compensate for CSF1R loss-of-function. Herein, we demonstrate that iluzanebart is a potent, dose-dependent, and specific activator of TREM2 signaling in human primary cells. Iluzanebart treatment rescued viability of human monocyte-derived macrophages (hMDM) and induced pluripotent stem cell-derived human microglia (iMGL) in multiple in vitro models of CSF1R-ALSP, including in induced pluripotent stem cell (iPSC) differentiated microglia carrying the heterozygous I794T mutation found in CSF1R-ALSP patients. Additionally, iluzanebart treatment in microglia modulated surface levels of CSF1R, resulting in increased receptor activation as measured by phosphorylation of CSF1R. Differentially expressed genes identified in the hippocampus of mice treated with iluzanebart were exemplary of TREM2 activation and were related to cell proliferation, regulation of inflammatory processes, and innate immune response pathways. Proliferation of microglia, changes in protein levels of specific chemokines identified by gene expression analysis, and increased CSF1R levels were also confirmed in vivo. These findings demonstrate that iluzanebart is a potent and selective TREM2 agonistic antibody, with pharmacology that supports the hypothesis that TREM2 activation can compensate for CSF1R dysfunction and its continued clinical development for individuals with CSF1R-ALSP.
2024-12-10 | Rescue of In Vitro Models of Adult-Onset Leukodystrophy by Iluzanebart: Mechanisms and Therapeutic Implications of TREM2 Agonism
Microglia dysfunction is implicated in several neurodegenerative disorders, including a rare microgliopathy; CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP). CSF1R-ALSP is caused by heterozygous loss-of-function mutations in the colony stimulating factor 1 receptor (CSF1R) gene, which encodes a receptor required for the differentiation of myeloid cells, as well as for microglial survival and proliferation. Similar functions have also been ascribed to triggering receptor expressed on myeloid cells 2 (TREM2), which shares an analogous microglia enrichment profile and converging intracellular signaling pathway mediated by spleen associated tyrosine kinase (SYK) and phosphoinositide-3-kinase (PI3K). Iluzanebart is a human monoclonal IgG1, human TREM2 (hTREM2) agonist antibody under development for the treatment of CSF1R-ALSP. To explore the therapeutic hypothesis that loss of CSF1R signaling and related microglial hypofunction can be circumvented via activation of TREM2, we evaluated the potential of iluzanebart to compensate for CSF1R loss-of-function. Herein, we demonstrate that iluzanebart is a potent, dose-dependent, and specific activator of TREM2 signaling in human primary cells. Iluzanebart treatment rescued viability of human monocyte-derived macrophages (hMDM) and induced pluripotent stem cell-derived human microglia (iMGL) in multiple in vitro models of CSF1R-ALSP, including in induced pluripotent stem cell (iPSC) differentiated microglia carrying the heterozygous I794T mutation found in CSF1R-ALSP patients. Additionally, iluzanebart treatment in microglia modulated surface levels of CSF1R, resulting in increased receptor activation as measured by phosphorylation of CSF1R. Differentially expressed genes identified in the hippocampus of mice treated with iluzanebart were exemplary of TREM2 activation and were related to cell proliferation, regulation of inflammatory processes, and innate immune response pathways. Proliferation of microglia, changes in protein levels of specific chemokines identified by gene expression analysis, and increased CSF1R levels were also confirmed in vivo. These findings demonstrate that iluzanebart is a potent and selective TREM2 agonistic antibody, with pharmacology that supports the hypothesis that TREM2 activation can compensate for CSF1R dysfunction and its continued clinical development for individuals with CSF1R-ALSP.
2024-04-09 | VGL101: An Immunotherapy that Enhances Microglial Survival for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (P9-9.013)
To characterize VGL101 as a high-affinity human TREM2 (hTREM2) agonistic monoclonal antibody and determine its capacity as a potential compensatory pharmacological approach to therapeutically circumvent colony-stimulating factor-1 receptor (CSF1R) dysfunction, which underlies the pathophysiology of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
gene therapies
2026-07-25 | The ILLUMINATE natural history study in colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, fatal, autosomal-dominant neurodegenerative disorder caused by pathogenic CSF1R variants and characterized by progressive cognitive, neuropsychiatric, and motor dysfunction, white matter lesions on brain imaging, and white matter demyelination, swollen axons, and pigmented glial cells on pathology. Limited data regarding clinical, biofluid or radiological biomarkers of disease severity are available, and no clinical trial endpoints have yet been validated. The objectives of this first-of-its-kind, prospective, observational natural history study were to characterize the clinical trajectory of CSF1R-ALSP and to identify and evaluate key biomarkers and clinical endpoints indicative of disease severity and progression. ILLUMINATE (NCT05020743) was a multicentre, noninterventional natural history study of adults with CSF1R-ALSP and prodromal carriers of CSF1R variants. Participants were followed for up to 36 months, with clinical assessments, fluid biomarkers and volumetric MRI assessments of brain atrophy collected at screening and every 6 months. This study was terminated early (4 June 2025). The analyses reported here include data collected through 19 February 2025. Of 53 participants, 19 were prodromal and 34 were symptomatic (11 of whom had a history of haematopoietic stem cell transplant and 23 who did not). Mean participant age was 47.8 (standard deviation, 4.5) years, and 36.4% were female. Prodromal participants remained relatively stable over 36 months, with little change in neurological function, neurodegeneration biomarkers or radiological disease burden. Impaired neurological function, MRI characteristics of CSF1R-ALSP, and elevated NfL (neurofilament light chain; neurodegeneration biomarker) and GFAP (glial fibrillary acidic protein; astrogliosis biomarker) levels were more pronounced at baseline and often showed progression over time among symptomatic participants who had not previously received haematopoietic stem cell transplant compared with participants who had previously received haematopoietic stem cell transplant. Significant correlations were observed at baseline and longitudinally between MRI measures of brain atrophy and clinical outcome measures. Based on the fluid biomarkers, MRI measures, and clinical outcome assessments evaluated here, active neurodegeneration, widespread changes visualized on brain MRI, and impaired cognitive and motor function were observed in symptomatic patients with CSF1R-ALSP. The neurological impairment can be assessed using the Montreal Cognitive Assessment and Cortical Basal ganglia Functional Scale. Our data suggest that quantification of brain atrophy using MRI volumetry is a potential biomarker of disease severity and progression in CSF1R-ALSP. It is hoped that this report will contribute to the understanding of disease progression in CSF1R-ALSP and inform future drug development.
2026-02-06 | CSF1R-related leukoencephalopathy presenting with early apathy, hypoactivity, and cognitive flattening: a case report of a diagnostic challenge.
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant leukodystrophy primarily caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene, characterized by progressive cognitive and motor decline. We present a case of a 42-year-old Chinese woman with a rapidly progressive syndrome featuring prominent apathy, cognitive impairment, and hypoactivity. Brain magnetic resonance imaging (MRI) revealed extensive confluent white matter hyperintensities (Fazekas grade 3) predominantly in frontal and parietal lobes, cerebral atrophy, and thinning of the corpus callosum. Comprehensive genetic testing identified a heterozygous missense mutation in the CSF1R gene (c.2342C > T, p.Ala781Val), located within the tyrosine kinase domain, confirming the Diagnosis of HDLS. This case highlights early apathy and hypoactivity as red-flag manifestations of CSF1R-related leukoencephalopathy in a 42-year-old woman with rapidly progressive cognitive decline. The atypical presentation, initially mimicking psychiatric or demyelinating disease, underscores the need to consider CSF1R sequencing when encountering early-onset cognitive or behavioral deterioration with unexplained white-matter changes, thereby facilitating timely diagnosis and genetic counseling.
2025-06-25 | A case report and review of the literature on hereditary diffuse leukoencephalopathy with spheroids presenting with stroke-like symptoms.
Hereditary diffuse leukoencephalopathy with spheroids (HDLS), a rare autosomal dominant disorder caused by CSF1R (Colony Stimulating Factor 1 Receptor) variants, manifests clinically as adult-onset cognitive-motor decline with progressive white matter degeneration. Notably, its phenotypic variability remains undercharacterized, with only limited case reports available globally. We systematically investigated a 47-year-old male presenting with acute stroke-like hemiparesis that progressed to fronto-subcortical dementia (MMSE=14) and extrapyramidal symptoms within six months. Comprehensive diagnostic evaluations included multimodal 3 T MRI and whole-exome sequencing (WES) targeting CSF1R. Neuroimaging revealed hallmark frontoparietal white matter rarefaction accompanied by persistent diffusion restriction (DWI+/ADC-). WES identified a de novo CSF1R nonsense variant (c.2462 G>A, p.Trp821Ter), which truncates the tyrosine kinase domain. This variant was classified as pathogenic, confirming a definitive HDLS diagnosis. This stroke-onset HDLS expands the phenotypic spectrum, establishing persistent diffusion restriction as an early diagnostic biomarker. CSF1R sequencing proves critical for sporadic case identification regardless of family history. Study limitations include absence of pedigree segregation analysis.
2025-01-14 | Clinical spectrum of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia in individuals of Korean ancestry.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare white matter disease characterized by axonal and glial injury. Although its clinical characteristics have been described in case reports, the prevalence of CSF1R mutations in clinically suspected ALSP cases remains unclear. Herein, we analysed the frequency of CSF1R mutations in patients with probable or possible ALSP and describe the genetic, clinical, radiological, and pathological findings of ALSP cases in individuals of Korean ancestry. Twenty-eight patients with probable or possible ALSP diagnosed at Samsung Medical Center, Seoul, between January 2014 and August 2020, were retrospectively reviewed. All participants underwent brain magnetic resonance imaging (MRI) and CSF1R genetic testing. Overall, 9 of the 28 patients (32.1%) [5/6 (83.3%) of probable ALSP and 4/22 (18.2%) of possible ALSP] were confirmed to have pathogenic or likely pathogenic variants in CSF1R gene. Additionally, one patient without CSF1R mutation exhibited histopathological findings consistent with ALSP on brain biopsy. All patients with CSF1R mutation presented with cognitive impairment and/or psychiatric symptoms. Brain MRI revealed bilateral white matter hyperintensities in all patients, and 5/8 (62.5%) showed diffusion-restricted lesions. Notably, patients with CSF1R mutation had younger age at onset, rapidly progressive course, and diffuse hyperintensity in the splenium compared to patients without CSF1R mutation. Our findings suggest that for definite diagnosis, CSF1R genetic testing is recommended in patients who meet the diagnostic criteria for possible or probable ALSP. Our findings provide insights into the genetic, clinical, radiological, and pathological dimensions of ALSP in individuals of Korean ancestry.
2024-12-17 | Progressive dementia and seizures as distinguishing features in adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia
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other
2022-12-14 | Microglia regulate central nervous system myelin growth and integrity
Abstract Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health 1 , it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease 2,3 .
2021-05-28 | Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy.
Microglia are resident macrophages of the central nervous system, and their unique molecular signature is dependent upon CSF-1 signaling. Previous studies have demonstrated the importance of CSF-1R in survival and development of microglia in animal models, but the findings are of uncertain relevance to understanding the influence of CSF-1R on microglia in humans. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) [also known as adult onset leukoencephalopathy with spheroids and pigmented glia (ALSP)] is a neurodegenerative disorder primarily affecting cerebral white matter, most often caused by mutations of CSF1R. Therefore, we hypothesized that the molecular profile of microglia may be affected in HDLS. Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling revealed reduced expression of IBA-1 and P2RY12 in both white and gray matter microglia of HDLS. In contrast, there was increased expression of CD68 and CD163 in microglia in affected white matter. In addition, expression of selective and specific microglial markers, including P2RY12, CX3CR1 and CSF-1R, were reduced in affected white matter. These results suggest that microglia in white matter in HDLS lose their homeostatic phenotype. Supported by gene ontology analysis, it is likely that an inflammatory phenotype is a key pathogenic feature of microglia in vulnerable brain regions of HDLS. Our findings suggest a potential mechanism of disease pathogenesis by linking aberrant CSF-1 signaling to altered microglial phenotype. They also support the idea that HDLS may be a primary microgliopathy. We observed increased expression of CSF-2 in gray matter compared to affected white matter, which may contribute to selective vulnerability of white matter in HDLS. Our findings suggest that methods that restore the homeostatic phenotype of microglia might be considered treatment approaches in HDLS.
2012-06-21 | The fusion protein of IFN-α and apolipoprotein A-I crosses the blood-brain barrier by a saturable transport mechanism.
IFN-α is widely used for the treatment of chronic viral hepatitis and malignancies. However, systemic IFN-α treatment causes severe neuropsychiatric complications in humans, including depression, anxiety, and cognitive impairments. We have previously reported that the fusion protein formed by IFN-α and apolipoprotein A-I (IA) circulates bound to high-density lipoproteins (HDLs) and exhibits liver targeting, increased half-life, enhanced immunostimulatory activity, and reduced cytotoxicity. As the transport of HDLs across the blood-brain barrier is a highly complex and regulated process, in this study, we examine the effects of IA on the brain. Determination of IFN-α in brain and serum after hydrodynamic administration of different doses of a plasmid encoding IFN-α or IA showed that IA penetrated into the brain by a saturable transport mechanism. Thus, at high serum levels of the transgenes, the induction of IFN-sensitive genes and the number of phospho-STAT1(+) cell nuclei in the brain were substantially higher with IFN-α than with IA. This was associated with attenuation of neurodepression in mice given IA, as manifested by shorter immobility time in the tail suspension test. However, when given low doses of rIFN-α or the same antiviral units of HDLs containing IA, the induction of IFN-stimulated genes in the brain was significantly greater with the latter. In conclusion, IA crosses the blood-brain barrier not by diffusion, as is the case of IFN-α, but by a facilitated saturable transport mechanism. Thus, linkage to apolipoprotein A-I may serve to modulate the effects of IFN-α on the CNS.
small molecules
2025-12-15 | Case Report: A pharmacist-led precision therapy framework for managing invasive fungal infection in CSF1R-Related leukoencephalopathy post Allo-HSCT.
Hereditary diffuse leukoencephalopathy with spheroids (HDLS), caused by CSF1R mutations, is a rare autosomal dominant leukodystrophy characterized by rapid neurological decline. Hematopoietic stem cell transplantation (HSCT) is a promising treatment, but the risk of post-transplant complications such as invasive fungal disease (IFD) remains underexplored. Microglial dysfunction in CSF1R-related disorder (CRD) may further impair host immune defense. We describe a Chinese male with a non-hotspot CSF1R mutation (c.2443-1G>C) who underwent allogeneic HSCT. A multidisciplinary team (MDT), including clinical pharmacists, implemented an individualized pharmacological strategy for antifungal management, guided by immune status, infection risk, pharmacokinetics, and next-generation pathogen diagnostics. Despite prophylaxis with voriconazole and levofloxacin, the patient developed febrile neutropenia and otitis media by day +16. Empirical meropenem therapy was ineffective, prompting escalation to teicoplanin and caspofungin. Pulmonary infection developed; targeted sequencing of bronchoalveolar lavage identified Aspergillus flavus. Antifungal therapy was intensified with voriconazole, resulting in clinical resolution by day +70. Treatment was maintained with good response. This case demonstrates the complexity of managing IFD in CSF1R-related disorder patients after HSCT. The interplay between systemic immunosuppression and intrinsic microglial dysfunction may heighten infection susceptibility. Precision antifungal therapy guided by multidisciplinary team expertise and pharmacological monitoring may improve outcomes in this rare and high-risk population.
2025-06-27 | Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity.
Microglia, the brain's resident macrophages, depend on interleukin-34 and colony-stimulating factor 1 (CSF1) for their development and maintenance, engaging the CSF1 receptor (CSF1R). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disorder affecting the brain's white matter, is caused by heterozygous pathogenic mutations in the CSF1R gene. This study investigated molecular mechanisms underlying ALSP using single-nucleus RNA sequencing on postmortem brain specimens. Results showed a significant reduction in microglia in ALSP brains, with remaining cells exhibiting a unique activation signature. This reduction correlated with decreased myelinating oligodendrocytes (OLs) and increased neuropilin-2+ OLs with a stress-response and anti-apoptotic signature, driven by STAT3 and fibroblast growth factor receptor pathways. Additionally, astrocytes displayed maladaptive activation and stress responses. These findings underscore microglia's crucial role in supporting OL myelination and limiting astrocyte repair responses, suggesting therapeutic strategies balancing CSF1R, fibroblast growth factor receptor and STAT3 pathways for ALSP and other genetically caused microgliopathies.
2025-04-20 | Microglia specific Csf1r haploinsufficiency induces depressive-like behaviors by promoting NLRP6/caspase-1 signaling in mice.
Depression is an early clinical manifestation of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), although the underlying molecular mechanisms remain poorly elucidated. The objective of this study was to investigate the mechanisms underpinning depressive behavior in the context of ALSP, utilizing microglial-specific Csf1r haploinsufficient mice. Our findings indicate that these mice exhibited depressive-like behaviors, as well as microglial hyper-ramification and aberrant synaptic pruning capacity. Blockade of CSF1R signaling with PLX3397 resulted in significant amelioration of depressive symptoms and restoration of normal microglial morphology and function. RNA sequencing analysis of microglia isolated from the medial prefrontal cortex (mPFC) of the brain indicated that NLRPs signaling pathways may play a significant role in the observed alterations in microglial Csf1r haploinsufficient mice. Notably, NLRP6, rather than NLRP3, was found to be upregulated, and the expression of caspase-1 exhibited colocalization with the microglial marker Iba1. Pharmacological inhibition of caspase-1 using VX-765 improved depressive-like behaviors, as well as microglial function. Taken together, our findings delineate a causal relationship between microglial Csf1r haploinsufficiency-induced activation of the NLRP6/caspase-1 signaling pathway and the manifestation of depressive-like behaviors in ALSP mice.
2024-06-13 | The effect of a dominant kinase-deadCsf1rmutation associated with adult-onset leukoencephalopathy on brain development and neuropathology
Abstract Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Previous analysis demonstrated that heterozygous mutation ( Csf1r E631K/+ ) had a dominant inhibitory effect on CSF1R signaling in vitro and in vivo but did not recapitulate the pathology of the human disease. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the impact of heterozygous Csf1r mutation on microglial phenotype, normal postnatal brain development, age-related changes in gene expression and on two distinct pathologies in which microgliosis is a prominent feature, prion disease and experimental autoimmune encephalitis (EAE). The heterozygous Csf1r E631K/+ mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 weeks and 43 weeks of age but had no selective effect on homeostatic markers such as P2ry12 . An epistatic interaction was demonstrated between Csf1r E631K/+ and Cxc3r1 EGFP/+ genotypes leading to dysregulated microglial and neuronal gene expression in both hippocampus and striatum. Heterozygous Csf1r E631K mutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, induced expression of inflammation-associated transcripts in the hippocampus and striatum was suppressed in parallel with microglia-specific transcripts, but spinal cord demyelination was exacerbated. The results support a dominant-negative model of CSF1R-associated leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology.
2023-06-22 | Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP
Abstract CSF1R mutations cause autosomal-dominant CSF1R -related leukoencephalopathy with axonal spheroids and pigmented glia ( CSF1R -ALSP) and autosomal-recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). The former is increasingly recognized, and disease-modifying therapy was introduced; however, literature is scarce on the latter. This review analyzes BANDDOS and discusses similarities and differences with CSF1R -ALSP. We systematically retrieved and analyzed the clinical, genetic, radiological, and pathological data on the previously reported and our cases with BANDDOS. We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3). We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion. All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay. The material is heterogenous, and the presented information refers to the number of patients with sufficient data on specific symptoms, results, or performed procedures. The first symptoms occurred in the perinatal period (n = 5), infancy (n = 2), childhood (n = 5), and adulthood (n = 1). Dysmorphic features were present in 7/17 cases. Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7). Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis – Pyle disease spectrum. Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10). Three patients died in infancy, two in childhood, and one case at unspecified age. A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications. In conclusion, BANDDOS presents in the perinatal period or infancy and has a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features. There is a significant overlap in the clinical, radiological, and neuropathological aspects between BANDDOS and CSF1R -ALSP. As both disorders are on the same continuum, there is a window of opportunity to apply available therapy in CSF1R -ALSP to BANDDOS.
cell therapies
2026-05-18 | Clinical and genetic characteristics of CSF1R-related leukoencephalopathy: a retrospective analysis of three cases.
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant neurodegenerative disorder caused by CSF1R variants, which lead to microglial dysfunction and progressive white matter degeneration. This study identified CSF1R variants in three unrelated Chinese patients with HDLS. We identified heterozygous CSF1R variants (NM_001288705.3) in three unrelated Chinese patients with HDLS: c.2522 A > C/p.(Tyr841Ser), c.2442 + 1G > A/p.?, and c.2546_2548del/p.(Phe849del). While the former two variants were categorized as likely pathogenic under the American College of Medical Genetics and Genomics framework, the latter (c.2546_2548del) was classified as a variant of uncertain significance due to insufficient evidence at the time of analysis. All patients exhibited cognitive decline, personality changes, and motor symptoms. Brain MRI showed characteristic diffuse white matter hyperintensities, restricted diffusion, corpus callosum atrophy, and brain atrophy. Symptoms progressed in Patient 1 (c.2522 A > C p.(Tyr841Ser)) and Patient 3 (c.2546_2548del p.(Phe849del)) despite standard symptomatic treatments. Clinical status remained relatively stable in Patient 2 (c.2442 + 1G > A/p.?) following allogeneic hematopoietic stem cell transplantation (HSCT). These findings expand the molecular and clinical spectrum of CSF1R in Chinese populations and highlight the diagnostic value of genetic sequencing in adult-onset leukoencephalopathies. Establishing a precise molecular diagnosis is crucial, as allogeneic HSCT remains a potentially disease-modifying therapy for patients with CSF1R-related leukoencephalopathy. Further longitudinal studies are warranted to evaluate the long-term efficacy of HSCT and to explore emerging targeted therapeutic strategies.
2026-05-08 | Microglia beyond boundaries: Paradigm shifts in origin, distribution, state diversity, and therapeutic regeneration.
Microglia have undergone a fundamental redefinition, transitioning from traditional CNS-restricted scavengers to a highly dynamic and systemically distributed immune lineage. This review synthesizes recent paradigm shifts that challenge long-standing concepts in neuroimmunology. We first discuss the revision of the classical vascular extravasation model by a newly identified integrin-dependent pial surface migration route for embryonic microglial progenitors. Second, we introduce the expanded concept of the "microglial lineage," which includes transcriptionally and ontogenetically homologous cells residing not only in the CNS but also in peripheral tissues such as the skin, heart, and peripheral nervous system, suggesting broader physiological functions. Third, we highlight the transition from the obsolete M1/M2 polarization model to a microenvironment-driven, dynamic multimodal framework that captures the complex and context-dependent nature of microglial states in health and disease. Finally, we review breakthroughs in regenerative therapy, from pharmacologically induced repopulation to exogenous replacement using iPSC-derived or gene-corrected microglia, offering new hope for genetic microgliopathies such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Collectively, these advances position microglia as central mediators of neuro-immune crosstalk and open novel avenues for treating neurodegenerative, neuroinflammatory, and developmental brain disorders.
2025-10-04 | From sentinels to engineers: The future of microglia in brain regeneration.
Recent studies highlight microglial replacement as a promising therapeutic approach for neurological disease. Wu et al.1 demonstrated that transplanted bone marrow-derived cells halted ALSP progression, while Mader et al.2 introduced a strategy that avoids systemic bone marrow ablation toxicity and reduces immune rejection, collectively validating this strategy's therapeutic potential.
2025-07-10 | Microglia replacement halts the progression of microgliopathy in mice and humans.
Colony-stimulating factor 1 receptor (CSF1R) is primarily expressed in microglia. Its monoallelic mutation causes CSF1R-associated microgliopathy (CAMP), a major form of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and a fatal neurological disease without clinical cure. We developed mouse models harboring human hotspot mutations of CAMP and replaced CSF1R-deficient microglia with CSF1R-normal cells through microglia replacement by bone marrow transplantation (Mr BMT), which attenuated pathology in mice. We further demonstrated that, in the context of CSF1R deficiency, traditional bone marrow transplantation (tBMT) in ALSP functions similarly to Mr BMT, efficiently replacing microglia and reducing disease progression. We then replaced CSF1R-deficient microglia in eight patients by tBMT. The disease progression was halted during the 24-month follow-up. Together, microglia replacement corrects pathogenic mutations and halts disease progression in mice and humans.
2024-09-26 | Hematopoietic stem cell transplantation in leukodystrophies.
More than 50 leukodystrophies have been described. This group of inherited disorders affects myelin development and/or maintenance and can manifest from birth to adulthood. Neuroinflammation is a hallmark of some leukodystrophies, explaining in part the therapeutic benefit of hematopoietic stem cell transplantation (HSCT). Indeed, in addition to supplying the CNS with myelomonocyte donor cells expressing the deficient protein or enzyme, HSCT allows the restoration of normal microglia function, which may act on neuroinflammation. In this chapter, we explore the rationale, indication, and outcome of HSCT in Cerebral Adrenoleukodystrophy (CALD), Metachromatic Leukodystrophy (MLD), Krabbe Disease (KD), and Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP), which are among the most frequent leukodystrophies. For these leukodystrophies, HSCT may modify notably the natural history and improve CNS-related deficits, provided that the procedure is performed early into the disease course. In addition, we discuss the recent development of ex vivo gene therapy for CALD and MLD as a promising alternative to allograft.
antibodies
2025-04-01 | Phase 1, First-In-Human, Single-/Multiple-Ascending Dose Study of Iluzanebart in Healthy Volunteers.
To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of iluzanebart, a fully human monoclonal antibody TREM2 (triggering receptor expressed on myeloid cells 2) agonist, after single- (SAD) and multiple-ascending-dose (MAD) administration. Healthy adult volunteers (N = 136) received intravenous placebo or iluzanebart 1-60 mg/kg (SAD) or 10-60 mg/kg (MAD) followed by serial pharmacokinetics and safety assessments. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory evaluations. Pharmacokinetics were assessed through noncompartmental analysis. The study also included open-label cohorts (3, 10, 20, 40, 60 mg/kg SAD; 10, 20, 40 mg/kg MAD) for cerebrospinal fluid (CSF) collection for exploratory pharmacodynamic biomarker analysis. Iluzanebart was safe and well tolerated following single and multiple doses of up to 60 mg/kg. Most AEs were mild and resolved spontaneously. The most frequently reported AE was pruritus. No serious AEs or investigational product-related clinically meaningful changes in vital signs, electrocardiograms, or laboratory assessments were reported. Iluzanebart serum exposure was related to dose, with a 29-day half-life that is supportive of monthly dosing and confirmed central nervous system (CNS) exposure (≈0.15% CSF-to-serum ratio). Durable and dose-dependent target engagement, evidenced by marked reductions in soluble TREM2 and increased soluble CSF1R (colony-stimulating factor 1 receptor) and osteopontin/SPP1 (secreted phosphoprotein 1) levels in CSF, was observed, indicating that iluzanebart changes microglial activity following single and repeat dosing. Iluzanebart demonstrated favorable safety, tolerability, pharmacokinetics, and pharmacological activity in the CNS, supporting further clinical development for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
2025-02-18 | Use of Model-informed Drug Development and Natural History Data to Inform the Development of Iluzanebart in ALSP: A Neurological Rare Disease
Objectives: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, autosomal dominant, neurodegenerative disorder caused by a loss-of-function mutation in the colony-stimulating factor 1 receptor gene (CSF1R) resulting in disruption of intracellular signaling and primary microglial dysfunction in the central nervous system (CNS). Iluzanebart, a fully human monoclonal antibody agonist of the triggering receptor expressed on myeloid cells 2 (TREM2), is currently being investigated as a potential treatment for ALSP. TREM2 agonism by iluzanebart is hypothesized to compensate for CSF1R loss-of-function, resulting in a potential slowing of clinical decline in patients with ALSP. The objective of this analysis is to demonstrate proof-of-concept for a model-informed drug development (MIDD) approach to quantify treatment effect in a Phase 2 study (P2, NCT05677659) utilizing data from a prospective natural history study (NHS, NCT05020743) as an external control.Methods: An integrated disease progression model was constructed to simultaneously describe the longitudinal time-course of biomarker and key clinical measurements using data from the NHS: soluble CSF1R (sCSF1R), neurofilament light chain (NfL), ventricle volume (as an indicator of brain volume loss), Cortical Basal Ganglia Functional Scale (CBFS), Montreal Cognitive Assessment (MoCA). Clinical trial simulations were performed to assess study precision using the model to determine the power to detect potentially relevant treatment effects using a model-based approach. Five hundred (500) replicate P2 studies were simulated for each sample size from 5 to 50 in increments of 5. The simulated open-label treatment data were pooled with the observed data from the NHS and a model parameter was estimated for treatment effect. Precision was assessed as the proportion of trial replicates in which the 95% Confidence Interval (CI) of the parameter estimate for treatment effect fell within 60% to 140% of the true effect size.Results: A joint indirect response disease progression model was fit to all endpoints simultaneously with correlation in random effects across responses. Standard model diagnostics and visual predictive checks demonstrated that the model adequately described each endpoint. Using the MIDD approach, precise estimates of treatment effect could be achieved with the sample size in the P2 study. Conclusions: The MIDD approach evaluated in this simulation study demonstrated proof-of-concept for use as a method of quantifying iluzanebart treatment effect using NHS as an external control. Such a MIDD approach may afford greater power than traditional biostatistical methods by leveraging all available data, including NHS, to detect treatment effect, quantify the contributions of demographic and clinical factors on disease and response, and assess the correlation of markers of disease to relevant clinical outcomes in neurological rare diseases such as ALSP.Citations: none
2025-02-01 | Rescue of in vitro models of CSF1R-related adult-onset leukodystrophy by iluzanebart: mechanisms and therapeutic implications of TREM2 agonism.
Microglia dysfunction is implicated in several neurodegenerative disorders, including a rare microgliopathy; CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP). CSF1R-ALSP is caused by heterozygous loss-of-function mutations in the colony stimulating factor 1 receptor (CSF1R) gene, which encodes a receptor required for the differentiation of myeloid cells, as well as for microglial survival and proliferation. Similar functions have also been ascribed to triggering receptor expressed on myeloid cells 2 (TREM2), which shares an analogous microglia enrichment profile and converging intracellular signaling pathway mediated by spleen associated tyrosine kinase (SYK) and phosphoinositide-3-kinase (PI3K). Iluzanebart is a human monoclonal IgG1, human TREM2 (hTREM2) agonist antibody under development for the treatment of CSF1R-ALSP. To explore the therapeutic hypothesis that loss of CSF1R signaling and related microglial hypofunction can be circumvented via activation of TREM2, we evaluated the potential of iluzanebart to compensate for CSF1R loss-of-function. Herein, we demonstrate that iluzanebart is a potent, dose-dependent, and specific activator of TREM2 signaling in human primary cells. Iluzanebart treatment rescued viability of human monocyte-derived macrophages (hMDM) and induced pluripotent stem cell-derived human microglia (iMGL) in multiple in vitro models of CSF1R-ALSP, including in induced pluripotent stem cell (iPSC) differentiated microglia carrying the heterozygous I794T mutation found in CSF1R-ALSP patients. Additionally, iluzanebart treatment in microglia modulated surface levels of CSF1R, resulting in increased receptor activation as measured by phosphorylation of CSF1R. Differentially expressed genes identified in the hippocampus of mice treated with iluzanebart were exemplary of TREM2 activation and were related to cell proliferation, regulation of inflammatory processes, and innate immune response pathways. Proliferation of microglia, changes in protein levels of specific chemokines identified by gene expression analysis, and increased CSF1R levels were also confirmed in vivo. These findings demonstrate that iluzanebart is a potent and selective TREM2 agonistic antibody, with pharmacology that supports the hypothesis that TREM2 activation can compensate for CSF1R dysfunction and its continued clinical development for individuals with CSF1R-ALSP.
2024-12-10 | Rescue of In Vitro Models of Adult-Onset Leukodystrophy by Iluzanebart: Mechanisms and Therapeutic Implications of TREM2 Agonism
Microglia dysfunction is implicated in several neurodegenerative disorders, including a rare microgliopathy; CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP). CSF1R-ALSP is caused by heterozygous loss-of-function mutations in the colony stimulating factor 1 receptor (CSF1R) gene, which encodes a receptor required for the differentiation of myeloid cells, as well as for microglial survival and proliferation. Similar functions have also been ascribed to triggering receptor expressed on myeloid cells 2 (TREM2), which shares an analogous microglia enrichment profile and converging intracellular signaling pathway mediated by spleen associated tyrosine kinase (SYK) and phosphoinositide-3-kinase (PI3K). Iluzanebart is a human monoclonal IgG1, human TREM2 (hTREM2) agonist antibody under development for the treatment of CSF1R-ALSP. To explore the therapeutic hypothesis that loss of CSF1R signaling and related microglial hypofunction can be circumvented via activation of TREM2, we evaluated the potential of iluzanebart to compensate for CSF1R loss-of-function. Herein, we demonstrate that iluzanebart is a potent, dose-dependent, and specific activator of TREM2 signaling in human primary cells. Iluzanebart treatment rescued viability of human monocyte-derived macrophages (hMDM) and induced pluripotent stem cell-derived human microglia (iMGL) in multiple in vitro models of CSF1R-ALSP, including in induced pluripotent stem cell (iPSC) differentiated microglia carrying the heterozygous I794T mutation found in CSF1R-ALSP patients. Additionally, iluzanebart treatment in microglia modulated surface levels of CSF1R, resulting in increased receptor activation as measured by phosphorylation of CSF1R. Differentially expressed genes identified in the hippocampus of mice treated with iluzanebart were exemplary of TREM2 activation and were related to cell proliferation, regulation of inflammatory processes, and innate immune response pathways. Proliferation of microglia, changes in protein levels of specific chemokines identified by gene expression analysis, and increased CSF1R levels were also confirmed in vivo. These findings demonstrate that iluzanebart is a potent and selective TREM2 agonistic antibody, with pharmacology that supports the hypothesis that TREM2 activation can compensate for CSF1R dysfunction and its continued clinical development for individuals with CSF1R-ALSP.
2024-04-09 | VGL101: An Immunotherapy that Enhances Microglial Survival for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (P9-9.013)
To characterize VGL101 as a high-affinity human TREM2 (hTREM2) agonistic monoclonal antibody and determine its capacity as a potential compensatory pharmacological approach to therapeutically circumvent colony-stimulating factor-1 receptor (CSF1R) dysfunction, which underlies the pathophysiology of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
gene therapies
2026-07-25 | The ILLUMINATE natural history study in colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, fatal, autosomal-dominant neurodegenerative disorder caused by pathogenic CSF1R variants and characterized by progressive cognitive, neuropsychiatric, and motor dysfunction, white matter lesions on brain imaging, and white matter demyelination, swollen axons, and pigmented glial cells on pathology. Limited data regarding clinical, biofluid or radiological biomarkers of disease severity are available, and no clinical trial endpoints have yet been validated. The objectives of this first-of-its-kind, prospective, observational natural history study were to characterize the clinical trajectory of CSF1R-ALSP and to identify and evaluate key biomarkers and clinical endpoints indicative of disease severity and progression. ILLUMINATE (NCT05020743) was a multicentre, noninterventional natural history study of adults with CSF1R-ALSP and prodromal carriers of CSF1R variants. Participants were followed for up to 36 months, with clinical assessments, fluid biomarkers and volumetric MRI assessments of brain atrophy collected at screening and every 6 months. This study was terminated early (4 June 2025). The analyses reported here include data collected through 19 February 2025. Of 53 participants, 19 were prodromal and 34 were symptomatic (11 of whom had a history of haematopoietic stem cell transplant and 23 who did not). Mean participant age was 47.8 (standard deviation, 4.5) years, and 36.4% were female. Prodromal participants remained relatively stable over 36 months, with little change in neurological function, neurodegeneration biomarkers or radiological disease burden. Impaired neurological function, MRI characteristics of CSF1R-ALSP, and elevated NfL (neurofilament light chain; neurodegeneration biomarker) and GFAP (glial fibrillary acidic protein; astrogliosis biomarker) levels were more pronounced at baseline and often showed progression over time among symptomatic participants who had not previously received haematopoietic stem cell transplant compared with participants who had previously received haematopoietic stem cell transplant. Significant correlations were observed at baseline and longitudinally between MRI measures of brain atrophy and clinical outcome measures. Based on the fluid biomarkers, MRI measures, and clinical outcome assessments evaluated here, active neurodegeneration, widespread changes visualized on brain MRI, and impaired cognitive and motor function were observed in symptomatic patients with CSF1R-ALSP. The neurological impairment can be assessed using the Montreal Cognitive Assessment and Cortical Basal ganglia Functional Scale. Our data suggest that quantification of brain atrophy using MRI volumetry is a potential biomarker of disease severity and progression in CSF1R-ALSP. It is hoped that this report will contribute to the understanding of disease progression in CSF1R-ALSP and inform future drug development.
2026-02-06 | CSF1R-related leukoencephalopathy presenting with early apathy, hypoactivity, and cognitive flattening: a case report of a diagnostic challenge.
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant leukodystrophy primarily caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene, characterized by progressive cognitive and motor decline. We present a case of a 42-year-old Chinese woman with a rapidly progressive syndrome featuring prominent apathy, cognitive impairment, and hypoactivity. Brain magnetic resonance imaging (MRI) revealed extensive confluent white matter hyperintensities (Fazekas grade 3) predominantly in frontal and parietal lobes, cerebral atrophy, and thinning of the corpus callosum. Comprehensive genetic testing identified a heterozygous missense mutation in the CSF1R gene (c.2342C > T, p.Ala781Val), located within the tyrosine kinase domain, confirming the Diagnosis of HDLS. This case highlights early apathy and hypoactivity as red-flag manifestations of CSF1R-related leukoencephalopathy in a 42-year-old woman with rapidly progressive cognitive decline. The atypical presentation, initially mimicking psychiatric or demyelinating disease, underscores the need to consider CSF1R sequencing when encountering early-onset cognitive or behavioral deterioration with unexplained white-matter changes, thereby facilitating timely diagnosis and genetic counseling.
2025-06-25 | A case report and review of the literature on hereditary diffuse leukoencephalopathy with spheroids presenting with stroke-like symptoms.
Hereditary diffuse leukoencephalopathy with spheroids (HDLS), a rare autosomal dominant disorder caused by CSF1R (Colony Stimulating Factor 1 Receptor) variants, manifests clinically as adult-onset cognitive-motor decline with progressive white matter degeneration. Notably, its phenotypic variability remains undercharacterized, with only limited case reports available globally. We systematically investigated a 47-year-old male presenting with acute stroke-like hemiparesis that progressed to fronto-subcortical dementia (MMSE=14) and extrapyramidal symptoms within six months. Comprehensive diagnostic evaluations included multimodal 3 T MRI and whole-exome sequencing (WES) targeting CSF1R. Neuroimaging revealed hallmark frontoparietal white matter rarefaction accompanied by persistent diffusion restriction (DWI+/ADC-). WES identified a de novo CSF1R nonsense variant (c.2462 G>A, p.Trp821Ter), which truncates the tyrosine kinase domain. This variant was classified as pathogenic, confirming a definitive HDLS diagnosis. This stroke-onset HDLS expands the phenotypic spectrum, establishing persistent diffusion restriction as an early diagnostic biomarker. CSF1R sequencing proves critical for sporadic case identification regardless of family history. Study limitations include absence of pedigree segregation analysis.
2025-01-14 | Clinical spectrum of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia in individuals of Korean ancestry.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare white matter disease characterized by axonal and glial injury. Although its clinical characteristics have been described in case reports, the prevalence of CSF1R mutations in clinically suspected ALSP cases remains unclear. Herein, we analysed the frequency of CSF1R mutations in patients with probable or possible ALSP and describe the genetic, clinical, radiological, and pathological findings of ALSP cases in individuals of Korean ancestry. Twenty-eight patients with probable or possible ALSP diagnosed at Samsung Medical Center, Seoul, between January 2014 and August 2020, were retrospectively reviewed. All participants underwent brain magnetic resonance imaging (MRI) and CSF1R genetic testing. Overall, 9 of the 28 patients (32.1%) [5/6 (83.3%) of probable ALSP and 4/22 (18.2%) of possible ALSP] were confirmed to have pathogenic or likely pathogenic variants in CSF1R gene. Additionally, one patient without CSF1R mutation exhibited histopathological findings consistent with ALSP on brain biopsy. All patients with CSF1R mutation presented with cognitive impairment and/or psychiatric symptoms. Brain MRI revealed bilateral white matter hyperintensities in all patients, and 5/8 (62.5%) showed diffusion-restricted lesions. Notably, patients with CSF1R mutation had younger age at onset, rapidly progressive course, and diffuse hyperintensity in the splenium compared to patients without CSF1R mutation. Our findings suggest that for definite diagnosis, CSF1R genetic testing is recommended in patients who meet the diagnostic criteria for possible or probable ALSP. Our findings provide insights into the genetic, clinical, radiological, and pathological dimensions of ALSP in individuals of Korean ancestry.
2024-12-17 | Progressive dementia and seizures as distinguishing features in adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia
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2022-12-14 | Microglia regulate central nervous system myelin growth and integrity
Abstract Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health 1 , it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease 2,3 .
2021-05-28 | Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy.
Microglia are resident macrophages of the central nervous system, and their unique molecular signature is dependent upon CSF-1 signaling. Previous studies have demonstrated the importance of CSF-1R in survival and development of microglia in animal models, but the findings are of uncertain relevance to understanding the influence of CSF-1R on microglia in humans. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) [also known as adult onset leukoencephalopathy with spheroids and pigmented glia (ALSP)] is a neurodegenerative disorder primarily affecting cerebral white matter, most often caused by mutations of CSF1R. Therefore, we hypothesized that the molecular profile of microglia may be affected in HDLS. Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling revealed reduced expression of IBA-1 and P2RY12 in both white and gray matter microglia of HDLS. In contrast, there was increased expression of CD68 and CD163 in microglia in affected white matter. In addition, expression of selective and specific microglial markers, including P2RY12, CX3CR1 and CSF-1R, were reduced in affected white matter. These results suggest that microglia in white matter in HDLS lose their homeostatic phenotype. Supported by gene ontology analysis, it is likely that an inflammatory phenotype is a key pathogenic feature of microglia in vulnerable brain regions of HDLS. Our findings suggest a potential mechanism of disease pathogenesis by linking aberrant CSF-1 signaling to altered microglial phenotype. They also support the idea that HDLS may be a primary microgliopathy. We observed increased expression of CSF-2 in gray matter compared to affected white matter, which may contribute to selective vulnerability of white matter in HDLS. Our findings suggest that methods that restore the homeostatic phenotype of microglia might be considered treatment approaches in HDLS.
2012-06-21 | The fusion protein of IFN-α and apolipoprotein A-I crosses the blood-brain barrier by a saturable transport mechanism.
IFN-α is widely used for the treatment of chronic viral hepatitis and malignancies. However, systemic IFN-α treatment causes severe neuropsychiatric complications in humans, including depression, anxiety, and cognitive impairments. We have previously reported that the fusion protein formed by IFN-α and apolipoprotein A-I (IA) circulates bound to high-density lipoproteins (HDLs) and exhibits liver targeting, increased half-life, enhanced immunostimulatory activity, and reduced cytotoxicity. As the transport of HDLs across the blood-brain barrier is a highly complex and regulated process, in this study, we examine the effects of IA on the brain. Determination of IFN-α in brain and serum after hydrodynamic administration of different doses of a plasmid encoding IFN-α or IA showed that IA penetrated into the brain by a saturable transport mechanism. Thus, at high serum levels of the transgenes, the induction of IFN-sensitive genes and the number of phospho-STAT1(+) cell nuclei in the brain were substantially higher with IFN-α than with IA. This was associated with attenuation of neurodepression in mice given IA, as manifested by shorter immobility time in the tail suspension test. However, when given low doses of rIFN-α or the same antiviral units of HDLs containing IA, the induction of IFN-stimulated genes in the brain was significantly greater with the latter. In conclusion, IA crosses the blood-brain barrier not by diffusion, as is the case of IFN-α, but by a facilitated saturable transport mechanism. Thus, linkage to apolipoprotein A-I may serve to modulate the effects of IFN-α on the CNS.
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Drug Discovery Landscape
1 orphan drug designation for Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
1 orphan drug designation for Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
iluzanebart | antibodies | FDA | 2022-07-27 | — | Vigil Neuroscience, Inc. |
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