ArticleAnnals of neurology2018
Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease.
Article in Annals of neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 92 citations in OpenAlex.
- A systematic review and meta-analysis of GFAP gene variants in Alexander disease.Scientific reports · 2024Pooled it
- Neuroradiological patterns and prognostic implications in type I Alexander disease.Molecular genetics and metabolism · 2026Article
- Adult-Onset Alexander Disease Presenting as Atypical Parkinsonism and Autonomic Dysfunction: A Case Series.Journal of clinical medicine · 2026Article
- Progressive gait and motor deficits in a rat model of Alexander disease.Behavioural brain research · 2026Article
- Curing the brain: in search for new astrocyte-specific therapies.Experimental & molecular medicine · 2026Review
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- Alexander's Disease: Potential Drug Targets and Future Directions.Molecular neurobiology · 2025Review
- Article
- Description of the Hamburg Alexander Leukodystrophy Cohort-Insights into Practical Classification and the Care Situation.Journal of clinical medicine · 2025Article
- Determination of the age-related changes in the rat cerebellar cortex by using histologic and histometric methods.Biogerontology · 2025Article
- Adult-Onset Alexander Disease: A Case Report and Literature Review of Glu207 Alterations.Cureus · 2025Article
- Systematic analysis of genetic and phenotypic characteristics reveals antisense oligonucleotide therapy potential for one-third of neurodevelopmental disorders.Genome medicine · 2025Article
- Neuroglial Pathophysiology of Leukodystrophies.Advances in neurobiology · 2025Review
- Astrocytes in Primary Familial Brain Calcification (PFBC): Emphasis on the Importance of Induced Pluripotent Stem Cell-Derived Human Astrocyte Models.Advances in experimental medicine and biology · 2025Review
- Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases.Current issues in molecular biology · 2024Review
- Case report: A novel mutation of glial fibrillary acidic protein gene causing juvenile-onset Alexander disease.Frontiers in neurology · 2024Article
- Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.Nature communications · 2023Article
- Using reported pathogenic variants to identify therapeutic opportunities for genetic diseases.Molecular genetics & genomic medicine · 2023Article
- Inflammation context in Alzheimer's disease, a relationship intricate to define.Biological research · 2022Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveAlexander disease is a fatal leukodystrophy caused by autosomal dominant gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the central nervous system. A key feature of pathogenesis is overexpression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. Here we investigate whether suppressing GFAP with antisense oligonucleotides could provide a therapeutic strategy for treating Alexander disease.
methodsIn this study, we use GFAP mutant mouse models of Alexander disease to test the efficacy of antisense suppression and evaluate the effects on molecular and cellular phenotypes and non-cell-autonomous toxicity. Antisense oligonucleotides were designed to target the murine Gfap transcript, and screened using primary mouse cortical cultures. Lead oligonucleotides were then tested for their ability to reduce GFAP transcripts and protein, first in wild-type mice with normal levels of GFAP, and then in adult mutant mice with established pathology and elevated levels of GFAP.
resultsNearly complete and long-lasting elimination of GFAP occurred in brain and spinal cord following single bolus intracerebroventricular injections, with a striking reversal of Rosenthal fibers and downstream markers of microglial and other stress-related responses. GFAP protein was also cleared from cerebrospinal fluid, demonstrating its potential utility as a biomarker in future clinical applications. Finally, treatment led to improved body condition and rescue of hippocampal neurogenesis.
interpretationThese results demonstrate the efficacy of antisense suppression for an astrocyte target, and provide a compelling therapeutic approach for Alexander disease. Ann Neurol 2018;83:27-39.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.