| Autor: |
Hagemann, Tracy L., Powers, Berit, Lin, Ni-Hsuan, Mohamed, Ahmed F., Dague, Katerina L., Hannah, Seth C., Bachmann, Gemma, Mazur, Curt, Rigo, Frank, Olsen, Abby L., Feany, Mel B., Perng, Ming-Der, Berman, Robert F., Messing, Albee |
| Zdroj: |
Science Translational Medicine; 11/17/2021, Vol. 13 Issue 620, p1-16, 16p |
| Abstrakt: |
Antisense for genetic leukodystrophy: Gain-of-function mutations in the GFAP gene are the cause of Alexander disease (AxD), a leukodystrophy characterized by motor and cognitive impairments and seizures, among other symptoms. Current rodent models do not fully recapitulate the clinical features and often show a mild phenotype. Now, Hagemann et al. developed a rat model of AxD that closely mimics the clinical phenotype and showed that the animals developed the major hallmarks of AxD as they matured. Antisense oligonucleotide (ASO) treatment targeting Gfap ameliorated histological and behavioral abnormalities in this model, even when the treatment was delivered late, at the peak of the disease, suggesting that ASOs targeting GFAP might be effective in patients with AxD. Alexander disease (AxD) is a devastating leukodystrophy caused by gain-of-function mutations in GFAP, and the only available treatments are supportive. Recent advances in antisense oligonucleotide (ASO) therapy have demonstrated that transcript targeting can be a successful strategy for human neurodegenerative diseases amenable to this approach. We have previously used mouse models of AxD to show that Gfap-targeted ASO suppresses protein accumulation and reverses pathology; however, the mice have a mild phenotype with no apparent leukodystrophy or overt clinical features and are therefore limited for assessing functional outcomes. In this report, we introduce a rat model of AxD that exhibits hallmark pathology with GFAP aggregation in the form of Rosenthal fibers, widespread astrogliosis, and white matter deficits. These animals develop normally during the first postnatal weeks but fail to thrive after weaning and develop severe motor deficits as they mature, with about 14% dying of unknown cause between 6 and 12 weeks of age. In this model, a single treatment with Gfap-targeted ASO provides long-lasting suppression, reverses GFAP pathology, and, depending on age of treatment, prevents or mitigates white matter deficits and motor impairment. In this report, we characterize an improved animal model of AxD with myelin pathology and motor impairment, recapitulating prominent features of the human disease, and use this model to show that ASO therapy has the potential to not only prevent but also reverse many aspects of disease. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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