PUBLICATION
Next-Generation SINE Compound KPT-8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD
- Authors
- English, K.G., Reid, A.L., Samani, A., Coulis, G.J.F., Villalta, S.A., Walker, C.J., Tamir, S., Alexander, M.S.
- ID
- ZDB-PUB-221028-5
- Date
- 2022
- Source
- Biomedicines 10(10): (Journal)
- Registered Authors
- Alexander, Matthew, Reid, Andrea, Samani, Adrienne
- Keywords
- DMD, KPT−8602, SINE compound, inflammation
- MeSH Terms
- none
- PubMed
- 36289662 Full text @ Biomedicines
Citation
English, K.G., Reid, A.L., Samani, A., Coulis, G.J.F., Villalta, S.A., Walker, C.J., Tamir, S., Alexander, M.S. (2022) Next-Generation SINE Compound KPT-8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD. Biomedicines. 10(10):.
Abstract
Duchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One of the major driving forces of DMD disease pathology is chronic inflammation. The current DMD standard of care is corticosteroids; however, there are serious side effects with long-term use, thus identifying novel anti-inflammatory and anti-fibrotic treatments for DMD is of high priority. We investigated the next-generation SINE compound, KPT-8602 (eltanexor) as an oral therapeutic to alleviate dystrophic symptoms. We performed pre-clinical evaluation of the effects of KPT-8602 in DMD zebrafish (sapje) and mouse (D2-mdx) models. KPT-8602 improved dystrophic skeletal muscle pathologies, muscle architecture and integrity, and overall outcomes in both animal models. KPT-8602 treatment ameliorated DMD pathology in D2-mdx mice, with increased locomotor behavior and improved muscle histology. KPT-8602 altered the immunological profile of the dystrophic mice, and reduced circulating osteopontin serum levels. These findings demonstrate KPT-8602 as an effective therapeutic in DMD through by promotion of an anti-inflammatory environment and overall improvement of DMD pathological outcomes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping