Effect of serotonin modulation on dystrophin-deficient zebrafish.

Autor:	Spinazzola JM; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, USA., Lambert MR; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, USA., Gibbs DE; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Conner JR; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Krikorian GL; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Pareek P; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Rago C; DMD Therapeutics Inc., Seattle, WA, USA., Kunkel LM; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA kunkel@enders.tch.harvard.edu.; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.; The Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; The Manton Center for Orphan Disease Research at Boston Children's Hospital, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	Biology open [Biol Open] 2020 Aug 28; Vol. 9 (8). Date of Electronic Publication: 2020 Aug 28.
DOI:	10.1242/bio.053363
Abstrakt:	Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutation of the dystrophin gene. Pharmacological therapies that function independently of dystrophin and complement strategies aimed at dystrophin restoration could significantly improve patient outcomes. Previous observations have suggested that serotonin pathway modulation ameliorates dystrophic pathology, and re-application of serotonin modulators already used clinically would potentially hasten availability to DMD patients. In our study, we used dystrophin-deficient sapje and sapje-like zebrafish models of DMD for rapid and easy screening of several classes of serotonin pathway modulators as potential therapeutics. None of the candidate drugs tested significantly decreased the percentage of zebrafish exhibiting the dystrophic muscle phenotype in the short-term birefringence assay or lengthened the lifespan in the long-term survival assay. Although we did not identify an effective drug, we believe our data is of value to the DMD research community for future studies, and there is evidence that suggests serotonin modulation may still be a viable treatment strategy with further investigation. Given the widespread clinical use of selective serotonin reuptake inhibitors, tricyclic antidepressants and reversible inhibitors of monoamine oxidase, their reapplication to DMD is an attractive strategy in the field's pursuit to identify pharmacological therapies to complement dystrophin restoration strategies. Competing Interests: Competing interestsL.M.K. is a consultant for Pfizer, Dyne Therapeutics, Myofinity and Sarepta Therapeutics for muscle disease drug therapies. C.R. was the CSO of DMD Therapeutics Inc. C.R. is now a partner in District 2 Capital. C.R. was Scientific Director of Ryan's Quest at the inception of the project and had a role in study design, and was CSO of DMD Therapeutics, Inc. The funders had no additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The remaining authors have declared no competing interests. (© 2020. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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