Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases.

Autor:	Tsoumpra MK; Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Kodaira-shi, Tokyo, Japan., Fukumoto S; Fujii Memorial Institute of Medical Sciences, University of Tokushima, Tokushima, Japan., Matsumoto T; Fujii Memorial Institute of Medical Sciences, University of Tokushima, Tokushima, Japan., Takeda S; Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Kodaira-shi, Tokyo, Japan., Wood MJA; Department of Pediatrics, University of Oxford, UK., Aoki Y; Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Kodaira-shi, Tokyo, Japan. Electronic address: tsugu56@ncnp.go.jp.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2019 Jul; Vol. 45, pp. 630-645. Date of Electronic Publication: 2019 Jun 27.
DOI:	10.1016/j.ebiom.2019.06.036
Abstrakt:	Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle degeneration, caused by the absence of dystrophin. Exon skipping by antisense oligonucleotides (ASOs) has recently gained recognition as therapeutic approach in DMD. Conjugation of a peptide to the phosphorodiamidate morpholino backbone (PMO) of ASOs generated the peptide-conjugated PMOs (PPMOs) that exhibit a dramatically improved pharmacokinetic profile. When tested in animal models, PPMOs demonstrate effective exon skipping in target muscles and prolonged duration of dystrophin restoration after a treatment regime. Herein we summarize the main pathophysiological features of DMD and the emergence of PPMOs as promising exon skipping agents aiming to rescue defective gene expression in DMD and other neuromuscular diseases. The listed PPMO laboratory findings correspond to latest trends in the field and highlight the obstacles that must be overcome prior to translating the animal-based research into clinical trials tailored to the needs of patients suffering from neuromuscular diseases. (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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