Universität zu Köln

Novak, James S., Hogarth, Marshall W., Boehler, Jessica F., Nearing, Marie ORCID: 0000-0002-5261-4544, Vila, Maria C., Heredia, Raul, Fiorillo, Alyson A., Zhang, Aiping, Hathout, Yetrib, Hoffman, Eric P., Jaiswal, Jyoti K., Nagaraju, Kanneboyina, Cirak, Sebahattin and Partridge, Terence A. (2017). Myoblasts and macrophages are required for therapeutic morpholino antisense oligonucleotide delivery to dystrophic muscle. Nat. Commun., 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

Full text not available from this repository.

Abstract

Exon skipping is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), employing morpholino antisense oligonucleotides (PMO-AO) to exclude disruptive exons from the mutant DMD transcript and elicit production of truncated dystrophin protein. Clinical trials for PMO show variable and sporadic dystrophin rescue. Here, we show that robust PMO uptake and efficient production of dystrophin following PMO administration coincide with areas of myofiber regeneration and inflammation. PMO localization is sustained in inflammatory foci where it enters macrophages, actively differentiating myoblasts and newly forming myotubes. We conclude that efficient PMO delivery into muscle requires two concomitant events: first, accumulation and retention of PMO within inflammatory foci associated with dystrophic lesions, and second, fusion of PMO-loaded myoblasts into repairing myofibers. Identification of these factors accounts for the variability in clinical trials and suggests strategies to improve this therapeutic approach to DMD.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Novak, James S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hogarth, Marshall W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehler, Jessica F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nearing, Marie UNSPECIFIED orcid.org/0000-0002-5261-4544 UNSPECIFIED Vila, Maria C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heredia, Raul UNSPECIFIED UNSPECIFIED UNSPECIFIED Fiorillo, Alyson A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Aiping UNSPECIFIED UNSPECIFIED UNSPECIFIED Hathout, Yetrib UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffman, Eric P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaiswal, Jyoti K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nagaraju, Kanneboyina UNSPECIFIED UNSPECIFIED UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED Partridge, Terence A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-214174
DOI:	10.1038/s41467-017-00924-7
Journal or Publication Title:	Nat. Commun.
Volume:	8
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DUCHENNE MUSCULAR-DYSTROPHY; MDX MOUSE; SYSTEMIC DELIVERY; REVERTANT FIBERS; SATELLITE CELLS; EXON; MICE; REGENERATION; INFLAMMATION; PATHOLOGY Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21417