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Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge
This review recollects my initial research focus on revertant fibers (expressing dystrophin in the background of frame-shifting mutation) in Duchenne muscular dystrophy (DMD) muscles in Professor Terrence Partridge’s Muscle Cell Biology Laboratory in MRC Clinical Research Science Center, Harmmersmit...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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IOS Press
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673541/ https://www.ncbi.nlm.nih.gov/pubmed/34151854 http://dx.doi.org/10.3233/JND-210692 |
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author | Lu, Qi Long |
author_facet | Lu, Qi Long |
author_sort | Lu, Qi Long |
collection | PubMed |
description | This review recollects my initial research focus on revertant fibers (expressing dystrophin in the background of frame-shifting mutation) in Duchenne muscular dystrophy (DMD) muscles in Professor Terrence Partridge’s Muscle Cell Biology Laboratory in MRC Clinical Research Science Center, Harmmersmith Hospital, London, UK. Our data indicated that revertant fibers are most likely resulted from epigenetic random events which skip exon(s) flanking the mutated exon, leading to the restoration of the reading frame. Some of these events establish themselves as relatively permanent skipping patterns, a mechanism similar to multiple transcript species established in various cell types. With this hypothesis, antisense oligonucleotide-mediated exon skipping is likely to have a great chance to achieve restoration of therapeutic levels of dystrophin in DMD muscles. This leads to our first reports of local and systemic efficacy of antisense oligonucleotide-mediated exon skipping for DMD treatment. The experience under Terry’s mentorship shaped my thinking and led me to explore another revertant feature in the dystroglycanopathy caused by mutations in the Fukutin Related Protein (FKRP) gene which functions as a glycosyltransferase. Mutant FKRPs retain partial function and produce a fraction of normal to no detectable levels of laminin-binding α-dystroglycan (matriglycan) in most of the muscle fibers. Reversion to near normal levels of matriglycan expression in muscles with FKRP mutations depends on muscle regeneration and in muscles of neonate mice, suggesting that changes in metabolism and gene expression could be sufficient to compensate for the reduced function of mutant FKRP genes even those associated with severe congenital muscular dystrophy (CMD). This is now supported by our successful demonstration that supply of FKRP mutant mice with ribitol, a precursor for substrate of FKRP, is sufficient to restore the levels of matriglycan with therapeutic significance. Our data overall suggest that rare events of reversion in muscular dystrophy, and likely other diseases could provide unique insight for mechanisms and therapeutic exploitation. |
format | Online Article Text |
id | pubmed-8673541 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | IOS Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86735412021-12-29 Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge Lu, Qi Long J Neuromuscul Dis Review This review recollects my initial research focus on revertant fibers (expressing dystrophin in the background of frame-shifting mutation) in Duchenne muscular dystrophy (DMD) muscles in Professor Terrence Partridge’s Muscle Cell Biology Laboratory in MRC Clinical Research Science Center, Harmmersmith Hospital, London, UK. Our data indicated that revertant fibers are most likely resulted from epigenetic random events which skip exon(s) flanking the mutated exon, leading to the restoration of the reading frame. Some of these events establish themselves as relatively permanent skipping patterns, a mechanism similar to multiple transcript species established in various cell types. With this hypothesis, antisense oligonucleotide-mediated exon skipping is likely to have a great chance to achieve restoration of therapeutic levels of dystrophin in DMD muscles. This leads to our first reports of local and systemic efficacy of antisense oligonucleotide-mediated exon skipping for DMD treatment. The experience under Terry’s mentorship shaped my thinking and led me to explore another revertant feature in the dystroglycanopathy caused by mutations in the Fukutin Related Protein (FKRP) gene which functions as a glycosyltransferase. Mutant FKRPs retain partial function and produce a fraction of normal to no detectable levels of laminin-binding α-dystroglycan (matriglycan) in most of the muscle fibers. Reversion to near normal levels of matriglycan expression in muscles with FKRP mutations depends on muscle regeneration and in muscles of neonate mice, suggesting that changes in metabolism and gene expression could be sufficient to compensate for the reduced function of mutant FKRP genes even those associated with severe congenital muscular dystrophy (CMD). This is now supported by our successful demonstration that supply of FKRP mutant mice with ribitol, a precursor for substrate of FKRP, is sufficient to restore the levels of matriglycan with therapeutic significance. Our data overall suggest that rare events of reversion in muscular dystrophy, and likely other diseases could provide unique insight for mechanisms and therapeutic exploitation. IOS Press 2021-11-30 /pmc/articles/PMC8673541/ /pubmed/34151854 http://dx.doi.org/10.3233/JND-210692 Text en © 2021 – The authors. Published by IOS Press https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Lu, Qi Long Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge |
title | Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge |
title_full | Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge |
title_fullStr | Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge |
title_full_unstemmed | Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge |
title_short | Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge |
title_sort | revertant phenomenon in dmd and lgmd2i and its therapeutic implications: a review of study under mentorship of terrence partridge |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673541/ https://www.ncbi.nlm.nih.gov/pubmed/34151854 http://dx.doi.org/10.3233/JND-210692 |
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