129:. This means that, out of the 79 exons that code for dystrophin, one or several in the middle may be removed, without affecting the exons that follow the deletion. This allows for a shorter-than-normal dystrophin protein that maintains a degree of functionality. In Duchenne muscular dystrophy, the genetic mutation is out-of-frame. Out-of-frame mutations cause a premature stop in protein generation - the ribosome is unable to “read” the RNA past the point of initial error - leading to a severely shortened and completely non-functional dystrophin protein.
84:(AON). An antisense oligonucleotide is a synthesized short nucleic acid polymer, typically fifty or fewer base pairs in length that will bind to the mutation site in the pre-messenger RNA, to induce exon skipping. The AON binds to the mutated exon, so that when the gene is then translated from the mature mRNA, it is “skipped” over, thus restoring the disrupted reading frame. This allows for the generation of an internally deleted, but largely functional protein.
243:, usually from blood samples, can be used to determine the precise nature and location of the DMD mutation in the dystrophin gene. It is known that these mutations cluster in areas known as the 'hot spot' regions — primarily in exons 45–53 and to a lesser extent exons 2–20. As the majority of DMD mutations occur in these 'hot spot' regions, a treatment which causes these exons to be skipped could be used to treat up to 50% of DMD patients.
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that do not upset the open reading frame, lead to a dystrophin protein that is internally deleted and shorter than normal, but still partially functional. Such mutations are associated with the much milder Becker muscular dystrophy. Mildly affected BMD patients carrying deletions that involve over two thirds of the central rod domain have been described, suggesting that this domain is largely dispensable.
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Dystrophin can maintain a large degree of functionality so long as the essential terminal domains are unaffected, and exon skipping only occurs within the central rod domain. Given these parameters, exon skipping can be used to restore an open reading frame by inducing a deletion of one or several
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within dystrophin create prematurely truncated proteins that are unable to perform their job. Such mutations lead to muscle fiber damage, replacement of muscle tissue by fat and fibrotic tissue, and premature death typically occurring in the early twenties of DMD patients. Comparatively, mutations
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In the case of
Duchenne muscular dystrophy, the protein that becomes compromised is dystrophin. The dystrophin protein has two essential functional domains that flank a central rod domain consisting of repetitive and partially dispensable segments. Dystrophin’s function is to maintain muscle fiber
65:. Exons are the sections of DNA that contain the instruction set for generating a protein; they are interspersed with non-coding regions called introns. The introns are later removed before the protein is made, leaving only the coding exon regions.
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Some mutations require exon skipping at multiple sites, sometimes adjacent to one another, in order to restore the reading frame. Multiple exon skipping has successfully been carried out using a combination of AONs that target multiple exons.
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when introns are being removed to form mature-mRNA that consists solely of exons. Starting in the late 1990s, scientists realized they could take advantage of this naturally occurring cellular splicing to downplay genetic
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is prematurely truncated, which leads to a non-functioning protein. Successful treatment by way of exon skipping could lead to a mostly functional dystrophin protein, and create a phenotype similar to the less severe
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The goal of exon skipping is to manipulate the splicing pattern so that an out-of-frame mutation becomes an in-frame mutation, thus changing a severe DMD mutation into a less harmful in-frame BMD mutation.
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stability during contraction by linking the extra cellular matrix to the cytoskeleton. Mutations that disrupt the
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Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van
Deutekom J, van Ommen GJ, den Dunnen JT (March 2009).
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527:"FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation"
160:(Viltepso), targeting dystrophin exon 53 was approved for medical use in the United States in August 2020.
152:(Vyondys 53) (targeting dystrophin exon 53), was approved in the United States in December 2019. A third
401:"Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations"
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van
Deutekom JC, van Ommen GJ (October 2003). "Advances in Duchenne muscular dystrophy gene therapy".
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35:) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.
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exons within the central rod domain, and thus converting a DMD phenotype into a BMD phenotype.
479:"Antisense-mediated exon skipping: a versatile tool with therapeutic and research applications"
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Goyenvalle A, Vulin A, Fougerousse F, Leturcq F, Kaplan JC, Garcia L, Danos O (December 2004).
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571:"FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation"
355:"The influence of antisense oligonucleotide length on dystrophin exon skipping"
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targeting exon 51 of human dystrophin. Another exon-skipping
Morpholino,
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are the genetic instructions for creating a protein, and are composed of
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Harding PL, Fall AM, Honeyman K, Fletcher S, Wilton SD (January 2007).
295:"Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping"
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Muscular
Dystrophy Campaign. N.p., 11 July 2009. Web. 05 Nov. 2012.
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The genetic mutation that leads to Becker muscular dystrophy is an
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used to cause cells to “skip” over faulty or misaligned sections (
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This article incorporates text from this source, which is in the
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This article incorporates text from this source, which is in the
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Exon skipping is being heavily researched for the treatment of
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One exon-skipping drug was approved in 2016, by the US FDA:
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The mechanism behind exon skipping is a mutation specific
276:"Exon Skipping in DMD: What Is It and Whom Can It Help?"
92:As a treatment for Duchenne muscular dystrophy
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477:Aartsma-Rus A, van Ommen GJ (October 2007).
453:What Is Exon Skipping and How Does It Work?
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164:exon skipping drugs approved for DMD
49:Exon skipping is used to restore the
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537:(Press release). 12 December 2019.
100:(DMD), where the muscular protein
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581:(Press release). 12 August 2020
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68:Splicing naturally occurs in
577:Food and Drug Administration
533:Food and Drug Administration
98:Duchenne muscular dystrophy
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274:Wahl M (1 October 2011).
154:antisense oligonucleotide
107:Becker muscular dystrophy
82:antisense oligonucleotide
612:Nature Reviews. Genetics
77:into less harmful ones.
320:10.1126/science.1104297
372:10.1038/sj.mt.6300006
280:Quest Magazine Online
146:Sarepta Therapeutics
311:2004Sci...306.1796G
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495:10.1261/rna.653607
458:2014-12-08 at the
418:10.1002/humu.20918
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359:Molecular Therapy
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45:RNA splicing
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545:12 December
234:March 2021
211:viltolarsen
158:viltolarsen
144:oligo from
259:References
225:casimerson
197:golodirsen
183:eteplirsen
150:golodirsen
142:Morpholino
138:eteplirsen
102:dystrophin
43:See also:
640:207859539
585:12 August
217:NS Pharma
75:mutations
39:Mechanism
659:Genetics
653:Category
632:14526374
539:Archived
513:17684229
456:Archived
435:45979175
427:19156838
381:17164787
329:15528407
247:See also
70:pre-mRNA
504:1986821
337:9359783
307:Bibcode
299:Science
231:Sarepta
203:Sarepta
189:Sarepta
175:company
109:(BMD).
59:introns
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636:S2CID
579:(FDA)
575:U.S.
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431:S2CID
333:S2CID
63:exons
55:Genes
33:exons
628:PMID
587:2020
547:2019
509:PMID
423:PMID
377:PMID
325:PMID
172:exon
169:drug
61:and
620:doi
499:PMC
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483:RNA
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