140:. 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.
95:(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.
254:, 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
76:. 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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538:"FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation"
171:(Viltepso), targeting dystrophin exon 53 was approved for medical use in the United States in August 2020.
163:(Vyondys 53) (targeting dystrophin exon 53), was approved in the United States in December 2019. A third
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412:"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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46:) 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.
490:"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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582:"FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation"
366:"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).
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306:"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
287:"Exon Skipping in DMD: What Is It and Whom Can It Help?"
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103:As a treatment for Duchenne muscular dystrophy
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488:Aartsma-Rus A, van Ommen GJ (October 2007).
464:What Is Exon Skipping and How Does It Work?
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175:exon skipping drugs approved for DMD
60:Exon skipping is used to restore the
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548:(Press release). 12 December 2019.
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592:(Press release). 12 August 2020
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79:Splicing naturally occurs in
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544:Food and Drug Administration
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109:Duchenne muscular dystrophy
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285:Wahl M (1 October 2011).
165:antisense oligonucleotide
118:Becker muscular dystrophy
93:antisense oligonucleotide
623:Nature Reviews. Genetics
88:into less harmful ones.
331:10.1126/science.1104297
383:10.1038/sj.mt.6300006
291:Quest Magazine Online
157:Sarepta Therapeutics
322:2004Sci...306.1796G
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506:10.1261/rna.653607
469:2014-12-08 at the
429:10.1002/humu.20918
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126:open reading frame
370:Molecular Therapy
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222:viltolarsen
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155:oligo from
270:References
236:casimerson
208:golodirsen
194:eteplirsen
161:golodirsen
153:Morpholino
149:eteplirsen
113:dystrophin
54:See also:
651:207859539
596:12 August
228:NS Pharma
86:mutations
50:Mechanism
670:Genetics
664:Category
643:14526374
550:Archived
524:17684229
467:Archived
446:45979175
438:19156838
392:17164787
340:15528407
258:See also
81:pre-mRNA
515:1986821
348:9359783
318:Bibcode
310:Science
242:Sarepta
214:Sarepta
200:Sarepta
186:company
120:(BMD).
70:introns
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590:(FDA)
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442:S2CID
344:S2CID
74:exons
66:Genes
44:exons
639:PMID
598:2020
558:2019
520:PMID
434:PMID
388:PMID
336:PMID
183:exon
180:drug
72:and
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510:PMC
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