China
Africa
Explore chapters and articles related to this topic
Muscular Dystrophy Diseases
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
Because of the mutational variability in the dystrophin gene, it is essential to use antibodies that correspond to more than one domain; to avoid any false-negative result. Very low levels of dystrophin expression can be detected in some DMD cases, probably from minor transcripts of the gene. It is recently thought to result from exon skipping.
Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
Antisense oligonucleotides can restore a disrupted reading frame and lead to the expression of a shortened but functional dystrophin protein.42 Eteplirsen (Exondys 51) is the first approved antisense therapy for Duchenne's dystrophy in United States designed to skip exon 51 and provides treatment option for 14% of all DMD patients.43 It is given as 30 mg/kg intravenously once a week. Other exon-skipping therapies targeting exons 53 and 45 are in early phase of clinical trials.
Molybdenum cofactor deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
At least 32 different disease-causing mutations have been reported [2]. Most have been missense mutations, but there have been a few deletions, one insertion and two splice-site mutations leading to exon skipping. Among the most common mutations found in more than 5 alleles in Europe were p.R73W in MOCS1A, p.R319Q in MOCS1A, c.1523-1524del AG in MOCS1B and c.726delAA in MOCS2B.
Perspectives on the advances in the pharmacotherapeutic management of Duchenne muscular dystrophy
Published in Expert Opinion on Pharmacotherapy, 2022
Kelsie D. Kracht, Nicole L. Eichorn, Daniel J. Berlau
Another concern that patients with DMD must overcome is the specificity of many of the new exon skipping medications. Because these new therapeutics are targeted at a specific exon, they are only minimally effective in patients who do not have that precise exon. Since there are so many mutations that can lead to DMD, many patients’ mutations are currently untreatable with current exon skipping medications. As mentioned above, new medications in this class are being developed, but some patients may still not see benefit from these medications as they are primarily targeting only the most common exons of interest. In addition, exon-skipping therapy requires frequent dosing to maintain the effects. Currently, eteplirsen requires weekly infusions, which can be challenging for many patients and their families. Ideally, future medications would utilize technologies to reduce the dosing frequency.
Developing DMD therapeutics: a review of the effectiveness of small molecules, stop-codon readthrough, dystrophin gene replacement, and exon-skipping therapies
Published in Expert Opinion on Investigational Drugs, 2021
Exon-skipping therapy, however, faces several important challenges. One barrier is the potential production of structurally unstable truncated dystrophin protein, which would not benefit patients [122]. This concern was raised based on the variable phenotype of patients with dystrophin in-frame deletion mutations [123,124]. Although technically more challenging, multiple exon-skipping using cocktails of AONs offers the prospect of selecting the most functional truncated dystrophin [125]. This approach is based on the association of exons 3–9 deletion and exons 45–55 deletion with very mild or asymptomatic BMD [123,124,126]. Another challenge is the requirement of rigorous optimization for AON sequences, as indicated for eteplirsen [92]. Interestingly, suvodirsen and drisapersen feature very similar sequences to eteplirsen and might feature similarly low exon-skipping efficiency [92,127]. Fortunately, recently developed tools including in silico modeling and immortalized muscle cell models have greatly enhanced our ability to optimize the oligonucleotide sequences [128,129], which leads to improved AON efficacy. In fact, golodirsen and viltolarsen sequences, both targeting DMD exon 53, are almost identical, although 25-mer golodirsen has 4 more bases than 21-mer viltolarsen [95]. Three independent studies all identified the same locus in exon 53 as the most effective target of PMOs [95]. Based on this finding, new trials for exon 51 and other exons should be also conducted with optimal sequences.
Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases
Published in Expert Opinion on Investigational Drugs, 2020
Kanmin Xue, Robert E. MacLaren
An alternative mode of action of ASOs is through alteration of pre-mRNA splicing. By hybridizing with a nascent splice donor site during RNA polymerase II-mediated transcription, an ASO could prevent the normal recruitment of splicing factors, thus causing skipping of the targeted exon during RNA splicing. Depending on the length of the skipped exon and whether the alternatively spliced transcript remains in-frame or becomes frame-shifted, the ASO could lead to either a shortened (but potentially functional) protein lacking a possible domain, or gene knockdown through non-sense mediated decay of the mRNA, respectively. The exon-skipping approach is ideally suited to partially restoring protein function to a large gene containing many exons and harboring a mutation hotspot. It has already demonstrated clinical success in treating a number of neurodegenerations, in particular, eteplirsen – also known as Exondys 51 (Sarepta Therapeutics Inc, Cambridge, MA, USA) for Duchenne muscular dystrophy and nusinersen (Biogen Inc, Cambridge, MA, USA) for spinal muscular dystrophy [14–17].