Golodirsen
(Synonyms: SRP-4053) 目录号 : GC64458
Golodirsen (SRP-4053) 是一种磷酸二亚胺的吗啉代低聚物 (PMO)，特异性地靶向肌营养不良蛋白培养蛋白前 mRNA 的外显子 53。Golodirsen 可用于杜氏肌营养不良症 (DMD) 的研究。
Cas No.:1422959-91-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Golodirsen (SRP-4053) is a phosphorodiamidate morpholino oligomer (PMO) that specifically targets exon 53 of dystrophin pre-mRNA. Golodirsen can be used for the research of Duchenne muscular dystrophy (DMD)[1][2].
Golodirsen specifically targets exon 53 of dystrophin pre-mRNA, resulting in its exclusion from the final mRNA product. Skipping of exon 53 results in restoration of the mRNA reading frame and leads to the production of a partially internally deleted dystrophin protein with intact C and N-terminal regions[2].
[1]. Heo YA. Golodirsen: First Approval. Drugs. 2020 Feb;80(3):329-333.
[2]. Scaglioni D, et, al. The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy. Acta Neuropathol Commun. 2021 Jan 6;9(1):7.
| Cas No. | 1422959-91-8 | SDF | Download SDF |
| 别名 | SRP-4053 | ||
| 分子式 | 分子量 | 8647 | |
| 溶解度 | 储存条件 | Store at -20°C | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.1156 mL | 0.5782 mL | 1.1565 mL |
| 5 mM | 0.0231 mL | 0.1156 mL | 0.2313 mL |
| 10 mM | 0.0116 mL | 0.0578 mL | 0.1156 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Golodirsen: First Approval
Drugs 2020 Feb;80(3):329-333.PMID:32026421DOI:10.1007/s40265-020-01267-2.
Golodirsen (Vyondys 53™), an antisense oligonucleotide of the phophorodiamidate morpholino oligomer (PMO) subclass designed to induce exon 53 skipping, has been developed by Sarepta Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). In December 2019, intravenous Golodirsen received its first global approval in the USA for the treatment of DMD in patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, based on positive results from a phase I/II clinical trial. Golodirsen is in phase III clinical development for the treatment of DMD worldwide. This article summarizes the milestones in the development of Golodirsen leading to this first approval for DMD.
Increased dystrophin production with Golodirsen in patients with Duchenne muscular dystrophy
Neurology 2020 May 26;94(21):e2270-e2282.PMID:32139505DOI:10.1212/WNL.0000000000009233.
Objective: To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. Methods: Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly Golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry. Results: Twelve patients were randomized to receive Golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg Golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry. Conclusion: Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization. Clinicaltrialsgov identifier: NCT02310906. Classification of evidence: This study provides Class I evidence that Golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.
Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial
Nucleic Acid Ther 2022 Feb;32(1):29-39.PMID:34788571DOI:10.1089/nat.2021.0043.
The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term Golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of Golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (Golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to Golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P < 0.001) and exon skipping (28.9-fold; P < 0.001). At 3 years, 6MWT change from baseline was -99.0 m for golodirsen-treated patients versus -181.4 m for external controls (P = 0.067), and loss of ambulation occurred in 9% versus 26% (P = 0.21). FVC%p declined 8.4% over 3 years in golodirsen-treated patients, comparing favorably with literature-reported rates. This study provides evidence for Golodirsen biologic activity and long-term safety in a declining DMD population and suggests functional benefit versus external controls. Clinical Trial Registration number: NCT02310906.
Golodirsen for Duchenne muscular dystrophy
Drugs Today (Barc) 2020 Aug;56(8):491-504.PMID:33025945DOI:10.1358/dot.2020.56.8.3159186.
Duchenne muscular dystrophy (DMD) is a life-shortening X-linked genetic disorder characterized by progressive wasting and weakening of muscles in boys. Loss-of-function mutations in the DMD gene, which codes for dystrophin, lead to this disease. The majority of mutations in this gene result in the exclusion of one or more exons from the transcript, eventually causing the remaining exons not to fit together correctly (i.e., out-of-frame mutations). Antisense oligonucleotides, e.g., phosphorodiamidate morpholino oligomers (PMOs), can induce therapeutic exon skipping during pre-mRNA processing to restore the reading frame of the primary transcript of DMD. As a result, truncated but partially functional dystrophin is produced, potentially slowing down the disease progression. Golodirsen is a provisionally approved PMO-based drug for approx. 8% of all DMD patients amenable to exon 53 skipping. This article summarizes Golodirsen's pharmacology, efficacy and safety information. It also discusses some controversies that Golodirsen met after the approval.
RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges
Pharmacol Rev 2020 Oct;72(4):862-898.PMID:32929000DOI:10.1124/pr.120.019554.
RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and Golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.