Tominersen
(Synonyms: RG6042; IONIS-HTTRx) 目录号 : GC64871
Tominersen (RG6042) 是第二代 2′-O-(2-甲氧基乙基) 反义寡核苷酸，靶向亨廷蛋白 (HTT) mRNA，有效抑制 HTT 的合成。Tominersen 可用于亨廷顿病的研究。
Cas No.:1709886-74-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Tominersen (RG6042) is a second-generation 2′-O-(2-methoxyethyl) antisense oligonucleotide that targets huntingtin protein (HTT) mRNA and potently suppresses HTT production. Tominersen can be used for the research of Huntington's disease[1].
Tominersen binds to its cognate mRNA by means of Watson-Crick base-pair interactions, triggering RNase H1-mediated degradation of the target mRNA[1].
[1]. Tabrizi SJ, et, al. Targeting Huntingtin Expression in Patients with Huntington's Disease. N Engl J Med. 2019 Jun 13;380(24):2307-2316.
| Cas No. | 1709886-74-7 | SDF | Download SDF |
| 别名 | RG6042; IONIS-HTTRx | ||
| 分子式 | 分子量 | 7078 | |
| 溶解度 | H2O : 50 mg/mL (7.06 mM; Need ultrasonic) | 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。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.1413 mL | 0.7064 mL | 1.4128 mL |
| 5 mM | 0.0283 mL | 0.1413 mL | 0.2826 mL |
| 10 mM | 0.0141 mL | 0.0706 mL | 0.1413 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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。
Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities
Lancet Neurol 2022 Jul;21(7):645-658.PMID:35716694DOI:10.1016/S1474-4422(22)00121-1.
Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide Tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.
Changes in brain activity with Tominersen in early-manifest Huntington's disease
Brain Commun 2022 Jun 9;4(3):fcac149.PMID:35774187DOI:10.1093/braincomms/fcac149.
It is unknown whether alterations in EEG brain activity caused by Huntington's disease may be responsive to huntingtin-lowering treatment. We analysed EEG recordings of 46 patients (mean age = 47.02 years; standard deviation = 10.19 years; 18 female) with early-manifest Stage 1 Huntington's disease receiving the huntingtin-lowering antisense oligonucleotide Tominersen for 4 months or receiving placebo as well as 39 healthy volunteers (mean age = 44.48 years; standard deviation = 12.94; 22 female) not receiving treatment. Patients on Tominersen showed increased resting-state activity within a 4-8 Hz frequency range compared with patients receiving placebo (cluster-based permutation test, P < 0.05). The responsive frequency range overlapped with EEG activity that was strongly reduced in Huntington's disease compared with healthy controls (cluster-based permutation test, P < 0.05). The underlying mechanisms of the observed treatment-related increase are unknown and may reflect neural plasticity as a consequence of the molecular pathways impacted by Tominersen treatment. Hawellek et al. report that patients with Huntington's disease treated with the huntingtin-lowering antisense oligonucleotide Tominersen exhibited increased EEG power in the theta/alpha frequency range. The underlying mechanisms of the observed changes are unknown and may reflect neural plasticity as a consequence of the molecular pathways impacted by Tominersen treatment.
Therapeutic targeting of Huntington's disease: Molecular and clinical approaches
Biochem Biophys Res Commun 2023 May 7;655:18-24.PMID:36913762DOI:10.1016/j.bbrc.2023.02.075.
Huntington's disease (HD) is an autosomal dominant ailment that affects a larger population. Due to its complex pathology operating at DNA, RNA, and protein levels, it is regarded as a protein-misfolding disease and an expansion repeat disorder. Despite the availability of early genetic diagnostics, disease-modifying treatments are still missing. Importantly, potential therapies are starting to make their way through clinical trials. Still, clinical trials are ongoing to discover potential drugs to relieve HD symptoms. However, now being aware of the root cause, the clinical studies are focused on molecular therapies to target it. The road to success has not been without bumps since a big phase III trial of Tominersen was unexpectedly discontinued due to exceeding risks than drug's benefit to the patients. Although the trial's conclusion was disappointing, there is still cause to be optimistic about what this technique may achieve. We have reviewed the present disease-modifying therapies in clinical development for HD and examined the current landscape of developing clinical therapies. We further investigated the pharmaceutical development of Huntington's medicine in the pharma industries and addressed the existing challenges in their therapeutic success.
Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials
Neural Regen Res 2023 Aug;18(8):1679-1683.PMID:36751779DOI:10.4103/1673-5374.363185.
We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on Tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.
A Remote Digital Monitoring Platform to Assess Cognitive and Motor Symptoms in Huntington Disease: Cross-sectional Validation Study
J Med Internet Res 2022 Jun 28;24(6):e32997.PMID:35763342DOI:10.2196/32997.
Background: Remote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring. Objective: The aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD. Methods: This analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating Tominersen (NCT03342053) and 2 untreated cohorts-the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic. Results: Participants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90). Conclusions: These results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD.