SBIR Phase I: Antibody-Enzyme Fusion for the Treatment of Myotubular Myopathy

SBIR I 期：抗体-酶融合治疗肌管性肌病

• 批准号: 2051854
• 负责人: Robert Shaffer
• 金额: $ 25.1万
• 依托单位: ENABLE THERAPEUTICS LLC
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2051854&HistoricalAwards=false
• 关键词: SBIR; Phase; Antibody; Enzyme; Fusion

The broader impact/ commercial potential of this Small Business Innovation Research (SBIR) Phase I project is the development of a novel antibody-enzyme fusion (AEF) for the treatment of a devastating rare disease called Myotubular Myopathy (MTM) that affects about 1 in 50,000 male births in the US. The proposed AEF addresses the underlying cause of the disease by increasing activity of a protein that has been shown to do so in mice. The market for approved MTM therapeutics is likely to exceed $1 billion over the next few years once a safe and effective drug is approved. No current treatments exist for MTM, but two experimental drugs are currently being studied in clinical trials. The proposed AEF may play an important treatment role by overcoming immune reactions to other drugs and may be essential for chronic treatment later in life after other gene therapy effects have diminished. This Small Business Innovation Research (SBIR) Phase I project aims to produce and deliver an important protein, BIN1, the exogenous delivery of which has been shown to rescue the molecular pathogenesis of the disease-causing MTM1 mutation in a mouse model. The key technical objectives of this project will demonstrate that Fab-BIN1 can be robustly produced using typical mammalian cell culture, penetrates disease-relevant cells, and restores abundance and phosphorylation levels of proteins known to be affected by disease-associated MTM1 mutations. The latter two goals will be accomplished by orthogonal methods immunofluorescence and Western blot, with a cell-penetrating antibody as an active negative control, and disease-recapitulating MTM1 knockout myoblasts as the in vitro test system. The anticipated outcome of this project will justify advancement of Fab-BIN1 to later-stage preclinical study.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这个小企业创新研究（SBIR）I期项目的更广泛的影响/商业潜力是开发一种新型抗体-酶融合（AEF），用于治疗一种称为肌管性肌病（MTM）的破坏性罕见疾病，该疾病在美国影响约1/50，000的男性新生儿。拟议的AEF通过增加一种蛋白质的活性来解决疾病的根本原因，这种蛋白质已在小鼠中被证明是这样做的。一旦一种安全有效的药物被批准，在未来几年内，批准的MTM治疗药物的市场可能超过10亿美元。目前还没有针对MTM的治疗方法，但目前正在临床试验中研究两种实验性药物。拟议的AEF可能通过克服对其他药物的免疫反应而发挥重要的治疗作用，并且在其他基因治疗效果减弱后，可能对以后的慢性治疗至关重要。这个小企业创新研究（SBIR）第一阶段项目旨在生产和提供一种重要的蛋白质，BIN 1，其外源性递送已被证明可以挽救小鼠模型中致病MTM 1突变的分子发病机制。该项目的关键技术目标将证明Fab-BIN 1可以使用典型的哺乳动物细胞培养物稳健地产生，渗透疾病相关细胞，并恢复已知受疾病相关MTM 1突变影响的蛋白质的丰度和磷酸化水平。后两个目标将通过正交方法免疫荧光和Western印迹来实现，其中细胞穿透抗体作为活性阴性对照，疾病重演MTM 1敲除成肌细胞作为体外测试系统。该项目的预期结果将证明Fab-BIN 1进入后期临床前研究是合理的。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估而被认为值得支持。