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

这项小企业创新研究（SBIR）一期项目的更广泛影响/商业潜力是开发一种新型抗体-酶融合（AEF），用于治疗一种名为肌管性肌病（MTM）的毁灭性罕见疾病，这种疾病在美国每5万名男婴中就有1人患病。提出的AEF通过增加一种蛋白质的活性来解决疾病的潜在原因，这种蛋白质在小鼠中已被证明具有这种作用。一旦一种安全有效的药物获得批准，未来几年批准的MTM疗法的市场可能会超过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。提出的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，并且可能在其他基因治疗效果减弱后的生命后期对慢性治疗至关重要。这个小企业创新研究（SBIR）一期项目旨在生产和递送一种重要的蛋白BIN1，外源性递送已被证明可以挽救小鼠模型中致病MTM1突变的分子发病机制。该项目的关键技术目标将证明，利用典型的哺乳动物细胞培养，Fab-BIN1可以稳定地产生，穿透疾病相关细胞，并恢复已知受疾病相关MTM1突变影响的蛋白质的丰度和磷酸化水平。后两个目标将通过免疫荧光和Western blot的正交方法来实现，以细胞穿透抗体作为主动阴性对照，以疾病重述MTM1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将Fab-BIN1推进到后期临床前研究。该奖项反映了美国国家科学基金会的法定使命，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，被认为值得支持。

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.