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.
