The long-term goal of this project is to develop Poloxamer-188 (P-188) for the delay or prevention of respiratory deficits in patients with Duchenne muscular dystrophy (DMD). Phrixus Pharmaceuticals Inc. is also developing P-188 for the treatment of acute decompensated heart failure (HF) and has an open IND under which it can run an exploratory, acute dosing, phase 2 clinical trial in DMD patients. Phrixus received Orphan Drug status for P-188 on January 19, 2010. Initial studies with P-188 in the mdx mouse model of DMD demonstrated that P-188 acts to seal and repair damage to the cell membrane that result from muscle contraction. By sealing the membrane, unregulated entry of calcium ions was stopped and the heart functioned more normally. P-188 also protects the heart from contraction-induced injury. Very recently, 60-day treatment, with a relatively high dose of P-188, was shown to prevent loss of heart function, stabilized heart structure and prevented cardiac muscle damage in a dog model of DMD (GRMD). If P-188 acts in DMD patients as it does in GRMD dogs, it could revolutionize the way DMD patients are managed. Since interestingly a stretch event is required to produce the membrane damage that is repairable by P-188, this observation has led to the hypothesis that P-188 is most active on the sarcolemma of myocytes that regularly and frequently contract. If this hypothesis is correct, then P-188 should protect diaphragm muscle from degeneration and dysfunction. This hypothesis will be tested in this proposal. The studies to test this hypothesis, in the mdx mouse model of DMD, make up the specific aims of this proposal: 1) Determine the effect of P-188 treatment on preventing and reversing respiratory dysfunction in mdx mice by whole body plethysmography;and 2) At the end of the treatment period, determine if diaphragm muscle degeneration is prevented or slowed by P-188 treatment using histopathology techniques. If P-188 is active on and protective of diaphragm muscle, then preventative therapy would have the potential to delay the onset of respiratory dysfunction in DMD patients. Even though significant improvements have been made in the respiration management of these boys, a significant delay in respiration deficit would significantly improve the quality of life. Since respiratory symptoms typically develop earlier than cardiac symptoms in the progression of DMD, evidence for impact on the diaphragm would justify earlier treatment with P-188 potentially benefiting both respiratory and cardiac function. If this phase I application is successful, a Phase II application would contain elements of this new development path. Moreover, based on conversations that Phrixus has had with potential investors and corporate partners, these results would trigger a large amount of interest in participating in this development effort. In this case, P-188 would represent a novel breakthrough in DMD therapy that improved cardiovascular and respiratory function, the largest issues facing this patient population. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to determine if the novel biological membrane-sealant, Poloxamer-188, can improve respiratory function and prevent the degeneration of diaphragm muscle in a mouse model of Duchenne muscular dystrophy. This therapy is expected to improve symptoms and the survival rate of this patient population. It is also expected to work well in combination with current therapies.