Development of a Direct Cellular Energy Delivery System

DESCRIPTION (provided by applicant): Adenosine triphosphate (ATP) is the universal energy currency of the body and is made in large amounts by cells using substrate and oxygen. In the absence of oxygen, such as in disease states or surgical procedures that affect oxygen delivery, sufficient amounts of ATP cannot be produced and life ceases. We have developed a solution which can deliver large and controlled amounts of ATP to cells and tissues using highly fusogenic lipid vesicles containing Mg-ATP (VitaSol) and thus significantly reduce the effects of ischemia. During knee surgeries and many extremity procedures, tourniquets are used to create a blood-free operation field. However, the use of tourniquets for periods in excess of 2 hrs significantly increases morbidity. The long-term goal of this project is to develop a safe and effective solution which can deliver ATP to tissues during tourniquet-induced ischemia and significantly decrease morbidity from reperfusion injury. This is a first step in eventually using VitaSol in many surgical procedures were ischemia or hypoxia are problematic. The ultimate goal is to be able to use VitaSol to decrease the effects of whole-body hypoxia. In Phase I, VitaSol was optimized and stabilized (as a freeze-dried powder), and we have proven its efficacy in maintaining animal viability and function in the absence of oxygen. We have maintained cells, tissues, organs, and organisms under hypoxia or chemical hypoxia (KCN) for periods of time that exceed any known method of preserving tissue. Composite tissues can be maintained viable for up to 21 hrs at room temperature with little or no loss in viability or function when perfused with VitaSol. In addition we can currently maintain rats for up to 1 hr without oxygen at normothermia or completely abolish the effects of an 8x lethal dose of IV injected KCN (2.5 mM). These and other exciting results clearly demonstrate the efficacy of this technique, and given that VitaSol(tm) has a shelf-life in excess of 12 months, will allow VitaSol to be tested to prevent the effects of tourniquet-induced ischemia. In Phase II of this proposal, we will optimize the delivery of VitaSol for tourniquet-induced ischemia, test VitaSol in a large vertebrate animal model of tourniquet-induced ischemia, and ready VitaSol for a Phase I clinical trial by running pre-clinical toxicity studies, preparing a pre-lND meeting, and producing VitaSol under cGMP. If the Phase II study is successful, VitaSol will be readied for a Phase I clinical trial. Once approved, VitaSol could be indicated for many other ischemic tissue procedures, such as free-flap surgery, limb replantation, resection of invasive tumors or lesions, repair of congenital anomalies, and bilateral extremity surgery. If these trials are successful and once we better understand its toxicity and efficacy, we will reenter VitaSol in trials for whole-body hypoxia.