Attempts to develop drug treatments for acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) have been marred by unfulfilled expectations. Such failures - often attributed to the heterogeneous pathophysiology of ALI/ARDS and uncertainty about molecular targets of drug action - have combined to fuel considerable skepticism about future drug development efforts for these currently untreatable disorders. Against this background, Exscien's Phase I project was based on two decades of NIH-supported research showing that mtDNA functions as a unique molecular sentinel controlling cytoxic response to oxidant stress. To extend this concept to the point of clinical application, we constructed fusion proteins directing DNA repair enzymes to mitochondria and found in multiple animal models that pharmacologic enhancement of mtDNA repair suppressed and reversed ALI. Our plan for clinical introduction of the fusion proteins - focusing on their inaugural use in lung transplant - is solidly supported by Phase I results and conceptually buttressed by two interrelated considerations: First, administration of the fusion proteins to donor lungs during procurement will eliminate the requirement for treatment of the recipient and reduce the cost and time for clinical studies. And second and most importantly, a common complication of lung transplant - primary graft dysfunction (PGD) related to lung ischemia-reperfusion injury - is similar to ALI/ARDS; suppression of PGD by the fusion proteins will unambiguously support their use in such oxidant stress disorders. We now propose two aims intended to: (1) Determine the safety, disposition, and efficacy of mt-targeted DNA repair enzyme in a porcine model of lung transplant and PGD; and (2)Verify in ex vivo perfused human lungs the bioequivalence, safety, and efficacy of the mt-targeted DNA repair enzyme in comparison to approved methods of lung preservation. Collectively, these studies will advance Exscien's mt-targeted DNA repair enzymes towards FDA clearance as a device or drug for use in lung transplant, where it is expected to increase the number of lungs available for transplant and reduce the incidence and severity of PGD. These studies also will position Exscien for a near- term submission of IND to pursue testing in ALI /ARDS.
Studies are proposed in this Phase II SBIR application to prosecute clinical application of a recently-developed fusion protein targeting a DNA repair enzyme to mitochondria for treatment for acute lung injury. A two-step experimental strategy is presented wherein the first set of experiments will verify the efficacy and safety and evaluate the biodistribution of the fusion protein in a porcine model of lung transplant while the second set addresses the same issues in ex vivo-perfused human lungs. The outcome of these experiments will lead to a new device or drug capable of increasing the number of transplantable lungs and suppressing transplanted- related primary graft dysfunction.
| Lee, Yann-Leei; Obiako, Boniface; Gorodnya, Olena M et al. (2017) Mitochondrial DNA Damage Initiates Acute Lung Injury and Multi-Organ System Failure Evoked in Rats by Intra-Tracheal Pseudomonas Aeruginosa. Shock 48:54-60 |
