Restoration of Skin Structure and Function Post-Wounding

DESCRIPTION (provided by applicant): The wound repair process in skin is initiated immediately after an injury and induces a cascade of events including inflammation, proliferation, and scar differentiation. The adverse changes in skin structure and function resulting from scar tissue affects over 35 million US citizens a year resulting in costs of more than 7 billion dollars). The founders of FirstString Research, Inc. (FSR), Drs. Robert Gourdie and Gautam Ghatnekar are co inventors of novel bioengineered peptides based on a carboxyl-terminal fragment of connexin43 (Cx43). The lead peptide (now called ACT1 peptide) is rationally designed to interfere with Cx43 protein-protein interactions and shows promise in enhancing healing and in normalizing skin appearance and mechanical function following injury. In the Phase I STTR partnership between FSR and MUSC, it was demonstrated that topical application of ACT1 peptide resulted in significantly reduced scarring and increased regeneration of normalized skin structure/function following wounding in pig and mouse models. Based on our ongoing work, Phase I results, and meeting with the FDA, it is FSR's first objective in this Phase II STTR to undertake necessary preclinical studies using the pig, mouse, and rabbit model to ascertain safety of our novel peptide prior to initiating human clinical trials. Moreover, to enhance our ability to understand and better predict translation to human application, we will undertake clinical efficacy studies using the female red Duroc pig model, which better predicts hypertrophic scarring. This Phase II project will enable the company to achieve the following project milestones: 1) To further evaluate the clinically beneficial effects of ACT1 peptide in a red Duroc pig wound model. 2) To assess the safety of ACT1 peptide-based topical wound healing gel in a pig, rodent and rabbit model under GLP conditions.2a) To determine pharmacokinetic (PK) characteristics of the peptide after topical administration in rats. 2b) To determine acute toxicity of ACT1 peptide after intravenous (IV) administration in rats. 2c) To assess the toxicokinetic (TK) profile of ACT1 peptide after 14-day repeat application toxicity study in pigs and to determine reversibility of any adverse effects. 2d) To assess primary skin and eye irritation of ACT1 peptide in rabbits. 3) To receive an Investigational New Drug (IND) approval from the FDA for human clinical trials.For this phase II application, we have enlisted the support of Dr. Paul Ehrlich, Director for the Wound Healing Research Laboratory in the Division of Plastic Surgery, Department of Surgery, Hershey Medical Center at Penn State University and Dr. Indu Parikh, President and CSO, BioMarck Pharmaceuticals, Durham, NC. The development of ACT1 peptide in a topical gel via milestones outlined in this STTR has been carefully designed to meet a specific need of patients and surgeons. PUBLIC HEALTH RELEVANCE: Any injury or trauma to the skin subsequently heals, leaving behind a scar. There are clinical issues associated with excessive scar tissue formation following healing including loss of function, restriction of movement (ex. Contractures over joints), restriction of growth, reduced strength of healed tissue, poor aesthetic appearance and in some cases adverse psychological effects. This technology provides promise for improving healing, reduced scarring and restoration of skin structure and function following injuries for millions of people.