Phase II: Anti-inflammatory and Anti-scarring Actions of Amniotic Membrane Extra

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DESCRIPTION (provided by applicant): Over the past decade, there has been a surge of interest in amniotic membrane transplantation (AMT) for ocular surface reconstruction. A number of studies have shown that AMT using cryopreserved AM (AmnioGraft(R)) manufactured by Bio-Tissue, Inc., a subsidiary of TissueTech, Inc., is effective in facilitating epithelial wound healing and reducing stromal inflammation, scarring and formation of unwanted new blood vessels. To facilitate the ease of patient care and reduce the overall medical cost, we have obtained SBIR Phase I and II grants (R43/R44 EY014768) to develop a "sutureless" AM graft so that AMT can be performed in a physician's office or at the bedside of an Intensive Care and Burn Unit without bringing the patient to the operating room. As a result, we have successfully developed ProKera(R), which has received the FDA's 510(k) clearance as a type II medical device. In 2008, we have distributed more than 4,000 units in the U.S. market for treating patients inflicted with a number of sight-threatening corneal surface diseases characterized by poor wound healing, unwanted inflammation, and excessive scarring. We envisioned that AM's inherent anti-inflammatory and anti- scarring actions can further be deployed to treat ocular surface diseases unmanageable by AmnioGraft(R) or ProKera(R), and to any other body sites where inflammation and scarring are of great concern. We further speculated that one solution to the physical constraint of AmnioGraft(R) or ProKera(R) is to develop a gel formulation based on AM extracts (AME). Through SBIR Phase I grant support (R43 EY017497), we have successfully validated the key manufacturing steps of generating AME and its lyophilized powder (AMP), and compared the relative potency of using collagen or hyaluronic acid (HA) as a vehicle to deliver their anti-inflammatory and anti-scarring actions (Aim 1). In addition, we have biochemically purified and characterized one covalent complex (HC7HA) containing HA and heavy chains (HC) of inter-a-inhibitor (IaI) as the active component in AME responsible for most, if not all, anti-inflammatory and anti-scarring effects observed in AM stroma (Aim 2). In Phase II, we thus propose to validate the potency of purified HC7HA complex in exerting in vitro anti-inflammatory and anti-scarring actions, verify the consistency of manufacturing HC7HA complex regarding its biochemical composition and purity, and optimize the HA gel formulation containing HC7HA complex (Aim 1). In addition, we propose to demonstrate clinical efficacies of the aforementioned gel formulation containing HC7HA complex in exerting an anti-inflammatory action in a murine model of HSV1-induced necrotizing stromal keratitis, and an anti-scarring action in a rabbit model of excimer laser-assisted photorefractive keratectomy (PRK) (Aim 2). Successful completion of the above two Aims will allow us to gather sufficient and pertinent data for IDE/IND submission to the FDA so that we may begin to commercialize the first ophthalmic topical formulation and continue to build a pipeline of new therapeutics based on AME or purified HC7HA complex so that we may expand our market spaces not only in ophthalmology, but also in other medical and surgical subspecialties. PUBLIC HEALTH RELEVANCE: This application proposes to develop a novel pipeline of therapeutics based on anti-inflammatory and anti-angiogenic actions of amniotic membrane extract as well as its purified covalent complex containing hyaluronan and heavy chains of inter-a-inhibitor. Successful completion of our proposed studies in Phase II will allow us to gather sufficient and pertinent data for IDE/IND submission to the FDA so that we may begin to commercialize the first ophthalmic topical formulation and expand our market spaces not only in ophthalmology, but also in other medical and surgical subspecialties.