SBIR-STTR Award

Photopolymerization has provided a powerful tool for tissue engineering through localized synthesis of therapeutic materials in situ. To date, strategies to create photopolymerized networks on the surface of a tissue, such as the inner lumen of a blood vessel or on the fracture surface of a bone have received the most attention. The proposal will demonstrate a clinically-relevant strategy to create a reinforcing network within a given tissue- the sclera- to halt pathological deformation of that tissue in degenerative myopia. An interdisciplinary team with expertise in ophthalmology, polymer chemistry, tissue viscoelastic properties and light delivery will pioneer this new strategy for engineering the mechanical properties of tissues in situ, particularly in the eye. The objective of this proposal is to demonstrate that photopolymerization of an FDA approved macromer (PEG-diacrylate) can be induced in the sclera to affect an adequate change in mechanical integrity of the sclera to prevent elongation of the globe of the eye in vitro. To determine the feasibility of enhancing the mechanical integrity of the sclera and preventing abnormal elongation of the eye in degenerative myopia we have the following goals: (1) Strengthen tissue sections in vitro using photopolymerization of PEGDM, (1.a) Increase water solubility and biocompatibility of photoinitiators, (1.b) Dose-response characteristics will be determined that relate treatment variables (PEG length, choice of methacrylate vs. acrylate end groups, photoinitiator structure and concentration, diffusion time and irradiation time) to the quantitative change in mechanical properties of sections of sclera characterized pre- and post-treatment in vitro; (2) Demonstrate photopolymerization treatment effectively stabilizes ocular shape in vitro using an elevated intraocular pressure model; and (3) Evaluate cytotoxicity of photopolymerized PEGDM(A) in cell culture and its biocompatibility in a rabbit model. To achieve these aims, we combine unique capabilities developed at Caltech with Visdex's expertise in light-delivery and photopolymerization in the eye. Significantly, methods to quantify mechanical properties of ocular tissues and correlate them with in vitro deformation behavior of the globe of the eye have already been established at Caltech. The proposed research will result in a therapeutic platform for treating diseases associated with inadequate mechanical stability of tissue, setting the stage for in vivo studies of the treatment of degenerative myopia in Phase II

Myopia affects 30% of the population in the U.S. and Europe, and 70-90% of the population in some Asian countries. High myopia of greater than 8 diopters affects 0.2 0.4% of the US population and up to 1% of the population in Asian countries. The principal change associated with degenerative myopia is progressive stretching and thinning of scleral tissues leading to posterior staphyloma formation. As scleral tissues stretch and thin, there is associated stretching of retinal and choroidal tissues that promote visual loss. Indeed, degenerative myopia is the leading cause of untreatable blindness in China, Taiwan, and Japan, and is ranked 7th in the United States. While visual loss from macular atrophy and choroidal neovascularization are most common in degenerative myopia, patients with this disease are also more prone to retinal detachment and macular hole formation. Although a large population is affected by this disease worldwide, there is currently no effective method to arrest progression and reduce the rate of visual loss. A proprietary treatment developed through collaboration of Visdex, Caltech and UCSF successfully stabilizes scleral shape and prevents globe enlargement in vitro. The treatment consists of topical application of the formulated drug candidates to the surface of the sclera, allowing the drug molecules to diffuse into the tissue and then irradiating the sclera with visible light. The procedure requires approximately 10 minutes and the drug candidates have been approved by the FDA for use in patients. Initial in-vivo experiments in rabbits show that the drug candidates and irradiation are well tolerated by the eye. The objective for this Phase II STTR project is to demonstrate that such a treatment can be translated into a clinically meaningful protocol that shows efficacy in an animal model of myopia. Based on in-vitro efficacy and in-vivo biocompatibility observed in Phase I, this innovative treatment will be optimized in vitro for stabilizing scleral shape in an intact eye expansion test (Aim 1), adapted to surgical procedures for administration of the drug candidates and irradiation in vivo and evaluated for toxicity and efficacy in a rabbit model (Aim 2), and tested for the ability to prevent myopia in vivo in a guinea pig model of degenerative myopia (Aim 3). This Phase II research and development effort will culminate in a treatment that halts progression of degenerative myopia by stabilizing the sclera. The subsequent Phase III development will be a continuation leading to human clinical trials and FDA approval.

Public Health Relevance:
Degenerative myopia is a progressively worsening condition in which the sclera thins and stretches, leading to globe elongation and damage of retinal and choroidal tissues. Although degenerative myopia affects nearly 1 million people in the United States, and approximately 20 million people worldwide, there is currently no effective treatment method. This project will result in an innovative, light-activated treatment that will arrest stretching of the sclera and prevent the associated retinal complications that lead to blindness.

Public Health Relevance:
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