Cataract, the clouding of the eye lens is responsible for 51% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataracts in the world. Cataract is easily treated by surgery. However, surgery is associated with significant complications: (i) 30-50% of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% are presented with endophthalmitis. In addition, in many remote and poor areas of the developing and under-developed regions of the world, people still remain blind from cataracts, primarily due to lack of access to eye care. As a result of which, cataract related blindness is as high as 50% or more in poor and remote regions of the world compared to only 5% in developed countries. Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataracts. The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A-chain (AAC) and can delay cataract formation in preclinical models. It has been estimated that delaying cataracts formation by 10 years can reduce the Medicare vision care expense by 50%. Our preliminary data supports the hypothesis that an FDA approved small-molecule drug, tafamidis (CAP4349) increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model. However, tafamids and its salts exhibit extremely poor aqueous solubility, limiting its potential as an ophthalmic drug. Therefore, the basic goal of our proposal is: optimization of tafamids to improve its solubility by using prodrug concept and demonstrate its potential as a promising topical anti-cataract agent using the following specific aims.
Aim 1 a. Design and synthesis of prodrugs of CAP4349.
Aim 1 b. Enzymatic evaluation of conversion of prodrugs into active metabolite.
Aim 2 a. Formulation of prodrugs for topical route of delivery to achieve enhanced corneal permeation and metabolic conversion.
Aim 2 b. Evaluation of compounds for corneal permeation and metabolic conversion using 3D human organotypic corneal tissue model.
Aim 3 a. Seven day repeat topical dose acute toxicity and safety in New Zealand white rabbits.
Aim 3 b. In-vivo ocular pharmacokinetics. Project milestone: Successful completion of these aims will identify a minimum of two optimized tafamids prodrugs with acceptable in-vivo efficacy and acceptable ocular PK to be advanced into non-GLP preclinical development and GLP enabling IND studies (Phase II).

Public Health Relevance

Cataracts are the leading cause of blindness worldwide, particularly in low- and middle-income countries. Data dating back to the beginning of this millennium showed that 30-60% of blindness in Africa and 60-80% in South East Asia is attributable to cataracts. The only treatment currently available is surgical extraction of the lens and replacement with an intraocular lens that is accompanied by a high public health burden. This proposal provides an innovative non-surgical approach to address this public health burden and reduce the disparity of cataract-related blindness globally.

National Institute of Health (NIH)
National Eye Institute (NEI)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Wujek, Jerome R
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Plex Pharmaceuticals, Inc.
San Diego
United States
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