# Re-purposing the small-molecule drug, tafamidis (CAP4349) for the non-surgical treatment of cataracts

> **NIH NIH R43** · PLEX PHARMACEUTICALS, INC. · 2021 · $149,295

## Abstract

Project Summary
 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 1a. Design and synthesis of prodrugs of CAP4349.
Aim 1b. Enzymatic evaluation of conversion of prodrugs into active metabolite. Aim 2a. Formulation of
prodrugs for topical route of delivery to achieve enhanced corneal permeation and metabolic conversion. Aim
2b. Evaluation of compounds for corneal permeation and metabolic conversion using 3D human organotypic
corneal tissue model. Aim 3a. Seven day repeat topical dose acute toxicity and safety in New Zealand white
rabbits. Aim 3b. In-vivo ocular pharmacokinetics. Project m...

## Key facts

- **NIH application ID:** 10202617
- **Project number:** 5R43EY031609-02
- **Recipient organization:** PLEX PHARMACEUTICALS, INC.
- **Principal Investigator:** Sambaiah Thota
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $149,295
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202617

## Citation

> US National Institutes of Health, RePORTER application 10202617, Re-purposing the small-molecule drug, tafamidis (CAP4349) for the non-surgical treatment of cataracts (5R43EY031609-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10202617. Licensed CC0.

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