Researchers receive $6.4 million grant from NEI to seek new treatment for blindness-causing diseases

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Christopher Cioffi, PhD, Thomas and Constance D’Ambra Professor in Organic Chemistry at Rensselaer Polytechnic Institute, is collaborating with Konstantin Petrukhin, PhD, Professor of Ophthalmic Science at Columbia University, to develop compounds to treat dry age-related macular degeneration (AMD) and Stargardt disease.

Their research has led to the identification of an advanced preclinical candidate, and Cioffi and Petrukhin have now received a $6.4 million grant from the National Eye Institute of the National Institutes of Health to support drug development and investigational new drug (IND)-enabling toxicology studies.¹

“This award moves us closer to advancing our compound into clinical trials,” Cioffi said. “We are assessing its potential to slow disease progression and preserve vision in patients with Stargardt disease and dry AMD.”

AMD is the leading cause of blindness in individuals aged 60 years and older in the United States, with dry AMD being the most common form. It is characterized by the buildup of lipofuscin in the retina. Stargardt disease, a rare genetic condition, typically causes vision loss starting in childhood due to lipofuscin accumulation in the macula, a small, central area of the retina. Lipofuscin includes yellow-brown pigment granules, specifically pyridinium bisretinoids, which are cytotoxic. Cioffi and Petrukhin aim to inhibit the synthesis of these bisretinoids to treat dry AMD.¹

The researchers explained the synthesis of bisretinoids depends on retinol transport from the bloodstream to the retina, mediated by the retinol-binding protein 4 (RBP4)-transthyretin (TTR) complex. RBP4 antagonists displace retinol from RBP4, causing dissociation of the RBP4-TTR complex and thereby reducing bisretinoid synthesis. However, this disruption could destabilize TTR tetramers, potentially leading to TTR amyloidosis in individuals with age-related predisposition to the disease.

In response, the team has identified novel orally bioavailable bispecific drugs that function as both RBP4 antagonists and TTR tetramer stabilizers. By binding to these target sites, these compounds prevent TTR aggregation into amyloids^.1

“We are using our expertise to develop a new class of bispecific visual cycle modulators,” Petrukhin noted. “Our development candidate aims to combine optimal safety and efficacy, offering a potentially groundbreaking therapy for macular degeneration that can benefit diverse patient populations.”

“These bispecific compounds have shown therapeutic potential in treating dry AMD and Stargardt disease,” Cioffi explained. “They may also help prevent TTR amyloidosis.”

TTR amyloidosis (ATTR) is a progressive disorder in which misfolded TTR protein aggregates into amyloid fibrils, often impacting the heart and nerves.

According to the Rensselaer Polytechnic Institute news release, Cioffi’s motivation stems from a desire to improve treatment options for patients.

“Therapeutic options for dry AMD are limited. Current treatments are only marginally effective, can cause severe side effects, and require direct ocular injections,” he explained. “We are developing an orally bioavailable drug that may offer greater efficacy and safety, reducing the compliance challenges of intravitreal injections.”

Cioffi added this work also supports potential benefits for Stargardt disease patients, a rare inherited retinal disorder affecting children and adolescents.

“Developing a drug that could help preserve their vision is a major motivation for our efforts,” he concluded.

“With this project, Drs. Cioffi and Petrukhin are advancing safe and effective new therapies for dry AMD and Stargardt disease,” said Curt Breneman, PhD, Dean of Rensselaer’s School of Science. “These conditions have limited treatment options, and their research has the potential to make a real difference in patients’ lives.”

Reference

1. Rensselaer researcher seeks new treatment for blindness-causing diseases. EurekAlert! Published October 28, 2024. Accessed October 31, 2024. https://www.eurekalert.org/news-releases/1062879