Rensselaer Polytechnic Institute researchers receive grant to study potential dry AMD treatment
A $6.4 million grant over 5 years from the National Institutes of Health’s National Eye Institute was awarded conduct drug development work and investigational new drug (IND)-enabling toxicology studies.
(Image credit: AdobeStock/masyastadnikova)
Rensselaer Polytechnic Institute, located in Troy, New York, has researchers working to develop compounds to treat dry age-related macular degeneration (AMD) and Stargardt disease. Christopher Cioffi, PhD, Thomas and Constance D'Ambra Professor in Organic Chemistry, in collaboration with Konstantin Petrukhin, PhD, Professor of Ophthalmic Science at Columbia University, have received a $6.4 million grant over 5 years from the National Institutes of Health’s National Eye Institute to conduct drug development work and investigational new drug (IND)-enabling toxicology studies.1
Cioffi commented on how this funding will further research on the compound in development, saying, “this award helps us get one step closer to bringing our advanced compound into the clinic. We will assess its ability to slow down disease progression and help preserve vision for Stargardt disease and dry AMD patients.”1
Both dry AMD and Stargardt macular degeneration are characterized by lipofuscin accumulation in the retina. Pyridinium bisretinoids are components of lipofuscin that kill cells or are cytotoxic. Cioffi and Petrukhin aim to inhibit the synthesis of bisretinoids to treat dry AMD.1
According to the research, the synthesis of bisretinoids is driven by the traffic of retinol from the bloodstream to the retina. The retinol binding protein 4 (RBP4) - Transthyretin (TTR) complex acts as the primary carrier for delivering retinol to the eye. RBP4 antagonists displace retinol from RBP4, causing the RBP4-TTR complex to dissociate, which suppresses lipofuscin bisretinoid synthesis. However, disrupting the RBP4-TTR interaction could potentially destabilize wild-type TTR tetramers and promote TTR aggregation in individuals with age-related predisposition to TTR amyloidosis disease (ATTR).1
In understanding this process, the team has identified novel and orally bioavailable bispecific drugs that act as both RBP4 antagonists and TTR tetramer kinetic stabilizers. By binding to these sites, the drugs prevent the aggregation of TTR into amyloids.1
Regarding the future of this research, Petrukhin said, “We are leveraging our drug development expertise to advance the development of a novel class of bispecific visual cycle modulators. We hope that our development candidate, which combines optimal safety and efficacy, will emerge as a new and improved therapy for macular degeneration, benefiting diverse patient populations in need of enhanced treatment options.”1
Cioffi also added1, “These bispecific compounds have shown therapeutic potential to treat atrophic age-related dry AMD and Stargardt disease. In addition, the compounds may also have the potential to prevent ATTR.”
ATTR is a progressive disease that occurs when the body's TTR protein misfolds and forms abnormal deposits called amyloid fibrils. The buildup of these deposits often affects the heart and nerves.1
