Team Discovers New Drugs with Potential for AMD and Other Diseases

A study led by the University of California, Irvine has revealed small-molecule drugs that could be useful in treating age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP).

The study, published under the title "Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition," is published in the Proceedings of the National Academy of Sciences.

"In this study, we introduce a new class of therapeutics called "Stress Resilience-Enhancing Drugs" (SREDs) for the treatment of neurodegenerative conditions, specifically the world's leading causes of blindness in age-related and inherited retinal diseases," said Krzysztof Palczewski, Ph.D., Donald Bren Professor of Ophthalmology at the UCI School of Medicine and corresponding author on the study. "Through selective, pharmacological inhibition of cyclic nucleotide phosphodiesterases, our prototypical SREDs slowed or halted the development and progression of retinopathies in a number of genetic and environmental animal models."

Molecular mechanisms of stress resilience-enhancing drug (SRED) therapy. Retinal degeneration involves a complex, multifactorial combination of genetic factors and environmental exposures that accumulate over a lifetime and eventually overwhelm intrinsic stress resilience mechanisms, which can be enhanced pharmacologically by SREDs to alleviate disease and preserve vision. Credit: UCI School of Medicine

In order to meet the urgent and unmet medical need for effective treatments for blindness, the researchers in this study developed a systems pharmacology platform utilizing cutting-edge disease modeling and characterization. The goal was to identify novel, mechanism-based therapies that target the root cause of the disease. Through the use of the SRED therapeutic intervention, the team found that they could enhance resilience to both acute and chronic stress in the degenerating retina.

This intervention effectively preserved tissue structure and function across multiple models of age-related or inherited retinal disease. By utilizing a systems pharmacology approach to drug discovery and development, the researchers uncovered a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.

"SREDs represent a promising strategy for patients and clinicians to combat disease in earlier stages with superior efficacy over the current standard of care, augmenting the arsenal of ophthalmic medications presently available in anti-angiogenics, corticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs)," said lead author Jennings Luu, MD/Ph.D. Doctoral Fellow of Pharmacology in the Medical Scientist Training Program at Case Western Reserve University and Visiting Scholar at University of California, Irvine.

"Ultimately, it is our expectation that SREDs will someday serve as a standard of care for human aging, effectively providing patients the means to diminish suffering from debilitating ailments for which there currently exist no viable therapeutic options, thereby extending human lifespan and healthspan irrespective of disease etiology."

Reference:

Jennings C. Luu et al, Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2221045120