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Stress resilience–enhancing drugs: New class of small molecules holds promise
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Therapeutics can prevent vision loss and neurodegeneration in patients.
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Reviewed by Jennings Luu, PhD
A new class of small-molecule drugs studied in animal models that demonstrated the hallmarks of glaucoma and age-related macular degeneration (AMD) was found to be efficacious in both animal models. The stress resilience–enhancing drugs (SREDs) therapy effectively improved the survival of retinal cell types affected by disease, resulting in overall improvement of both retinal morphology and function, according to Jennings Luu, PhD.
Luu is Harrington Scholar and Medical Scientist Training Program doctoral fellow at the School of Medicine at Case Western Reserve University in Cleveland, Ohio, and a visiting scholar at the University of California, Irvine. He was joined in this study by Krzysztof Palczewski, PhD, Distinguished Donald Bren Professor and Irving H. Leopold Chair of Ophthalmology at the Center for Translational Vision Research at the University of California, Irvine. The investigators reported their findings at the Association for Research in Vision and Ophthalmology 2024 Annual Meeting in Seattle, Washington.
Therapeutic options
The rationale for the study of such treatments was that the therapeutic options for an estimated 420 million patients affected globally by AMD, diabetic retinopathy (DR), retinitis pigmentosa (RP), and glaucoma remain limited, especially in earlier disease stages when the opportunity to preserve retinal neurons and visual function is the greatest. Their discovery of this new class of small molecules slowed or halted disease progression in multiple genetic and environmental animal models of AMD, DR, RP, and glaucoma.
“Stress is universal to human aging and disease,” they commented. “Chronic, progressive retinal diseases, such as AMD, DR, and RP, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness.”
Small-molecule drugs
In results from their most recent study,1 they found that these small-molecule drugs “activate intrinsic biological mechanisms of stress resilience” and that SREDs, the new class of therapeutics, may be broadly effective in treating acute and chronic stress–associated pathological conditions while initially focusing on age-related and inherited retinal diseases.
Their previous investigations,2,3 respectively, demonstrated preservation of retinal morphology and function in mouse models exhibiting epigenetic and pathological hallmarks of AMD. In these studies, the respective efficacy rates of distinct subclasses of SREDs were reported to be up to 90% and 95%.
In commenting on their findings, they said, “Based on a systems pharmacology platform that leverages state-of-the-art disease modeling and characterization, our findings reveal important cell types and signaling pathways involved in modulating stress resilience and neurodegeneration in the retina. By exploiting integrative mechanisms of action in complex, multifactorial disorders, SREDs represent a promising strategy for clinicians to combat disease with superior efficacy in earlier stages of pathogenesis, thereby augmenting the arsenal of ophthalmic medications currently available in antiangiogenics, corticosteroids, and nonsteroidal anti-inflammatory drugs.”
SREDs study
The reported research under discussion is an extension of their previous work on selective phosphodiesterase inhibitors (PDEi), a prototypical subclass of SREDs, which were efficacious in the streptozotocin mouse model of DR and the retinal degeneration 10 mouse model of RP. In this study, Luu and Palczewski focused on PDEi to treat glaucoma in the murine model of elevated IOP.
They also used the photosensitive Abca4-/-Rdh8-/- mouse model that shows the pathological hallmarks of AMD to evaluate epigenetic modulators, another subclass of SREDs consisting of selective inhibitors of histone deacetylases (HDACi) and methyltransferases (SUVi). The results in the groups treated with SREDs were compared with vehicle-treated controls based on the findings on optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO), immunohistochemistry (IHC), and/or electroretinography (ERG).
Luu reported that continuous oral administration of PDEi in the mouse IOP model improved retinal ganglion cell (RGC) function by approximately 2.2-fold when compared with the control as seen on pattern ERG (n ≤ 4; P = .0168).
Moreover, IHC showed a 73% improvement in RGC survival following IOP stress. In the Abca4-/-Rdh8-/- model, both HDACi and SUVi treatments improved retinal function following bright-light stress by up to 2-fold on photopic ERG; this was consistent with improved photoreceptor survival and retinal morphology on OCT and SLO imaging.
Future of SREDs
The take-home message is that SREDs may be efficacious in treating a wide range of age-related and neurodegenerative disorders. “The data that we have support broad efficacy,” Luu concluded. “Beyond retinal disease, we hope to achieve validation of the SRED platform in treating a variety of neurodegenerative conditions, with clinical trials started for dementia, multiple sclerosis, traumatic brain injury, and other indications. Ultimately, I am optimistic our efforts will culminate in an entire class of broad-spectrum therapies representing a new standard of care for acute and chronic disorders associated with aging, stress, and/or neurodegeneration.”
References:
Luu JC, Saadane A, Leinonen H, et al. Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition. Proc Natl Acad Sci U S A. 2023;120(19):e2221045120. doi:10.1073/pnas.2221045120
Chen Y, Palczewska G, Masuho I, et al. Synergistically acting agonists and antagonists of G protein-coupled receptors prevent photoreceptor cell degeneration. Sci Signal. 2016;9(438):ra74. doi:10.1126/scisignal.aag0245
Luu J, Kallestad L, Hoang T, et al. Epigenetic hallmarks of age-related
macular degeneration are recapitulated in a photosensitive mouse model. Hum Mol Genet. 2020;29(15):2611-2624. doi:10.1093/hmg/ddaa158
