A drug previously used to treat high blood pressure has potential to keep light-sensitive photoreceptors alive in three models of Leber congenital amaurosis type 10 (LCA 10).
The inherited retinal ciliopathy disease, that often results in severe visual impairment or blindness in early childhood is most commonly caused by mutations of the cilia-centrosomal gene (CEP290), accounting for 20% to 25% of cases. These mutations also cause multiple syndromic diseases involving a range of organ systems.
Reserpine, a compound already approved by the United States Food and Drug Administration, was found to keeps light-sensitive photoreceptors alive in three models of LCA 10.
Such a treatment strategy could potentially address retinal ciliopathies caused by many of the more than 160 disease-causing genes, regardless of the specific gene involved
The Search for Treatment
Using a mouse model of LCA10 and two types of lab-created tissues from stem cells known as organoids, a team of researchers led by National Eye Institute screened more than 6,000 FDA-approved compounds to identify ones that promoted survival of photoreceptors, the types of cells that die in LCA, leading to vision loss. The high-throughput screening identified five potential drug candidates, including Reserpine, which was approved in 1955 for the treatment of high blood pressure. Improved medications for hypertension have since become available.
Professor Anand Swaroop, senior investigator and chief of the NEI Neurobiology Neurodegeneration and Repair Laboratory said “Observation of the LCA models treated with Reserpine shed light on the underlying biology of retinal ciliopathies, suggesting new targets for future exploration”.
Specifically, the models showed dysregulation of autophagy, the process by which cells break down old or abnormal proteins, which in this case resulted in abnormal primary cilia, a microtubule organelle that protrudes from the surface of most cell types. Once thought to be an evolutionary vestige, the primary cilium has emerged as a key organelle that senses the external environment and modulates signalling pathways in many types of tissue. Gene mutations that lead to primary cilium dysfunction are linked to numerous diseases and disorders, collectively called ciliopathies, which range from kidney and brain malformations to congenital retinal degeneration.
In LCA10, CEP290 gene mutations cause dysfunction of the primary cilium in retinal cells. Reserpine appeared to partially restore autophagy, resulting in improved primary cilium assembly.
Reserpine targets dysregulated intracellular signalling pathways downstream of the primary cilium. Such a treatment strategy could potentially address retinal ciliopathies caused by many of the more than 160 disease-causing genes, regardless of the specific gene involved. That’s in contrast to gene therapy, which requires a very expensive and labour-intensive process to tailor an individual gene-based therapeutic approach for each mutation.
“Patients suffering from vision loss due to photoreceptor cell death might eventually benefit from our findings, as small molecule drugs represent a relatively affordable and scalable option,” Professor Swaroop said.
“Repurposing already FDA‐approved drugs reduces the cost and accelerates the transition from bench to bedside,” he said.
Led by Professor Swaroop, the work was performed in collaboration with the National Center for Advancing Translational Sciences, both part of the National Institutes of Health. The team plans to perform dose‐response and toxicity assays to demonstrate the safety of reserpine‐derived drugs for clinical trials.
Reference
Chen HY, Swaroop M, Papal S, Mondal AK, Song HB, Campello L, Tawa GJ, Regent F, Shimada H, Nagashima K, de Val N, Jacobson SG, Zheng W, Swaroop A. “Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects,” Published online Mar 28, 2023 in eLife https://doi.org/10.7554/eLife.83205
