Small molecule drugs for early-onset vitelliform macular dystrophy - Abstract Early-onset vitelliform macular dystrophy, also known as Best vitelliform macular dystrophy (BVMD) is a genetic eye disorder that typically appears in childhood and leads to blindness in the fifth decade of life. This disease causes progressive vision loss by damaging cells in the macula, a small area of the retina responsible for sharp central vision needed for tasks like reading, driving, and recognizing faces. The estimated prevalence of BVMD is 1 in 5,500 in the population, which calculates to more than 60,000 patients in the U.S. and 1.5 million patients in the world. The gene linked to this disorder encodes an ion channel predominantly enriched on the membrane of retinal pigment epithelium (RPE) cells, which are key to healthy vision. The vast majority of BVMD cases are associated with loss-of-function (LOF), where the ion channel’s function is significantly reduced, while gain-of-function (GOF) is extremely rare (< 1 in 1,000,000). LOF mutations decrease or extinguish the channel’s capacity to efflux Cl-, causing accumulation of fluid and harmful waste products in the subretinal space that separates photoreceptor cells from the RPE. The results are elevated short-wavelength fundus autofluorescence within the lesion, photoreceptor cell impairment and increased production of bisretinoid lipofuscin in photoreceptor outer segments. Currently, there is neither a clinical treatment nor any on-going trial for BVMD. To fill this unmet need, a rational strategy is to overcome LOF by small molecule Best1 activators, such that the enhanced channel function can compensate for the LOF caused by the disease-causing mutation. Our initial research has identified a novel activator that potently promotes the functionality of the channel. Using single-particle cryogenic electron microscopy (cryo-EM), we have solved the activator-bound channel structures which illustrate the binding site. By chemical engineering of this activator, we have generated optimized lead compounds that strongly stimulate the channel function and rescue the deficiency of disease-causing mutations in both cell- and animal-based BVMD disease models. Taken together, our results demonstrate the underlying mechanism and great promise of developing the lead compounds to a clinically applicable drug for the treatment of BVMD. Based on our preliminary data, we propose to further optimize the lead compound by chemical engineering and assess the rescue efficacy of the resultant candidates in the established animal models, with the ultimate goal of advancing the most effective small compound to human trials. Overall, this research could not only produce a new drug to cure BVMD, but also benefit multiple fields, including eye health, ion channel function, and drug development, with potential applications of the identified small molecule channel activators in both basic science and clinical treatments.
