Pharmacokinetic and Physicochemical Evaluation of Novel Drug Candidates for Retinitis Pigmentosa




Garrett, Meredith
Curry, Stacy
Feris, Sherri
Martin, Stephen
Clark, Abbot
Kastellorizios, Michail


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Retinitis pigmentosa is a set of inherited ocular diseases that affect nearly 3 million people worldwide. The condition is inherited and causes the progressive deterioration of the retina. Retinitis pigmentosa begins with the loss of rod photoreceptors which cause night blindness and a decrease in peripheral vision. After significant loss of rod cells, cone cells also begin to die, decreasing central vision until complete blindness. More than 150 genetic mutations in 80 different genes have thus far been identified to contribute to progression pathways of the condition. Despite ongoing stem cell and gene therapy investigations, thus far there are no curative options. Most existing treatments focus on slowing the progression of retinal deterioration by reducing oxidative stress on the retina. Unfortunately, these treatments only achieve limited success and cannot halt progression. Recently, the sigma 2 receptor (σ2r) was identified to be endoplasmic reticulum membrane protein 97 (TMEM97). This protein (σ2r/TMEM97) has been shown to have neuroprotective effects on retinal cells and is thus of interest as a potential drug target for retinitis pigmentosa. Here we synthesized and tested a series of six compounds which have previously been found to modulate σ2r/TMEM97. To determine which of these compounds is a suitable drug candidate, each underwent in vivo and in vitro testing with the goal of selecting the best candidate for further clinical development.


We tested the compounds in a rat model to determine retinal uptake following intravitreal injection. Each drug was dissolved in dimethyl sulfoxide (DMSO) and injected into the eye. At set time points, animals were sacrificed, and retinas were isolated from harvested eyes. The retina was separated and homogenized using sonication. A small portion was removed and underwent protein precipitation to purify the sample. The samples were then analyzed via liquid chromatography mass spectrometry (LCMS) to find the drug concentration remaining at each timepoint. In addition to obtaining a pharmacokinetic profile, the compounds were physiochemically characterized for chemical stability, solubility, in vitro drug release from vitreous humor, thermal analysis, and surface tension.


Our goal is to select those drug candidates with the highest chance of clinical success. The pharmacokinetic profiles as well as physicochemical characteristics and stability of the compounds obtained in this study revealed important differences between the compounds that were used in selecting which to advance to in vivo efficacy testing. Ongoing studies include completion of physicochemical characterization and in vivo efficacy in a retinitis pigmentosa rat model that will be used to identify top candidates for further development.


Research Appreciation Day Award Winner - School of Biomedical Sciences, 2023 Department of Pharmaceutical Sciences & Pharmacotherapy Award - 2nd Place