Preclinical Characterization of Novel Drug Candidates for Ocular Drug Delivery




0000-0003-0452-8294 (Garrett, Meredith)
0000-0002-8287-0143 (Kastellorizios, Michail)

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Retinitis pigmentosa (RP) is the leading cause of vision loss and blindness for people under 60 years old. RP is an inherited disease causing progressive and irreversible deterioration of the retina. To date, over 150 mutations in 90 genes have been identified to contribute to the disease through various pathways. Except for a single mutation responsible for less than 5% of cases, RP is incurable. Currently available treatments largely focus on slowing progression by relieving oxidative stress and are met with limited success. The sigma 2 receptor, also established as transmembrane protein 97 of the endoplasmic reticulum (s2r/TMEM97), has been shown to have neuroprotective effects on retinal cells and is a potential drug target for RP. Recently, a series of novel drug compounds have been identified to modulate the s2r/TMEM97 protein and are under investigation as possible candidates for treatment of RP.

Here, as part of preclinical evaluation, we performed thermal analysis of the novel compounds, including thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). These techniques give insight to drug behavior at different temperatures and provide information on stability and structure. We also conducted a series of drug release studies which monitored movement of the compounds from vitreous humor through a dialysis membrane. This will allow for correlation with previously collected data.


TGA was performed on a TGA550 thermogravimetric analyzer from TA Instruments. The instrument measured the mass of the pan as the temperature was increased from 20°C to 700°C at a rate of 10°C/min. DSC was completed using a DSC250 from TA Instruments. The instrument was programed to increase the temperature of the sample chamber from 10°C to 200°C at a rate of 5°C/min while measuring the heat flux of each pan. A series of drug release studies were performed using a specialized dialysis plate. Drug movement from vitreous humor across a membrane was evaluated over a 12-hour period.


The data collected here for the novel compounds did not show any red flags which would indicate a poor drug candidate. TGA data showed all compounds were thermally stabile until approximately 175°C, at which point they began to lose mass. DSC differential thermograms did not exhibit crystalline behavior. Drug release studies did not show a strong interaction between the compounds and vitreous humor.


Our goal is to aid in narrowing the series of novel drug compounds by providing robust preclinical characterization. TGA thermograms obtained demonstrated the compounds were thermally stabile up to approximately 175°C, which is standard for small molecules. DSC results reveal the compounds are not crystalline and indicate the need for a special formulation. The drug release studies show there were no strong interactions with the compounds and vitreous humor. The data here was included with stability, solubility, and in vitro and in vivo pharmacokinetic analysis and used to select the two leading candidates to advance to in vivo efficacy studies in a transgenic rat model for retinitis pigmentosa.


Research Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Pharmaceutical & Pharmacotherapy Award - 2nd Place