Department of Ophthalmology and Visual Sciences
University of Michigan
Ann Arbor, Michigan

BASIC RESEARCH PROJECT

Developing a novel treatment to prevent vision loss due to recurrent retinal toxoplasmosis

Research Interests

Toxoplasma gondii (Tg) relies critically on a protease called Cathepsin L (TgCPL) to sustain chronic infection in humans. Chronic Tg infection can result in numerous human diseases, including ocular toxoplasmosis. We have shown previously that pharmacological inhibition of this enzyme reduces Tg burden in chronically infected animals. We propose here to test novel TgCPL chemical inhibitors for the treatment of ocular toxoplasmosis.

Dr. Weh hypothesizes that inhibition of the Tg Cathepsin L protease (TgCPL) will abolish chronic infection and prevent the development of ocular disease. To test this hypothesis, Dr. Weh will identify promising lead inhibitor compounds by determining retinal toxicity and efficacy in killing parasites in vivo. As a critical step toward the long-term goal of a safe, effective, and clinically available treatment for chronic Tg infection, the objective of this project is to define the role of selectivity for TgCPL over HsCPL along with the duration that injected compounds persist within the eye.

Plans for 2024

During 2024, the lab will focus more on compounds that have higher selectivity for the parasite enzyme over the human form of the enzyme. The data from Triazine-3 suggest that this selectivity may be the key to specifically targeting and killing toxoplasma parasites. At the same time, Dr. Weh will investigate the pharmacokinetic properties of these compounds to identify candidates that remain within the eye for longer periods of time. Additionally, by using a renewed strain of parasite, the lab team is able to induce a higher intraocular parasite burden, making the detection of even a small decrease in parasites following drug treatment more effective.

Specific Aims:
Aim 1. Assess safety and intraocular duration of novel TgCPL lead compounds when delivered directly to the retina. Dr. Weh will deliver TgCPL lead-compounds directly to the retina using intravitreal (IVT) injection and assess the overall toxicity and length of time these compounds remain in the retina.
Aim 2. Evaluate the efficacy of novel TgCPL inhibitors in a model of chronic ocular toxoplasmosis. Mice experiencing chronic Tg infection will be treated with highly selective TgCPL inhibitors via IVT dose to eliminate chronic stage parasites from the retina.

Progress in 2023

Dr. Weh’s laboratory team was able to test for toxicity of an additional candidate compound (Triazine-3). This compound was also found to have no significant effect on retinal health or function following a single intravitreal dose. They tested the efficacy of Clindamycin and LHVS following a single intravitreal dose; however, could not detect any significant decrease in parasite burden. A pharmacokinetic study found that LHVS is rapidly cleared from the eye and is undetectable by 24 hours after injection.  The team performed a new efficacy study (LHVS and Trizaine-3) using 2 IVT doses one week apart. Again, no significant decrease in parasite numbers was found; however, there is trend towards a decrease in parasite numbers with Triazine-3, suggesting that selectivity for the parasite enzyme may be important.