R01HD102487

Bumped-Kinase Inhibitor Drug Development for Toxoplasmosis - Abstract

Toxoplasma gondii infection is the most common known parasitic infection and causes systemic infections, particularly severe in immunocompromised humans, that damage the central nervous system. No clear beneficial therapy exists for pregnant women, who are experiencing new infections and possible fetal infection. Bumped-Kinase Inhibitors (BKIs) target calcium-dependent protein kinase 1, necessary for cell entry and growth of T. gondii. We have developed and shown proof-of-concept for treating Toxoplasma gondii CNS infections and pregnancy infections with BKIs. However, our late leads still have some issues such as optimal CNS penetration and metabolites associated with safety issues.

In Aim 1 of the proposed work, we will develop BKIs that retain high systemic concentrations and distribution to both the central nervous system (CNS) and the fetus with acceptable safety attributes for use in pregnancy. This work will be aided by the extensive knowledge of our leads, computational predictions, and iterative experimentation addressing the few remaining issues. We will elucidate the pharmacodynamics and pharmacokinetics (PK/PD) associated with efficacious T. gondii therapy, an area that hasn't been explored before in toxoplasmosis therapy.

Once optimal BKIs are obtained and the optimal PK/PD known, in Aim 2 we will test BKI late leads for effects in rodent and ovine models of congenital toxoplasmosis. The pregnant mice T. gondii congenital model will be useful for prioritizing compounds to further study in the pregnant sheep T. gondii congenital model. The pregnant sheep T. gondii congenital model is a superior model for human T. gondii congenital therapy than the mouse model because of similarities in sheep and humans (vs. mice) in length of gestation, numbers of fetuses per pregnancy, similarities in outcomes of congenital infection, and immune recognition of T. gondii.

Our deliverables will be late lead BKIs, with demonstrated safety and efficacy in two animal models of congenital toxoplasmosis, to advance to GLP toxicity testing required for IND approval. Our likelihood for success is greatly improved by our collective knowledge from working on these compounds for cryptosporidiosis and the well-established scientific team together with advisors and consultants from our partners at PATH, AbbVie, and Bayer, who have decades of experience in pharmaceutical development.

University Of Washington

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Seattle, Washington 981094766 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 375% from $701,303 to $3,328,490.