NAMs for Clinical Translation of Therapeutics for Systemic Gynecology Diseases

Specific Aims: NAMs Technology Development Center for Women’s Health, “NAMs TDC-WH” The “NAMs TDC-WH” brings together an international multidisciplinary team, from basic scientists to clinical practitioners, lower the barriers for developing new drugs to treat a spectrum of gynecology disorders ranging from endometriosis to heavy menstrual bleeding and polycystic ovary syndrome (PCOS). This overarching goal will be facilitated by an existing well-funded core infrastructure at MIT in Center for Gynepathology Research that links clinicians, engineers, and scientists in academia and industry to build living patient avatars for endometriosis, adenomyosis and other gynecology diseases (Figure 1. The living patient avatars that will be rigorously tested and translated in the NAMS TDC-WH have been developed since their inception as “combinatorial NAMs”. Computational systems biology and bioinformatics analysis of clinical data (deep phenotyping and -omics) guided the design and operation of microphysiological systems (MPS) to capture key biological phenomena involved in disease and response to drugs, with performance of the MPS benchmarked against in vivo data. For this proposed project, we expand the computational and the clinical teams to capture a more comprehensive picture of the patient population, including genetic diversity and evolving aspects of the pain phenotype. We focus primarily here on combinatorial NAMs for female reproductive tissues, but include liver and other organ systems, recognizing the systemic nature of these diseases and the requirement that any drugs developed with gynecology tissues as a target require metabolic and safety assessments in a systemic manner. We test the hypothesis that pain phenotypes in humans relevant for endometriosis can be captured adequately via the combinatorial NAMs approach. The aims of the TDC-WH are to (i) elevate these technologies to the rigorous criteria needed for regulatory activities related to planning and interpreting human clinical trials for these drugs (ii) further strengthen the ties to the clinical phenotyping, genetics and bioinformatics communities whose input are needed to design physiologically relevant NAMs and benchmark them against in vivo for specific therapeutic targets (iii) translate the NAMs into use via example pre-clinical use cases in collaboration with Pharma. Finally, in addition to the technologies that have already been commercialized or in the process of being commercialized, we aim to translate the new platform technologies under development into wide availability through commercial partners. This will be accomplished through a comprehensive spectrum of education and outreach activities, including videos, hands-on tutorials, and translation of alpha versions of technologies for early feedback on user experience.