2024 Developmental Grant Funded Research

Old dog new tricks - Developing new mode-of-action calcineurin inhibitors for acute colitis therapeutics

PI(s):  Ehud Zigmond, MD-PhD, Director of The Center of Liver Diseases, Sheba Medical Center; Maayan Gal, PhD, Gray Faculty of Medical and Health Sciences, Tel Aviv University;

AWARD AMOUNT: 200,000$

PROJECT PERIOD: 11/2024-10/2026

PROJECT OVERVIEW

Colitis, especially acute severe ulcerative colitis, is an autoimmune disease with limited treatment modalities. Current drugs are non-specific, causing severe side effects, and, due to toxicity considerations, are often suitable for short-term use only. Here, we will develop a safer therapeutic by targeting the interaction between two proteins (calcineurin and NFAT), which play a key role in immune activation and disease progression. Inhibition of protein-protein interactions is one of the most promising avenues in modern drug discovery. Based on our recent findings, we screened a large library of potential drugs and found several attractive peptide candidates. In this research project, we will characterize and improve these initial candidates and work towards translating them into new therapeutics.

ANTICIPATED IMPACT/INNOVATION

Calcineurin inhibitors such as cyclosporine are among the mainstay therapies for steroid-refractory patients. Despite their clinical activity, the adverse side effects of these treatments fail the medical therapy for a large number of patients. As current therapies often fall short in maintaining remission of the disease, there is an unmet need for treatments with reduced side effects for long-term treatment of acute severe colitis.

• Discovery of New Mechanisms: The drugs we are developing act in a novel mechanism of inhibiting protein-protein interactions. This contrasts with classic small-molecule drugs, which inhibit the catalytic sites of enzymes.

• Potential IP Generation: Each molecule we are developing forms a new chemical entity and could be protected by a composition of matter patent.

• Clinical Translation Potential: Following in vitro and in vivo characterization, the molecules could further proceed for clinical development.

Mini-Me-on-a-Chip: A Novel Platform for Assessing Autoimmune Disease

Ben Maoz School of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel.

AWARD AMOUNT: 200,000$

PROJECT PERIOD: 7/2024- omited 

PROJECT OVERVIEW

Currently, there is no available platform for studying the human adaptive immune system, which plays a significant role in autoimmune disease. The immune system is challenging to study as it can react with non-allogenic tissues, limiting the available methods. Additionally, autoimmune diseases require personalized medicine and patient-specific trials since each patient has a unique response. Recent technologies such as iPSC and Organs-on-a-Chip have enabled better in-vitro mimicry of human physiology. This proposal aims to integrate these technologies to develop the next-generation platform for studying autoimmune disease. The proposed "Mini-Me-on-a-Chip" platform will introduce the adaptive immune system to the platform and will not be activated unless there is a disease since it is isogenic (patient-specific). The platform will be validated and used to study autoimmune diseases with a genetic background such as Type 1 diabetes and MF, providing a Personalized-Human-System-on-a-Chip that will assess the response of the adaptive immune system.