Testing MALT1 inhibitors as a treatment for the rare pediatric inborn error of immunity CARD11 gain of function

CARD11 gain of function (GOF) is a rare genetic disorder due to inborn variants in the CARD11 gene that confer a biochemical gain of function. In children, these inborn errors cause recurrent infections, severe autoimmunity, enlarged lymph nodes and spleen, and increased risks of lymphoma. There is currently no cure for this disease, and patients are managed with steroids or bone marrow transplantation. Rarefied Biosciences is developing a precisely targeted treatment for CARD11 GOF. Our preliminary data and work from our consultant, collaborator, and discoverer of CARD11 GOF, Dr. Andrew Snow, show that blockade of MALT1, the protease that works in complex with CARD11, could be an effective treatment for CARD11 GOF. Rarefied Biosciences is a new startup that acquired a small-molecule, orally available MALT1 inhibitor from Rheos Medicines, which ran out of money in 2023. Rarefied was founded by the PI (Dr. Butte), an international leader in pediatric immunology for ~20 years and the E. Richard Stiehm Professor of Pediatric Immunology at UCLA and Division Chief. I am a T-cell immunologist and have run a research lab at UCLA and Stanford funded with over $15M from the NIH, NSF, foundations, and philanthropy. I have published over 200 papers, h-index 58, and have deep expertise basic and clinical immunology. I have devoted my career to treating inborn errors of immunity, in many cases by repurposing drugs that are precisely targeted to a molecular pathway gone awry. I sought a MALT1 inhibitor as a treatment for CARD11 GOF after taking care of a child with severe autoimmunity and infections due to CARD11 GOF. The board of directors of Rheos approached me after they were defunct to form Rarefied, take over the MALT1 inhibitor, and develop it for this rare disease. Motivated by my fruitful academic career in inborn errors of immunity, I am now seeking SBIR Phase 1 funds to develop in vitro data to support the commercial potential for MALT1 inhibitors as a treatment for CARD11 GOF. Our MALT1 inhibitor drug has an approved IND (for autoimmune diseases) and has already undergone significant preclinical development: it has excellent oral bioavailability, high safety margins in toxicology studies in dogs and rats, and excellent in vitro safety data. A phase 1 clinical trial to establish safety in healthy humans (not our goal here) begins in March 2025. Rheos had focused on autoimmunity and did not test their inhibitor in CARD11 GOF diseases. We need preclinical data to show its utility in CARD11 GOF diseases, which is the goal of this proposal. These studies will offer mechanism of action data needed for FDA considerations. Here we will conduct tests using cells and cell lines from BENTA patients and healthy controls. If successful, we will then move on to studying the drug in mouse models of BENTA disease in a future application. Success would pave the way for future clinical trials in children suffering with these diseases.