Early Identification and Prevention of Type 1 Diabetes Using Polygenic Risk Score Screening and CAR-T-reg Therapy - ABSTRACT Objective: Type 1 diabetes (T1D) is a common, lifelong autoimmune disease that typically begins in childhood and affects over 1.6 million people in the United States. Despite its prevalence, no current treatment can prevent T1D. However, recent changes in our understanding of the progression of disease reveal that the risk of T1D can be identified early, enabling the opportunity to intervene before the disease develops. This project aims to develop a model for identifying children at highest risk for T1D – based on polygenic risk scores (PRS) – and to prevent disease onset through a novel, targeted cell therapy: CAR-T-regulatory (CAR-T-reg) therapy. Goals and Approach: To create a program for use in clinical settings to predict T1D risk early and deliver personalized preventive therapies. This proposal will focus on two main objectives: Identify Children at High Risk of T1D: To detect children at the highest risk for T1D, we will use a combination of genetic data and electronic health records (EHRs) from 4,000 pediatric participants, of whom 3,117 have already been recruited. A PRS algorithm developed by our Team combines the effects of multiple genetic markers to screen children at CHOP). This approach enables us to identify those at greatest risk of T1D long before symptoms appear, with 115 high-risk children already identified and tracked through work with the electronic Medical Records and Genomics (eMERGE) network. Natural history, proof-of-safety, and proof-of-principal study: To describe disease progression from pre-stage 1 and stage 1, we will screen high risk individuals for diabetes antibodies and other measures 6 months. High PRS individuals who are double- or triple-antibody positive will be recruited to receive CAR-T cells to determine if targeted CAR-T-reg therapy is safe and effective. In addition, we will recruit non-PRS identified individuals with stage 2 or 3 diabetes. We hypothesize that CAR-T-reg therapy is safe and reduces the rate of T1D progression. Expected Impact: This research addresses a major gap in T1D management by focusing on prevention, rather than treatment after diagnosis. If successful, this project could lead to a scalable, real-world program for predicting and preventing T1D in children at highest risk. It would also enable, once pancreatic reconstitution is possible, treatment of individuals with T1D. Finally, it has the potential to lay the groundwork for similar approaches to prevent other autoimmune diseases, paving the way for a new era of precision medicine. Relevance: T1D can lead to serious complications, such as cardiovascular disease, nerve damage, and kidney failure. This research seeks to change the outlook for children at risk by stopping T1D before it begins. By focusing on early identification and prevention, this project has the potential to improve long-term health, reduce healthcare costs, and transform the lives of children and families affected by T1D. It aligns with several NIH priorities, specifically the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to accelerate research into the causes, treatment, and prevention of conditions such as T1D.
