Targeted lympho-ablation as an alternative to HSCT to cure T1D

点击翻译按钮获取中文摘要

With insulin being the only approved treatment of Type 1 diabetes mellitus (T1DM), there is a very large unmet medical need for a definitive cure for pediatric and adult patients. Increase in obesity, unhealthy diet, and physical inactivity are driving the prevalence of diabetes among all ages. In the U.S., diabetes currently affects 14% of the population of all ages, and it is the seventh leading cause of death, with an estimated cost of $237 billion every year to the healthcare system. The medical community has recognized diabetes as an autoimmune disease and proposed different immunotherapeutic approaches to cure it. However, only hematopoietic stem cell transplantation (HSCT) after reset of the immune system with toxic chemotherapy, has so far shown temporary restoration of insulin independence. The mission of AVM Biotechnology is to develop a disruptive solution for diabetes based on a novel regimen for immunologic reset that safely removes the complete autoimmune pathophysiologic substrates from diabetes patients and can be safely re-administered in case of relapse. The goal of this project is to establish proof-of-concept data for AVM0703, a novel proprietary oral formulation for the treatment of diabetes. In our early-stage preclinical validation, we verified that a single oral dose of AVM0703 induces complete non-myeloablative lymphodepletion without side effects. In this Phase I application, we have two specific aims: (1) Determine the optimal doses of AVM0703 for immunologic reset in the pre-clinical Non-Obese Diabetic (NOD) mouse model. (2) Assess the therapeutic effect AVM0703 in NOD mice and compare it with the one of other standard immunosuppressive medications. We expect to identify one concentration of AVM0703 that is able to safely remove >97% of autoimmune pathophysiologic substrates within 48 hours from its oral administration in NOD mice (Aim1), and that AVM0703 treated mice will achieve normal urine glucose levels within 20 days from dosing preventing insulitis in more than 95% of the cases (Aim2). The successful conclusion of the proposed phase I studies will lay a solid foundation for IND-enabling PK and PD studies in the SBIR phase II period that will lead to clinical trials to evaluate the effects of this novel therapeutic lead in recent-onset juvenile type I diabetes patients.