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

由于胰岛素是1型糖尿病(T1 DM)唯一被批准的治疗方法，存在着非常大的未满足 对于儿科和成人患者来说，医学上需要一个彻底的治愈方法。肥胖、不健康饮食和身体状况的增加 缺乏运动正在推动所有年龄段的糖尿病患病率。在美国，糖尿病目前影响着14%的人 所有年龄段的人口，它是第七大死因，估计成本为2370亿美元 每年都给医疗保健系统。医学界已经认识到糖尿病是一种自身免疫性疾病。 并提出了不同的免疫治疗方法来治愈这种疾病。然而，只有造血干细胞 细胞移植(HSCT)在用毒性化疗重新启动免疫系统后，迄今已显示 暂时恢复胰岛素的独立性。AVM Biotech的使命是开发一种颠覆性的 基于一种新的免疫重置方案的糖尿病解决方案，该方案可安全地移除 来自糖尿病患者的自身免疫病理生理底物，在以下情况下可以安全地重新给药 旧病复发。本项目的目标是建立AVM0703的概念验证数据，AVM0703是一种新型的专有口腔药物 治疗糖尿病的配方。在我们的早期临床前验证中，我们验证了一种单一的口腔 剂量的AVM0703可导致完全的非清髓性淋巴枯竭，且无副作用。在此阶段I 应用方面，我们有两个具体的目的：(1)确定AVM0703用于免疫重置的最佳剂量 临床前非肥胖糖尿病(NOD)小鼠模型。(2)评价AVM0703在NOD中的疗效 并将其与其他标准免疫抑制药物之一进行比较。我们希望能找出一个 AVM0703浓度，能够安全地清除体内97%的自身免疫病理生理底物 在NOD小鼠(Aim1)口服后48小时内，AVM0703治疗的小鼠将达到正常 超过95%的病例在服药后20天内的尿糖水平可预防胰腺炎(AIM2)。这个 拟议的第一阶段研究的圆满结束将为促进IND的PK和PD奠定坚实的基础 SBIR第二阶段的研究将导致临床试验，以评估这种新疗法的效果 新近发病的青少年I型糖尿病患者体内的铅。

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.