Efficacy assessment of intraocular islet transplant in nonhuman primates

摘要 临床试验表明，肝内胰岛移植治疗脆性1型糖尿病(T1D) 显著提高他们的生活质量。这是通过改善血糖控制、恢复 提高对严重低血糖的认识，预防糖尿病相关疾病。然而，它也 显而易见，肝内胰岛移植物的寿命受到肝脏特有的并发症的限制，例如 IBMIR(即时血液介导的炎症反应)、缺氧和药物毒性。因此，有几个新的 胰岛移植的部位正在进行临床试验，包括眼前房(ACE； 参见ClinicalTrials.gov/NCT02846571)。我们广泛的临床前研究表明，ACE是一种可行的 胰岛移植的地点，有几个可以利用的技术优势，以促进移植物寿命。 我们最近在狒狒身上展示了在ACE中同种异体胰岛移植物在停止很长时间后的长期存活 免疫抑制。因此，在我们先前工作的基础上，本项目的主要目标是 评估是否可以完全摆脱外源性胰岛素治疗 同一糖尿病患者单纯眼内胰岛移植或随访二次外周移植 在ACE的初始胰岛移植过程中已经耐受的受体狒狒。成功者 这项拟议研究的实施将进一步支持人工眼的临床过渡/应用 胰岛移植是治疗T1D的一种有效且可持续的方法。

ABSTRACT Clinical trials have shown that intrahepatic islet transplant in patients with brittle type 1 diabetes (T1D) improves their quality-of-life significantly. This is achieved through improvement in glycemic control, restoration of severe hypoglycemia awareness, and prevention of diabetes-associated morbidities. However, it has also become evident that the longevity of the intrahepatic islet graft is limited by liver-specific complications, such as IBMIR (Instant Blood Mediated Inflammatory Reaction), hypoxia, and drug toxicity. Consequently, several new sites for islet transplant are being evaluated in clinical trials including the anterior chamber of the eye (ACE; see ClinicalTrials.gov/NCT02846571). Our extensive preclinical studies have shown that the ACE is a viable site for islet transplantation with several technical advantages that can be exploited to promote graft longevity. We recently demonstrated in the baboon long-term survival of islet allografts in the ACE long after stopping immunosuppression. Building on our prior work, the primary objective of the current project is, therefore, to evaluate whether complete independence from exogenous insulin therapy can be achieved following intraocular islet transplant alone or with a follow-up second transplant in the periphery in same diabetic recipient baboons that have been tolerized through initial islet transplant in the ACE. The successful implementation of this proposed research will further support the clinical transition/application of intraocular islet transplant as an effective and sustainable therapy of T1D.