Last updated on June 2020

Pancreatic Islet Transplantation Into the Anterior Chamber of the Eye

Brief description of study

The treatment in this trial consists of intraocular islet transplantation. A single dose of 1000 - 2000 Islet Equivalents (IEQ)/kg recipient body weight (BW) will be infused into the anterior chamber of the eye through a self-sealing incision of the peripheral cornea. The procedure is projected to take approximately 20-30 minutes. Subject will remain flat on their back for 1-3 hours after islet infusion to maximize adhesion of the islets to the iris.

Detailed Study Description

The impact of Type 1 Diabetes. In the U.S. alone, approximately 1.3 million people, including children and adolescents, suffer from type 1 diabetes (T1D); the disease incidence is increasing in many countries, also in children and adolescents. Chronic autoimmune T cell responses against pancreatic beta -cells are considered the primary cause of T1D, leading to loss of beta cell mass and insulin secretion and in turn a life-long dependence on insulin injections.

The disease severely impacts quality of life and confers risk of both acute and chronic complications linked to significant morbidity and mortality, such as end-stage renal disease, blindness, cardiovascular disease, diabetic ketoacidosis and hypoglycemia. The economic burden caused by T1D amounts to approximately $14.4 billion in medical costs and lost income. There is a significant need to develop new therapies or improve existing ones to prevent, treat, and cure T1D. Diabetes socioeconomic impact primarily stems from the serious complications associated with it. Such complications include blindness, amputations, kidney failure, heart and vascular disease, stroke, nerve damage, and even birth defects during pregnancy.

Although the specific etiology of T1D remains unknown, it is well established that T1D results from the autoimmune destruction of the insulin-producing beta cells in the endocrine pancreas (i.e., the islets of Langerhans). Consequently, treatment options in T1D are limited to insulin supplementation. Insulin supplementation can be either in the form of multiple insulin injections daily, or biological replacement of the insulin-producing beta cells which provides a natural source of insulin. On the one hand, conventional insulin supplementation via injection has saved countless lives of diabetic patients since the discovery of insulin in the early 1900s. However, it is well established that exogenous insulin injection therapy is suboptimal in preventing hyper- and hypo-glycemia fluctuations. On the other hand, it has been shown that even a partial level of endogenous insulin secretion protects from chronic diabetic complications such as hypoglycemia and diabetic ketoacidosis, which can lead to death.

Therefore, beta cell replacement therapy through transplantation of isolated pancreatic islets offers a great therapeutic option in T1D. Several approaches of beta cell replacement have been pursued in the last few decades. Regenerative approaches such as regeneration of existing mature beta cells, differentiation of stem cells and/or trans-differentiation of other endocrine or non-endocrine (e.g., ductal and exocrine) cells into insulin-producing cells hold great promise in treating T1D. However, these approaches have yet to materialize into safe and reliable clinical application. Transplantation is also another option of biological replacement but has limitations as well. Limited availability of donor tissue remains a significant obstacle in transplantation therapies in general, including pancreatic islets. Other limitations of transplantation therapy are associated with the mandatory use of systemic anti-rejection immunosuppressive drugs. Chronic systemic immunosuppression exposes transplant recipients to serious and potentially deadly side-effects and complications such as increased susceptibility to infections, sepsis and cancer. Therefore, immunosuppressive agents are continuously being improved and new ones are being developed to better protect transplanted tissues (e.g., pancreatic islets) while reducing undesired side-effects of systemic immunosuppression and its associated complications.

T1D patients currently receive transplant therapy either in the form of whole pancreas or isolated pancreatic islets. On the one hand, whole pancreas transplantation has been shown to achieve insulin independence in T1D patients, but it is also very invasive and is associated with high risk of complications and adverse events including mortality. On the other hand, transplantation of isolated pancreatic islets is minimally invasive and has significantly less complications compared to whole pancreas transplant, but survival of the islet graft might be severely limited due to complications associated with the current site for clinical islet transplant, the portal (venous) system of the liver. Nevertheless, hundreds of T1D patients have received islet transplants in the liver in the last three decades of clinical trials of islet transplantation. These studies have demonstrated that islet transplant recipients benefit from improved glycemic control, reduced hypoglycemia episodes, and prevention of diabetes-associated complications. These benefits improve the patients' quality of life significantly. Importantly, it has been shown in transplanted T1D patients that restored hypoglycemia awareness following transplant is maintained even after some of these patients had to get back on insulin therapy due to rejection or loss of the islet graft. Therefore, transplantation of isolated pancreatic islets has emerged as a promising therapy for T1D. Consequently, islet transplantation has become standard-of-care in many countries and is on the verge of being so in the United States.

Clinical Study Identifier: NCT02846571

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Recruitment Status: Open

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