The American Diabetes Association reports that 38.4 million Americans had diabetes in 2021, which accounts for 11.6% of the population. About 77% of them were diagnosed (29.7 million) and the rest were undiagnosed (8.7 million). With an estimated 1.2 million new diagnoses every year, the number of people living with diabetes in the U.S. alone is estimated to increase by the end of the decade to 45.6 million. Approximately 95% of diabetics have type 2 diabetes (T2D) and the rest (\~2 million) are type 1 diabetics (T1D); although, the prevalence of T1D is also increasing. According to the Juvenile Diabetes research Foundation (JDFR), an anticipated 64,000 new T1D diagnoses are expected each year in the U.S., and similar trends have been observed in children and adolescents in many other countries. Consequently, the combined global economic cost of diabetes healthcare is expected to be around $2.2 trillion by 2030.

While the etiologies of T1D and T2D may vary, both can lead to insulin insufficiency and hyperglycemia (increased blood sugar levels). Chronic hyperglycemia results in diabetic complications that severely impact on the quality-of-life of patients and some can be life-threatening, like diabetic ketoacidosis. Therefore, insulin supplementation in insulin-dependent diabetes is required. Insulin supplementation can be either in the form of multiple daily insulin injections (manual or via pump) or by biological replacement of the insulin-producing beta cells through transplantation, which provides a natural source of insulin. On the one hand, since the discovery of insulin in the early 1900s, exogenous insulin supplementation has saved countless lives of diabetic patients. However, it is well established that exogenous insulin injection therapy is suboptimal in preventing fluctuation in blood sugar levels (i.e., hyper- and hypoglycemia) due to mis-dosing and other factors. On the other hand, transplantation provides an endogenous source of insulin and c-peptide in real-time without the need for pre-meal dosing or the risk of miscalculating the dose in manual administration or for the challenging predictive algorithms in the case of insulin pumps. Importantly, it has been shown that even partial levels of endogenous insulin secretion can improve glycemic lability and protect from chronic diabetic complications and life-threatening hypoglycemia and diabetic ketoacidosis.

It is now established that beta cell replacement therapy through transplantation of isolated pancreatic islets offers a great therapeutic option in insulin-dependent diabetes, and FDA recently approved it as the first cellular therapy in T1D. However, islet transplantation also has limitations. In general, the limited availability of donor tissue remains a significant obstacle in transplant therapies, including that of pancreatic islets. Other limitations are associated with the mandatory use of systemic anti-rejection immunosuppressive drugs because chronic systemic immunosuppression exposes the transplant recipients to serious and potentially deadly side-effects and complications, such as, but not limited to, increased susceptibility to infections, sepsis, and cancer. While improving systemic immunosuppression regimens would reduce off-target effects and the associated systemic complications, avoiding generalized immunosuppression altogether via localized application would significantly reduce such undesired complications.

Currently, diabetic patients receive transplant therapy either in the form of whole pancreas or isolated pancreatic islets. On the one hand, whole pancreas transplant has been shown to achieve insulin independence in T1D patients, but it is also very invasive and is associated with a 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 by complications associated with the current clinical transplant site, the portal system of the liver. Nevertheless, thousands of patients have received islet transplants in their livers in clinical trials that demonstrated its benefits and the significant improvement in the quality-of-life of islet transplant recipients brought about through improved glycemic control, reduced hypoglycemia episodes, and the prevention of diabetes-associated complications. Notably, some transplanted patients with restored awareness of hypoglycemia maintained this benefit even after going back on exogenous insulin therapy due to islet-graft loss. Many transplant recipients with diabetic retinopathy (D.R.) also experienced improvement in their D.R. Recent experimental evidence indicates that this improvement is mediated by c-peptide inhibiting VEGF-induced vasculopathies, which occur in both T1D and T2D patients. Therefore, transplantation of pancreatic islets is a good treatment option in insulin-dependent diabetes.

The current trial is evaluating the safety of intraocular islet transplantation with localized maintenance immunosuppression via topical application of eye-drops.