The anterior chamber of the eye as an islet transplantation site in type-2 diabetes

Abstract

Diabetes mellitus is a chronic disease, one of the leading causes of death and a consistent financial burden globally. It occurs when insulin is insufficient for glucose homeostasis. Pancreatic islet transplantation drew attention as an attractive therapeutic option for treating Type-1 diabetes. In the past few decades, islet transplantation has received significant attention worldwide since the Edmonton protocol was established in 2000. The infusion of pancreatic islets into the recipient's portal vein has been a gold standard procedure. However, it is associated with certain drawbacks when the islets are directly exposed to the blood cells and the transplantation site is flooded with inflammatory cytokines. The anterior chamber of the eye (ACE) is an emerging alternative experimental islet transplantation site as it bears several benefits to the transplanted grafts, such as oxygen-rich milieu, immune privilege site, and lesser number of islets needed for transplantation. In addition, the confined natural incubator is feasible for local therapeutic approaches such as immunosuppression to preserve the allogeneic islet grafts and even improve function of the grafts.

In my thesis, I evaluated the efficacy of intraocular islet grafts on Type-2 diabetic human surrogates. I showed that the intraocular islet recipient achieved a significantly lower fasting plasma glucose level and even reversed the Type-2 diabetes progression. In addition, there was an improvement in long-term metabolic markers, such as HbA1C and Fructosamine. It also showed that the islet dosage required for intraocular transplantation is lower than the traditional method involving transplantation to the portal vein, owing to the immune privilege properties and less severe blood-mediated immune reactions. By taking advantage of the unique properties of the ACE, I tested the feasibility of a local therapeutic approach in intraocular islet grafts. A local application of dexamethasone implant was given as immunosuppression, and the results showed a significant improvement in the grafts' survival compared to the nontreated control group. This proof-of-concept study showed that a local immunosuppression/therapeutic approach was feasible and could benefit the intraocular islet grafts. Finally, I improved the efficacy of the isolated islets by genetic manipulation using AAVs to knock down the beta-3 subunit of the voltage-gated calcium channel of the pancreatic islets from non-human primates. The in-vitro results showed an improved insulin secretion profile in the knockdown islets. In addition, the recipients of such islets also showed a better glucose profile with superior glucose clearance than the control group.

In conclusion, the ACE may constitute a novel promising site for islet transplantation for insulin-dependent Type-2 diabetes patients with the possibility of local therapeutic intervention.