A novel approach to pancreatic islet transplant in the eye is being evaluated at the Diabetes Research Institute to treat type 1 diabetes.
Type 1 diabetes (T1D) is a devastating disease that results from the attack by one’s own immune system against the insulin-producing cells in the pancreas, an abnormal phenomenon referred to as autoimmunity. The continued autoimmune attack against these cells leads to insulin insufficiency and increased blood sugar levels.
Therefore, T1D patients, most often at a very young age, must replace the missing insulin by injecting insulin made from external sources multiple times per day to maintain near-normal blood sugar levels and avoid the potentially life-threatening complications of continuously elevated sugar levels, such as kidney failure, heart and blood vessel disease, nerve damage, and blindness due to damage to the retina (also known as diabetic retinopathy). Insulin injections, though lifesaving, are extremely inconvenient and fraught with missed and wrong dosing errors that often lead to poorly controlled blood sugar levels.
Insulin replacement through transplantation
Another form of insulin replacement is through the transplantation of either the whole pancreas or the isolated clusters of cells where the insulin-producing cells reside, known as pancreatic islets. Either transplant type provides insulin endogenously (from within) without the need for exogenous (external) insulin injections. Having an internal source of insulin is significantly superior to insulin injections because the transplant continuously senses the need for insulin and responds in real-time.
Whole pancreas transplants are approved as standard-of-care therapy in most countries, but islet transplantation is still considered experimental in the United States, and a biological license application (BLA) is currently under consideration by FDA to make it standard-of-care. Major advantages of islet transplantation compared to pancreas transplantation include that it is a minimally invasive procedure and has a lower rate of complications.
Complications and flaws
Islet transplantation is currently performed in the venous system of the liver, where the isolated islets are infused in a minimally invasive procedure assisted with ultrasound imaging. On the one hand, patients who have received islet transplantation have experienced significant improvements in their quality of life. On the other hand, clinical experience has shown certain limitations associated with the liver itself as a transplant site. These limitations include islets’ lower exposure to oxygen levels, as well as an inflammatory reaction known as instant blood-mediated inflammatory reaction (IBMIR), which limits the efficacy of islet transplants in the long-term.
Additionally, transplantation of islets into the liver requires anti-rejection medication. The best anti-rejection therapy we know of today is generalized (systemic) immune suppression. Unfortunately, despite improvements in drug design and regimens, these drugs still have extremely dangerous side effects, including increased susceptibility to infections and cancer formation. This has spurred a search for new sites where isolated pancreatic islets can be transplanted without the complications encountered in the liver.
A better solution
Researchers at the Diabetes Research Institute (DRI), led by Dr. Midhat H. Abdulreda, Ph.D., in collaboration with the Bascom Palmer Eye Institute (BPEI), believe they have a solution. The eye is one of the few “immune privileged” sites in the body, meaning that it does not reject transplantations. Therefore, Dr. Abdulreda and his team are investigating a first-of-its-kind approach to transplant pancreatic islets the eye — an intraocular islet transplant.
In extensive preclinical research on nonhuman models, Dr. Abdulreda and his colleagues have demonstrated the advantages of transplanting islets into the eye. Though excited about his preclinical results, Dr. Abdulreda acknowledges that the ongoing safety trial is critical for additional future clinical studies building on these findings.
In the pilot human clinical trial approved by FDA, the researchers hope to establish the eye as a new site for islet transplant to treat T1D, unlocking the potential of inducing immune tolerance to islet transplantations and avoiding rejection without the need for continuous immune suppression. In this pilot trial, the DRI and BPEI researchers aim to evaluate the general safety and potential efficacy of transplanting isolated islets in the anterior chamber of the eye of legally blind T1D patients who suffer from persistent, severe hypoglycemia. The study is active and recruiting patients.
Candidates between 18 and 70 years of age who meet the below inclusion criteria are eligible to participate in the trial.
Ophthalmic inclusion criteria:
- Patient with at least one eye with extensive loss of vision from hand motion to no light perception.
- No evidence of advanced or uncontrolled diabetic retinopathy (i.e., proliferative D.R).
- Stable intraocular lens (natural or synthetic) in the blind eye.
- Normal cornea with good visualization of the anterior chamber.
- Normal anterior chamber anatomy including the iris bed.
General and metabolic inclusion criteria:
- Clinical history compatible with type 1 diabetes with onset of diabetes at less than 40 years of age, insulin-dependence for more than 5 years at the time of enrollment, and a sum of subject age and insulin-dependent diabetes duration of greater than 23 years.
- Absent stimulated c-peptide (<0.3 ng/mL) in response to a mixed meal tolerance test (MMTT) measured at 60 and 90 min after the start of consumption.
- Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more.
- For islet transplant alone (without existing kidney transplant), at least one episode of severe hypoglycemia in the 12 months prior to study enrollment; OR time in hypoglycemia range (< 70mg/dL) greater than or equal to 8% during 24 hours as assessed by continuous glucose monitoring.
- Stable kidney function without or with a kidney transplant if applicable.
For other inclusion criteria and a complete list of exclusions that prevent participation the trial, see study NCT02846571 at clinicalTrials.gov. Also visit https://diabetesresearch.org/intraocular-islet-transplant/ to learn more about the trial and to download the islet transplant application form.