Pancreatic Islet Transplantation Into the Anterior Chamber of the Eye

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 ß-cells are considered the primary cause of T1D, leading to loss
of beta cell mass and insulin secretion and in turn life-long dependence on insulin
injections. The disease severely impacts quality of life and confers risk for 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 of improve existing ones to
prevent, treat, and cure T1D. Diabetes socioeconomic impact primarily stems from the serious
complications associated with this devastating disease. 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 remain 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
provide 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 hypoglycemia fluctuations. On the other hand, it has
been shown that even a partial level of endogenous insulin secretion protects from chronic
diabetic complications, hypoglycemia and diabetic ketoacidosis, which can all 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 clinical
transplant site, the portal system of the liver. Nevertheless, hundreds of T1D patients have
received islet transplants in the liver in the last two and a half 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. This improves 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 the patients have 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 is on the verge of becoming standard-of-care in the United States and other
countries.

Inclusion Criteria:

- Patients who meet all of the following criteria are eligible for participation in the
study:

Ophthalmic inclusion criteria:

1. Patient with at least one eye with extensive loss of vision from hand motion to no
light perception.

2. No evidence of advanced or uncontrolled diabetic retinopathy.

3. Phakic or pseudophakic with a stable intraocular lens in the blind eye.

4. Normal cornea with good visualization of the anterior segment.

5. Normal anterior segment anatomy including the iris bed.

General and metabolic inclusion criteria:

1. Male and female subjects age 18 to 70 years of age and no history of non-compliance.

2. Stable kidney transplant recipient with ongoing immunosuppression.

3. Ability to provide written informed consent.

4. Mentally stable and able to comply with the procedures of the study protocol.

5. Clinical history compatible with T1D with onset of disease at <40 years of age,
insulin-dependence for >5 years at the time of enrollment, and a sum of subject age
and insulin-dependent diabetes duration of ≥23.

6. Absent stimulated c-peptide (<0.3 ng/mL) in response to a mixed meal tolerance test
(MMTT; Boost®Plus 6 mL/kg body weight to a maximum of 360 mL; another product with
equivalent caloric and nutrient content may be substituted for Boost®Plus) measured at
60 and 90 min after the start of consumption.

7. Involvement in intensive diabetes management, defined as self-monitoring of glucose
values no less than a mean of three times each day averaged over each week and by the
administration of three or more insulin injections each day or insulin pump therapy.
Such management must be under the direction of an endocrinologist, diabetologist, or
diabetes specialist, with at least 3 clinical evaluations during the 12 months prior
to study enrollment.

8. Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more; OR HYPO
score greater than or equal to the 90th percentile (1047) during the screening period;
OR marked glycemic lability characterized by wide swings in BG despite optimal
diabetes therapy and defined by an LI score greater than or equal to the 90th
percentile (433 mmol/L2/h·wk-1) during the screening period; OR composite of a Clarke
score of less than 4 and a HYPO score greater than or equal to the 75th percentile
(423) and a LI greater than or equal to the 75th percentile (329) during the screening
period.

Exclusion Criteria:

- Patients who meet any of these criteria are not eligible for participation in the study:

Ophthalmic exclusion criteria (only in surgical eye):

1. Poor visualization of the anterior chamber (corneal opacity, corneal edema, Herpes
Keratitis).

2. Aphakic status (no lens). 3. Narrow angle of iris anatomy: Spade Scale IV. 4. History of
glaucoma that had required surgical intervention (trabeculectomy, shunting devices), and
uncontrolled glaucoma or neovascularization.

5. History of uveitis. 6. Untreated diabetic retinopathy in either eye.

General and metabolic exclusion criteria:

1. Positive c-peptide.

2. Poor compliance history.

3. Body Mass Index (BMI) >30 kg/m2 or patient weight ≤50 kg.

4. Insulin requirement of >1.0 U/kg/day or <15 U/day.

5. HbA1c >10%.

6. Blood Pressure: SBP >160 mmHg or DBP >100 mmHg.

7. Calculated GFR of ≤ 40 mL/min/1.73 m2, using the subject's measured serum creatinine
and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation1.

8. Strict vegetarians (vegans) will be excluded only if their estimated GFR is ≤
35mL/min/1.73 m2.

9. Proteinuria (albumin/creatinine ratio or ACr >300mg/dl) of new onset since kidney
transplantation.

10. Calculated panel-reactive anti-HLA antibodies > 50%. Subjects with calculated panel
reactive anti-HLA antibodies ≤ 50% will be excluded if any of the following are
detected:

i. Positive cross-match. ii. Islet donor-directed anti-HLA antibodies detected by
Luminex Single Antigen specificity bead assay including weakly reactive antibodies
that would not be detected by flow cross-match.

iii. Antibodies to the renal donor (i.e. presumed de-novo).

11. For female subjects: Positive pregnancy test, presently breast-feeding, or
unwillingness to use effective contraceptive measures for the duration of the study
and 4 months after discontinuation. For male subjects: intent to procreate during the
duration of the study or within 4 months after discontinuation or unwillingness to use
effective measures of contraception. Oral contraceptives, Norplant®, Depo-Provera®,
and barrier devices with spermicide are acceptable contraceptive methods; condoms used
alone are not acceptable.

12. Presence or history of active infection including hepatitis B, hepatitis C, HIV, or
tuberculosis (TB). Subjects with laboratory evidence of active infection are excluded
even in the absence of clinical evidence of active infection.

13. Negative screen for Epstein-Barr Virus (EBV) by IgG determination.

14. Invasive aspergillus, histoplasmosis, and coccidioidomycosis infection within one year
prior to study enrollment.

15. Any history of malignancy except for completely resected squamous or basal cell
carcinoma of the skin.

16. Known active alcohol or substance abuse.

17. Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia
(<1,000/µL), neutropenia (<1,500/µL), or thrombocytopenia (platelets <100,000/µL).
Participants with lymphopenia are allowed if the investigator determines there is no
additional risk and obtains clearance from a hematologist.

18. Severe co-existing cardiac disease, characterized by any one of these conditions:

i. Recent myocardial infarction (within past 6 months). ii. Evidence of ischemia on
functional cardiac exam within the last year. iii. Left ventricular ejection fraction
<30%.

19. Hyperlipidemia despite medical therapy (fasting low-density lipoprotein [LDL]
cholesterol > 130 mg/dL, treated or untreated; and/or fasting triglycerides > 200
mg/dL).

22. Receiving treatment for a medical condition requiring chronic use of systemic steroids,
except for the use of ≤5 mg prednisone daily, or an equivalent dose of hydrocortisone, for
physiological replacement only.

23. Treatment with any anti-diabetic medications other than insulin within 4 weeks of
enrollment.

24. Use of any investigational agents within 4 weeks of enrollment. 25. Administration of
live attenuated vaccine(s) within 2 months of enrollment. 26. Any medical condition that,
in the opinion of the investigator, will interfere with the safe participation in the
trial.

27. A previous islet transplant. 28. A previous pancreas transplant, unless the graft
failed within the first week due to thrombosis, followed by pancreatectomy and the
transplant occurred more than 6 months prior to enrollment.