Long-term safety of alginate-poly-L-ornithine microcapsules, enveloping human islet allografts, into nonimmunosuppressed patients with type 1 diabetes mellitus

Many years ago, we reported on a pilot clinical trial of alginate-poly-L-ornithine (AG/PLO) microencapsulated human islet treatment (TX) into four nonimmunosuppressed patients with long-standing type 1 diabetes (file 19382, PRE 805, September 2003) under intensive exogenous insulin therapy, throughout 3 years post-TX follow up^{1, 2}. The four recipients were selected from patients with long-standing type 1 diabetes (≥25 years), with no significant secondary complications of the disease, but unfair metabolic control, and out-of-range glycated hemoglobin levels. Under local anesthesia, and using ecography guidance, the microencapsulated human islets were delivered by gravity into the peritoneal cavity. No adverse effects during and after the procedure were observed. The clinical outcome was consistent with successful graft function, as assessed as by: (1) serum C-peptide levels, that were undetectable before the graft, and appeared and were sustained in all patients, rising to 2 ng/dL in one recipient (high sensitivity C-reactive protein assay); (2) significant improvement of several biochemical parameters, such as fasting and post-prandial blood glucose levels, stabilization of glycated hemoglobin values ≤7%, and 50–75% reduction of the exogenous insulin daily dose (with 1/4 patients going off insulin, although transiently), throughout 400 days post-transplant, when the graft function was lost; (3) disappearance of nocturnal hypoglycemia unawareness in all recipients; and (4) no immune sensitization to islet cell antigens (negative ICA, anti-GAD65 and anti-HLA I–II antibodies) at 3 years post-TX in all recipients, which confirmed the immunobarrier competence associated with the AG/PLO microcapsules. Retrieval of a fraction of microcapsules from patient 1 at 3 years of TX showed almost still intact microspheres, containing no longer viable islets². During the subsequent years, all four patients reverted back to their usual daily insulin schedule.

Currently, at 20 years of the TX, we wished to clinically re-evaluate the four patients. All of them are disease-free, except for type 1 diabetes, and enjoy fair metabolic control, on intensive exogenous insulin therapy. The four patients have undertaken clinical chemistry profile testing, as well as chest and abdominal imaging procedures (Table 1). Neither side-effects, related to the intraperitoneal microencapsulated islet grafting procedure, nor abnormalities at the level of either internal organs or clinical chemistry parameters, were detected.

In conclusion, intraperitoneal AG/PLO microencapsulated islet allografts have been proven to represent a safe procedure, virtually free of any unwanted sequelae, at 20 years post-TX, despite the finite functional lifespan of the graft. Although a search for better-performing graft sites, as well as alternative sources of insulin-producing cells, are actively being pursued, the AG/PLO-based microcapsules granted full immunoprotection with no short- and long-term adverse effects. It is likely that full graft and long-term metabolic success was not achieved in this pilot clinical, because of the suboptimal grafted islet cell mass, partly due to a limited supply of human donor pancreases. However, because AG/PLO microcapsules are suitable for hosting other insulin-producing cell types (i.e., induced pluripotent stem cells) and xenogeneic islet cells, as per previous experimental trials, it is beneficial that a sufficient insulin output from the microencapsulated cells could lead, in the future, to insulin independence of the treated patients^{3, 4}.

Approval of the research protocol: Italian Ministry of Health (Protocol #19382, PRE 805).

Informed Consent: Informed consent was obtained from all patients.

Approval date of Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.