Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement

Bartlett, Stephen T.; Markmann, James F.; Johnson, Paul; Korsgren, Olle; Hering, Bernhard J.; Scharp, David W.; Kay, Thomas W. H.; Bromberg, Jonathan S.; Odorico, Jon S.; Weir, Gordon C.; Bridges, Nancy D.; Kandaswamy, Raja; Stock, Peter G.; Friend, Peter J.; Gotoh, Mitsukazu; Cooper, D. K. C.; Park, Chung Gyu; OʼConnell, P J.; Stabler, Cherie L.; Matsumoto, Shinichi; Ludwig, Barbara; Choudhary, Pratik; Kovatchev, Boris; Rickels, Michael R.; Sykes, Megan; Wood, Kathryn A.; Kraemer, Kristy; Hwa, Albert; Stanley, Edward; Ricordi, Camillo; Zimmerman, Mark C.; Greenstein, Julia L.; Montanya, Eduard; Otonkoski, Timo

doi:10.1097/tp.0000000000001055

Cited by 68 publications

(59 citation statements)

References 376 publications

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“…Thus, this trial is the first phase 3 trial to show effectiveness of any therapy in restoring both sustained normoglycemia and protection from SHEs in patients with long-standing T1D complicated by IAH and recent SHEs. Emerging diabetes technologies such as next-generation insulin pumps with predictive low-glucose management technology (38) and closed-loop pumps with glucose-responsive insulin or insulin and glucagon delivery (39) have not yet been tested in patients with T1D and problematic hypoglycemia; further testing is needed to determine how these interventions compare with islet transplantation (40). …”

Section: Discussionmentioning

confidence: 99%

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

et al. 2016

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OBJECTIVEImpaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50–80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment.RESEARCH DESIGN AND METHODSThis multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant.RESULTSThe primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients.CONCLUSIONSTransplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

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Section: Discussionmentioning

confidence: 99%

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

et al. 2016

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“…Once the field eventually produces the functional equivalent of primary human pancreatic beta cells, a crucial obstacle will be to protect these cells from the stresses associated with transplantation, especially prior to complete engraftment, and recurrent autoimmunity in people with type 1 diabetes [12,65]. Some have argued that this will be impossible with fully functional beta cells, and that less mature products will be more robust at withstanding the stresses associated with transplantation and recurrent immunity.…”

Section: Remaining Obstacles-beyond Beta Cell Generationmentioning

confidence: 99%

“…Virtually all sites will be unable to mimic portal vein access to the liver, and will lack native innervation and vasculature. However, the initial functionality obtained with current human islet transplant protocols suggests that these concerns do not preclude success [12].…”

Section: Remaining Obstacles-beyond Beta Cell Generationmentioning

confidence: 99%

“…In either case, immunoisolation is being proposed as a method to protect cell products from host immunity. Immunoisolation strategies to prevent autoimmune destruction roughly fall into three categories: macro-encapsulation with devices; microencapsulation with materials such as alginate; and so-called device-less encapsulation, which seeks to identify immune-privileged transplant sites [12,43,66]. However, all of these approaches necessarily place the grafted cells further from the blood source, creating the possibility of a relatively hypoxic environment.…”

Section: Remaining Obstacles-beyond Beta Cell Generationmentioning

confidence: 99%

“…A 2016 follow-up paper reported that encapsulated SC-β cells could reverse hyperglycaemia in streptozotocin-injected C57BL/6 mice [43]; however, the transient effects of this beta cell toxin can make interpretation difficult without removal of the graft. This work, which has also been reviewed by multiple experts [3,10,[12][13][14][15], is an important advance and, together with the work from BetaLogics/University of British Columbia, provides the first convincing evidence of glucose responsiveness from human embryonic stem cell derived cells in vitro. Additional studies are required to convincingly show that these in vitro derived cells respond in a quantitatively similar manner to healthy human primary cells.…”

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The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds

Johnson

2016

Diabetologia

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The production of fully functional insulin-secreting cells to treat diabetes is a major goal of regenerative medicine. In this article, I review progress towards this goal over the last 15 years from the perspective of a beta cell biologist. I describe the current state-of-the-art, and speculate on the general approaches that will be required to identify and achieve our ultimate goal of producing functional beta cells. The need for deeper phenotyping of heterogeneous cultures of stem cell derived islet-like cells in parallel with a better understanding of the heterogeneity of the target cell type(s) is emphasised. This deep phenotyping should include high-throughput single-cell analysis, as well as comprehensive 'omics technologies to provide unbiased characterisation of cell products and human beta cells. There are justified calls for more detailed and well-powered studies of primary human pancreatic beta cell physiology, and I propose online databases of standardised human beta cell responses to physiological stimuli, including both functional and metabolomic/proteomic/ transcriptomic profiles. With a concerted, community-wide effort, including both basic and applied scientists, beta cell replacement will become a clinical reality for patients with diabetes.Keywords Embryonic stem cells . Glucose-stimulated insulin release . Human pancreatic islet beta cells . Review Abbreviation PDX1 Pancreatic and duodenal homeobox 1The case for beta cell replacement in diabetes Diabetes mellitus was recognised early in the era of regenerative medicine research as an obvious indication for a stem cell based therapy. Type 1 diabetes results from the loss of more than 80% of an individual's pancreatic beta cells, while type 2 diabetes occurs when there is insufficient functional beta cell mass to meet the body's needs. The replacement of lost or dysfunctional beta cells in all patients that require it is one of the most important, but elusive, goals of diabetes research. The rationale for beta cell replacement is clear, given the success with which islet cell transplants reduce dangerous hypoglycaemic events and slow the progression of complications [1][2][3]. Pancreatic beta cells have evolved as master regulators of metabolic homeostasis, sensing glucose and other nutrients and releasing appropriate insulin to induce their storage. We understand the basics of beta cell biology, especially the ionic mechanisms underlying insulin release in response to large and abrupt glucose stimuli, which include a rapid rise in cytosolic Ca 2+ subsequent to the metabolismdriven closure of K ATP channels, as well as a plethora of coupling factors [4]. However, we do not understand precisely how human beta cells respond to physiological stimuli and make fate decisions.There are a number of possible ways to replace beta cells in patients with diabetes. Beta cell proliferation could theoretically be induced from the few remaining beta cells in people Electronic supplementary material The online version of this article

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Transplantation of Pancreatic Islets

Hering

Bellin

2018

The Pancreas

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Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement

Cited by 68 publications

References 376 publications

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds

Transplantation of Pancreatic Islets

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