Long‐term Outcomes after Islet Transplantation

Shapiro, A.M. James; Ricordi, Camillo

doi:10.1002/9781118873434.ch108

Cited by 6 publications

(6 citation statements)

References 333 publications

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“…Both modalities have become established as an efficacious means to achieve normoglycemia, prevent hypoglycemia, and potentially protect against vascular complications of T1D ( Barton et al., 2012 , Choudhary et al., 2015 , Gruessner and Gruessner, 2013 , Thompson et al., 2011 ). Despite marked progress in clinical islet transplantation with the achievement and maintenance of insulin independence in over half of recipients up to 5 years ( Shapiro and Ricordi, 2014 ), transplant approaches are limited to those with life-threatening hypoglycemic unawareness or severe glucose lability ( Shapiro et al., 2000 ). Furthermore, this approach remains restricted due to the scarcity of human pancreas donors.…”

Section: Introductionmentioning

confidence: 99%

Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site

et al. 2017

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SummaryBeta-cell replacement therapy is an effective means to restore glucose homeostasis in select humans with autoimmune diabetes. The scarcity of “healthy” human donor pancreata restricts the broader application of this effective curative therapy. “β-Like” cells derived from human embryonic stem cells (hESC), with the capacity to secrete insulin in a glucose-regulated manner, have been developed in vitro, with limitless capacity for expansion. Here we report long-term diabetes correction in mice transplanted with hESC-derived pancreatic endoderm cells (PECs) in a prevascularized subcutaneous site. This advancement mitigates chronic foreign-body response, utilizes a device- and growth factor-free approach, facilitates in vivo differentiation of PECs into glucose-responsive insulin-producing cells, and reliably restores glycemic control. Basal and stimulated human C-peptide secretion was detected throughout the study, which was abolished upon graft removal. Recipient mice demonstrated physiological clearance of glucose in response to metabolic challenge and safely retrieved grafts contained viable glucose regulatory cells.

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Section: Introductionmentioning

confidence: 99%

Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site

et al. 2017

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“…The outcome of islet transplantation has steadily improved over time as the overall percentage of recipients who were insulin independent at 3 years posttransplantation increased from 27% in the 1999-2002 era to 44% in the 2007-2010 era (Barton et al, 2012;Bellin et al, 2012;Tiwari et al, 2012). Success rates for islet transplantation average 50%-70% insulin independence at 5 years in some transplant centers (Barton et al, 2012;Bellin et al, 2012;Shapiro and Ricordi, 2014). Nevertheless, current success rates suggest that available induction and maintenance immunosuppression regimens are unable to completely block islet cell loss in transplant recipients.…”

Section: Introductionmentioning

confidence: 99%

Tolerance Induction and Reversal of Diabetes in Mice Transplanted with Human Embryonic Stem Cell-Derived Pancreatic Endoderm

et al. 2015

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Type 1 diabetes (T1D) is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells in the islets of Langerhans. In most cases, reversal of disease would require strategies combining islet cell replacement with immunotherapy that are currently available only for the most severely affected patients. Here, we demonstrate that immunotherapies that target T cell costimulatory pathways block the rejection of xenogeneic human embryonic-stem-cell-derived pancreatic endoderm (hESC-PE) in mice. The therapy allowed for long-term development of hESC-PE into islet-like structures capable of producing human insulin and maintaining normoglycemia. Moreover, short-term costimulation blockade led to robust immune tolerance that could be transferred independently of regulatory T cells. Importantly, costimulation blockade prevented the rejection of allogeneic hESC-PE by human PBMCs in a humanized model in vivo. These results support the clinical development of hESC-derived therapy, combined with tolerogenic treatments, as a sustainable alternative strategy for patients with T1D.

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“…However, introduction of an ethyl ester (15) at this position decreased cytotoxicity (~3-fold) compared to OTSS167 (R-Luc CC 50 = 186 nM (15) vs. 64 nM ( 5)) with little effect on DYRK1A inhibition potency [DYRK1A-Luc EC 50 = 7 nM (15) vs. 5 nM (5)]. Similarly, R 1 substitutions with various carboxamides (17)(18)(19)(20)(21)(22)(23)(24) minimally affected cytotoxicity or DYRK1A inhibition, consistent with our OTS167-DYRK1A interaction model. Carboxamides derived from secondary amines, like the morpholino (25) and dimethyl amide (26), exhibited no cytotoxicity (R-Luc CC 50 = >10,000 nM, both); however these compounds also showed decreased DYRK1A inhibition (DYRK1A-Luc EC 50 = 641 nM (25) and 354 nM (26)).…”

Section: Primary Screen Of Dyrk1a Inhibition and Cytotoxicitymentioning

confidence: 99%

“…16,17,19 Importantly, replacement of β-cell mass with islet/pancreas transplantation can restore glucose homeostasis in T1D and T2D patients. [20][21][22] While islet transplantation, whether cadaveric-or stem-cell-derived, may play an increased role in future T1D treatment, the expense and complexity of these procedures will limit widespread use. Consequently, developing a safe regenerative medication to expand residual β-cell mass would be transformative.…”

Section: Introductionmentioning

confidence: 99%

Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization

Allegretti

Horton

Abdolazimi

et al. 2020

Bioorganic & Medicinal Chemistry

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Small molecule stimulation of β-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance β-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human β-cell replication. Unfortunately, OTS167's target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS 167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human β-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human β-cell replication-promoting compounds yet *

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Long‐term Outcomes after Islet Transplantation

Cited by 6 publications

References 333 publications

Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site

Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site

Tolerance Induction and Reversal of Diabetes in Mice Transplanted with Human Embryonic Stem Cell-Derived Pancreatic Endoderm

Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization

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