Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement

Stephen T. Bartlett, James F. Markmann, Paul Johnson, Olle Korsgren, Bernhard J. Hering, David Scharp, Thomas W H Kay, Jonathan Bromberg, Jon S. Odorico, Gordon C. Weir, Nancy Bridges, Raja Kandaswamy, Peter Stock, Peter Friend, Mitsukazu Gotoh, David K C Cooper, Chung Gyu Park, Phillip O'Connell, Cherie Stabler, Shinichi MatsumotoBarbara Ludwig, Pratik Choudhary, Boris Kovatchev, Michael R. Rickels, Megan Sykes, Kathryn Wood, Kristy Kraemer, Albert Hwa, Edward Stanley, Camillo Ricordi, Mark Zimmerman, Julia Greenstein, Eduard Montanya, Timo Otonkoski

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Biologic or biomechanical therapy capable of replacing the β cell mass has the potential to positively impact the health and well being of millions of people with insulindependent diabetes. Research in this area stands at a pivotal moment at which a number of viable strategies exist or are under development. Broad application depends on achieving both technical and financial feasibility. The ultimate goal of a "true cure," in which diabetic individuals achieve euglycemia with a single procedure associated with minimal risk, without long-termtoxic drugs, and unfettered by external devices and/or frequent monitoring, appears to still be some years away. However, dramatic progress has been achieved toward themore proximate objectives of improved glycemic control and elimination of hypoglycemia and long-term vascular complications. Long-term whole organ pancreas and isolated islet results have improved significantly over the last decade,with the latter now approaching the success of the former in insulin independence rates at the 5-year mark. It seems likely that allogeneic pancreas and islet transplantation will remain a treatment of choice for the foreseeable future in kidney recipients already obligated to lifelong immunosuppression until a more complete and permanent restoration of euglycemia is available. Nascent tolerance promoting protocols could aid in improving the risk-to-benefit balance for both islets and whole organ pancreas. With the present supply of transplantable pancreases used optimally, nomore than 13% of the annual incident cases of T1D can be cured. In practical terms though, today, fewer than 5% of the annual incident cases are transplanted. The reality of the limited supply of deceased donor organs ultimately constrains the impact of islet and pancreas transplantation and compels researchers to press forward to develop broader strategies such as the AP, xenogeneic islets, and stem cell-derived β cells for which the supply will be limitless; in these areas, recent progress has been most impressive. The AP continues to be refined withmore sophisticated delivery algorithms, improved sensors and exploration of mobile device control. For xenogeneic islets, dramatic progress is evident in the long-term survival of porcine islets in primates using genetically modified donors and/or improved biologic immunosuppressants. Microencapsulation and macroencapsulation devices that exclude direct immunity by physical means may further aid in fostering xenogeneic islet graft survival but will likely find their primary place in the containment and protection of early versions of stem cell-derived allogeneic β cells. Deriving functional β cells from stem cells has experienced the most celebrated recent advances. Improved differentiation protocols that permit large scale/ unlimited production of IPCs are nowavailable, and although "normal" β-cell function has not yet been achieved, the ever quickening pace of progress suggests they are not far off. Importantly, this therapeutic modality will ultimately need to confront the likely requirement for a containment device and the need to be retransplanted periodically. These blemishes notwithstanding, the tremendous perceived potential of the approach for clinical application is evident in the huge venture capital investment that was rapidly garnered after the report of the most recent advance in embryonic stem cell differentiation into proper β cells. Consistent with the informal survey we conducted, iPS-derived β cells, which currently suffer from regulatory hurdles and the lack of a viable business model, and the seemingly more remote regeneration of native β cells,may offer the ultimate chance for a personalized true cure of insulin-dependent diabetes by avoidance of barrier devices and toxic immunosuppressive drugs. The research agenda we have detailed is designed to facilitate full exploration of the potential of each proposed β-cell replacement solution so the optimal therapy is advanced as quickly as possible. Success in this endeavor will require broad and deep financial support from philanthropic (JDRF, Diabetes Research and Wellness Foundation, ADA, and so on) and public funding agencies worldwide; the investment needed is large but the potential reward will be profound. It is imperative that high impact, scientifically sound approaches are not overwhelmed by industry, private, or venture capital-supported priorities just because they hold a more lucrative near-term business model; scientific merit should dictate the course. The adherence of the historical funding agencies to traditional peer-reviewed methodology will be the incubator of novel approaches. This is a rapidly evolving landscape, and new data and novel ideas may radically divert the path forward. However, the diverse recent progress is tangible and undeniable, and the next decade is bound to witness a fascinating unfolding of competing solutions to cure insulin-dependent diabetes. Our assessment of the data presented creates the opportunity for IPITA/TTS to endorse the following broad agenda for specific support by the peer-reviewed agencies.

Original languageEnglish (US)
Pages (from-to)S1-S44
JournalTransplantation
Volume100
DOIs
StatePublished - 2016

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Equipment and Supplies
Pancreas
Pancreas Transplantation
Islets of Langerhans Transplantation
Stem Cells
Insulin
Immunosuppressive Agents
Economics
Research
Tissue Donors
Financial Support
Incubators
Drug Compounding
Foster Home Care
Poisons
Homologous Transplantation
Graft Survival
Therapeutics
Embryonic Stem Cells
Islets of Langerhans

ASJC Scopus subject areas

  • Transplantation

Cite this

Bartlett, S. T., Markmann, J. F., Johnson, P., Korsgren, O., Hering, B. J., Scharp, D., ... Otonkoski, T. (2016). Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement. Transplantation, 100, S1-S44. https://doi.org/10.1097/TP.0000000000001055

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; Kay, Thomas W H; Bromberg, Jonathan; Odorico, Jon S.; Weir, Gordon C.; Bridges, Nancy; Kandaswamy, Raja; Stock, Peter; Friend, Peter; Gotoh, Mitsukazu; Cooper, David K C; Park, Chung Gyu; O'Connell, Phillip; Stabler, Cherie; Matsumoto, Shinichi; Ludwig, Barbara; Choudhary, Pratik; Kovatchev, Boris; Rickels, Michael R.; Sykes, Megan; Wood, Kathryn; Kraemer, Kristy; Hwa, Albert; Stanley, Edward; Ricordi, Camillo; Zimmerman, Mark; Greenstein, Julia; Montanya, Eduard; Otonkoski, Timo.

In: Transplantation, Vol. 100, 2016, p. S1-S44.

Research output: Contribution to journalArticle

Bartlett, ST, Markmann, JF, Johnson, P, Korsgren, O, Hering, BJ, Scharp, D, Kay, TWH, Bromberg, J, Odorico, JS, Weir, GC, Bridges, N, Kandaswamy, R, Stock, P, Friend, P, Gotoh, M, Cooper, DKC, Park, CG, O'Connell, P, Stabler, C, Matsumoto, S, Ludwig, B, Choudhary, P, Kovatchev, B, Rickels, MR, Sykes, M, Wood, K, Kraemer, K, Hwa, A, Stanley, E, Ricordi, C, Zimmerman, M, Greenstein, J, Montanya, E & Otonkoski, T 2016, 'Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement', Transplantation, vol. 100, pp. S1-S44. https://doi.org/10.1097/TP.0000000000001055
Bartlett ST, Markmann JF, Johnson P, Korsgren O, Hering BJ, Scharp D et al. Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement. Transplantation. 2016;100:S1-S44. https://doi.org/10.1097/TP.0000000000001055
Bartlett, Stephen T. ; Markmann, James F. ; Johnson, Paul ; Korsgren, Olle ; Hering, Bernhard J. ; Scharp, David ; Kay, Thomas W H ; Bromberg, Jonathan ; Odorico, Jon S. ; Weir, Gordon C. ; Bridges, Nancy ; Kandaswamy, Raja ; Stock, Peter ; Friend, Peter ; Gotoh, Mitsukazu ; Cooper, David K C ; Park, Chung Gyu ; O'Connell, Phillip ; Stabler, Cherie ; Matsumoto, Shinichi ; Ludwig, Barbara ; Choudhary, Pratik ; Kovatchev, Boris ; Rickels, Michael R. ; Sykes, Megan ; Wood, Kathryn ; Kraemer, Kristy ; Hwa, Albert ; Stanley, Edward ; Ricordi, Camillo ; Zimmerman, Mark ; Greenstein, Julia ; Montanya, Eduard ; Otonkoski, Timo. / Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement. In: Transplantation. 2016 ; Vol. 100. pp. S1-S44.
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abstract = "Biologic or biomechanical therapy capable of replacing the β cell mass has the potential to positively impact the health and well being of millions of people with insulindependent diabetes. Research in this area stands at a pivotal moment at which a number of viable strategies exist or are under development. Broad application depends on achieving both technical and financial feasibility. The ultimate goal of a {"}true cure,{"} in which diabetic individuals achieve euglycemia with a single procedure associated with minimal risk, without long-termtoxic drugs, and unfettered by external devices and/or frequent monitoring, appears to still be some years away. However, dramatic progress has been achieved toward themore proximate objectives of improved glycemic control and elimination of hypoglycemia and long-term vascular complications. Long-term whole organ pancreas and isolated islet results have improved significantly over the last decade,with the latter now approaching the success of the former in insulin independence rates at the 5-year mark. It seems likely that allogeneic pancreas and islet transplantation will remain a treatment of choice for the foreseeable future in kidney recipients already obligated to lifelong immunosuppression until a more complete and permanent restoration of euglycemia is available. Nascent tolerance promoting protocols could aid in improving the risk-to-benefit balance for both islets and whole organ pancreas. With the present supply of transplantable pancreases used optimally, nomore than 13{\%} of the annual incident cases of T1D can be cured. In practical terms though, today, fewer than 5{\%} of the annual incident cases are transplanted. The reality of the limited supply of deceased donor organs ultimately constrains the impact of islet and pancreas transplantation and compels researchers to press forward to develop broader strategies such as the AP, xenogeneic islets, and stem cell-derived β cells for which the supply will be limitless; in these areas, recent progress has been most impressive. The AP continues to be refined withmore sophisticated delivery algorithms, improved sensors and exploration of mobile device control. For xenogeneic islets, dramatic progress is evident in the long-term survival of porcine islets in primates using genetically modified donors and/or improved biologic immunosuppressants. Microencapsulation and macroencapsulation devices that exclude direct immunity by physical means may further aid in fostering xenogeneic islet graft survival but will likely find their primary place in the containment and protection of early versions of stem cell-derived allogeneic β cells. Deriving functional β cells from stem cells has experienced the most celebrated recent advances. Improved differentiation protocols that permit large scale/ unlimited production of IPCs are nowavailable, and although {"}normal{"} β-cell function has not yet been achieved, the ever quickening pace of progress suggests they are not far off. Importantly, this therapeutic modality will ultimately need to confront the likely requirement for a containment device and the need to be retransplanted periodically. These blemishes notwithstanding, the tremendous perceived potential of the approach for clinical application is evident in the huge venture capital investment that was rapidly garnered after the report of the most recent advance in embryonic stem cell differentiation into proper β cells. Consistent with the informal survey we conducted, iPS-derived β cells, which currently suffer from regulatory hurdles and the lack of a viable business model, and the seemingly more remote regeneration of native β cells,may offer the ultimate chance for a personalized true cure of insulin-dependent diabetes by avoidance of barrier devices and toxic immunosuppressive drugs. The research agenda we have detailed is designed to facilitate full exploration of the potential of each proposed β-cell replacement solution so the optimal therapy is advanced as quickly as possible. Success in this endeavor will require broad and deep financial support from philanthropic (JDRF, Diabetes Research and Wellness Foundation, ADA, and so on) and public funding agencies worldwide; the investment needed is large but the potential reward will be profound. It is imperative that high impact, scientifically sound approaches are not overwhelmed by industry, private, or venture capital-supported priorities just because they hold a more lucrative near-term business model; scientific merit should dictate the course. The adherence of the historical funding agencies to traditional peer-reviewed methodology will be the incubator of novel approaches. This is a rapidly evolving landscape, and new data and novel ideas may radically divert the path forward. However, the diverse recent progress is tangible and undeniable, and the next decade is bound to witness a fascinating unfolding of competing solutions to cure insulin-dependent diabetes. Our assessment of the data presented creates the opportunity for IPITA/TTS to endorse the following broad agenda for specific support by the peer-reviewed agencies.",
author = "Bartlett, {Stephen T.} and Markmann, {James F.} and Paul Johnson and Olle Korsgren and Hering, {Bernhard J.} and David Scharp and Kay, {Thomas W H} and Jonathan Bromberg and Odorico, {Jon S.} and Weir, {Gordon C.} and Nancy Bridges and Raja Kandaswamy and Peter Stock and Peter Friend and Mitsukazu Gotoh and Cooper, {David K C} and Park, {Chung Gyu} and Phillip O'Connell and Cherie Stabler and Shinichi Matsumoto and Barbara Ludwig and Pratik Choudhary and Boris Kovatchev and Rickels, {Michael R.} and Megan Sykes and Kathryn Wood and Kristy Kraemer and Albert Hwa and Edward Stanley and Camillo Ricordi and Mark Zimmerman and Julia Greenstein and Eduard Montanya and Timo Otonkoski",
year = "2016",
doi = "10.1097/TP.0000000000001055",
language = "English (US)",
volume = "100",
pages = "S1--S44",
journal = "Transplantation",
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publisher = "Lippincott Williams and Wilkins",

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TY - JOUR

T1 - Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement

AU - Bartlett, Stephen T.

AU - Markmann, James F.

AU - Johnson, Paul

AU - Korsgren, Olle

AU - Hering, Bernhard J.

AU - Scharp, David

AU - Kay, Thomas W H

AU - Bromberg, Jonathan

AU - Odorico, Jon S.

AU - Weir, Gordon C.

AU - Bridges, Nancy

AU - Kandaswamy, Raja

AU - Stock, Peter

AU - Friend, Peter

AU - Gotoh, Mitsukazu

AU - Cooper, David K C

AU - Park, Chung Gyu

AU - O'Connell, Phillip

AU - Stabler, Cherie

AU - Matsumoto, Shinichi

AU - Ludwig, Barbara

AU - Choudhary, Pratik

AU - Kovatchev, Boris

AU - Rickels, Michael R.

AU - Sykes, Megan

AU - Wood, Kathryn

AU - Kraemer, Kristy

AU - Hwa, Albert

AU - Stanley, Edward

AU - Ricordi, Camillo

AU - Zimmerman, Mark

AU - Greenstein, Julia

AU - Montanya, Eduard

AU - Otonkoski, Timo

PY - 2016

Y1 - 2016

N2 - Biologic or biomechanical therapy capable of replacing the β cell mass has the potential to positively impact the health and well being of millions of people with insulindependent diabetes. Research in this area stands at a pivotal moment at which a number of viable strategies exist or are under development. Broad application depends on achieving both technical and financial feasibility. The ultimate goal of a "true cure," in which diabetic individuals achieve euglycemia with a single procedure associated with minimal risk, without long-termtoxic drugs, and unfettered by external devices and/or frequent monitoring, appears to still be some years away. However, dramatic progress has been achieved toward themore proximate objectives of improved glycemic control and elimination of hypoglycemia and long-term vascular complications. Long-term whole organ pancreas and isolated islet results have improved significantly over the last decade,with the latter now approaching the success of the former in insulin independence rates at the 5-year mark. It seems likely that allogeneic pancreas and islet transplantation will remain a treatment of choice for the foreseeable future in kidney recipients already obligated to lifelong immunosuppression until a more complete and permanent restoration of euglycemia is available. Nascent tolerance promoting protocols could aid in improving the risk-to-benefit balance for both islets and whole organ pancreas. With the present supply of transplantable pancreases used optimally, nomore than 13% of the annual incident cases of T1D can be cured. In practical terms though, today, fewer than 5% of the annual incident cases are transplanted. The reality of the limited supply of deceased donor organs ultimately constrains the impact of islet and pancreas transplantation and compels researchers to press forward to develop broader strategies such as the AP, xenogeneic islets, and stem cell-derived β cells for which the supply will be limitless; in these areas, recent progress has been most impressive. The AP continues to be refined withmore sophisticated delivery algorithms, improved sensors and exploration of mobile device control. For xenogeneic islets, dramatic progress is evident in the long-term survival of porcine islets in primates using genetically modified donors and/or improved biologic immunosuppressants. Microencapsulation and macroencapsulation devices that exclude direct immunity by physical means may further aid in fostering xenogeneic islet graft survival but will likely find their primary place in the containment and protection of early versions of stem cell-derived allogeneic β cells. Deriving functional β cells from stem cells has experienced the most celebrated recent advances. Improved differentiation protocols that permit large scale/ unlimited production of IPCs are nowavailable, and although "normal" β-cell function has not yet been achieved, the ever quickening pace of progress suggests they are not far off. Importantly, this therapeutic modality will ultimately need to confront the likely requirement for a containment device and the need to be retransplanted periodically. These blemishes notwithstanding, the tremendous perceived potential of the approach for clinical application is evident in the huge venture capital investment that was rapidly garnered after the report of the most recent advance in embryonic stem cell differentiation into proper β cells. Consistent with the informal survey we conducted, iPS-derived β cells, which currently suffer from regulatory hurdles and the lack of a viable business model, and the seemingly more remote regeneration of native β cells,may offer the ultimate chance for a personalized true cure of insulin-dependent diabetes by avoidance of barrier devices and toxic immunosuppressive drugs. The research agenda we have detailed is designed to facilitate full exploration of the potential of each proposed β-cell replacement solution so the optimal therapy is advanced as quickly as possible. Success in this endeavor will require broad and deep financial support from philanthropic (JDRF, Diabetes Research and Wellness Foundation, ADA, and so on) and public funding agencies worldwide; the investment needed is large but the potential reward will be profound. It is imperative that high impact, scientifically sound approaches are not overwhelmed by industry, private, or venture capital-supported priorities just because they hold a more lucrative near-term business model; scientific merit should dictate the course. The adherence of the historical funding agencies to traditional peer-reviewed methodology will be the incubator of novel approaches. This is a rapidly evolving landscape, and new data and novel ideas may radically divert the path forward. However, the diverse recent progress is tangible and undeniable, and the next decade is bound to witness a fascinating unfolding of competing solutions to cure insulin-dependent diabetes. Our assessment of the data presented creates the opportunity for IPITA/TTS to endorse the following broad agenda for specific support by the peer-reviewed agencies.

AB - Biologic or biomechanical therapy capable of replacing the β cell mass has the potential to positively impact the health and well being of millions of people with insulindependent diabetes. Research in this area stands at a pivotal moment at which a number of viable strategies exist or are under development. Broad application depends on achieving both technical and financial feasibility. The ultimate goal of a "true cure," in which diabetic individuals achieve euglycemia with a single procedure associated with minimal risk, without long-termtoxic drugs, and unfettered by external devices and/or frequent monitoring, appears to still be some years away. However, dramatic progress has been achieved toward themore proximate objectives of improved glycemic control and elimination of hypoglycemia and long-term vascular complications. Long-term whole organ pancreas and isolated islet results have improved significantly over the last decade,with the latter now approaching the success of the former in insulin independence rates at the 5-year mark. It seems likely that allogeneic pancreas and islet transplantation will remain a treatment of choice for the foreseeable future in kidney recipients already obligated to lifelong immunosuppression until a more complete and permanent restoration of euglycemia is available. Nascent tolerance promoting protocols could aid in improving the risk-to-benefit balance for both islets and whole organ pancreas. With the present supply of transplantable pancreases used optimally, nomore than 13% of the annual incident cases of T1D can be cured. In practical terms though, today, fewer than 5% of the annual incident cases are transplanted. The reality of the limited supply of deceased donor organs ultimately constrains the impact of islet and pancreas transplantation and compels researchers to press forward to develop broader strategies such as the AP, xenogeneic islets, and stem cell-derived β cells for which the supply will be limitless; in these areas, recent progress has been most impressive. The AP continues to be refined withmore sophisticated delivery algorithms, improved sensors and exploration of mobile device control. For xenogeneic islets, dramatic progress is evident in the long-term survival of porcine islets in primates using genetically modified donors and/or improved biologic immunosuppressants. Microencapsulation and macroencapsulation devices that exclude direct immunity by physical means may further aid in fostering xenogeneic islet graft survival but will likely find their primary place in the containment and protection of early versions of stem cell-derived allogeneic β cells. Deriving functional β cells from stem cells has experienced the most celebrated recent advances. Improved differentiation protocols that permit large scale/ unlimited production of IPCs are nowavailable, and although "normal" β-cell function has not yet been achieved, the ever quickening pace of progress suggests they are not far off. Importantly, this therapeutic modality will ultimately need to confront the likely requirement for a containment device and the need to be retransplanted periodically. These blemishes notwithstanding, the tremendous perceived potential of the approach for clinical application is evident in the huge venture capital investment that was rapidly garnered after the report of the most recent advance in embryonic stem cell differentiation into proper β cells. Consistent with the informal survey we conducted, iPS-derived β cells, which currently suffer from regulatory hurdles and the lack of a viable business model, and the seemingly more remote regeneration of native β cells,may offer the ultimate chance for a personalized true cure of insulin-dependent diabetes by avoidance of barrier devices and toxic immunosuppressive drugs. The research agenda we have detailed is designed to facilitate full exploration of the potential of each proposed β-cell replacement solution so the optimal therapy is advanced as quickly as possible. Success in this endeavor will require broad and deep financial support from philanthropic (JDRF, Diabetes Research and Wellness Foundation, ADA, and so on) and public funding agencies worldwide; the investment needed is large but the potential reward will be profound. It is imperative that high impact, scientifically sound approaches are not overwhelmed by industry, private, or venture capital-supported priorities just because they hold a more lucrative near-term business model; scientific merit should dictate the course. The adherence of the historical funding agencies to traditional peer-reviewed methodology will be the incubator of novel approaches. This is a rapidly evolving landscape, and new data and novel ideas may radically divert the path forward. However, the diverse recent progress is tangible and undeniable, and the next decade is bound to witness a fascinating unfolding of competing solutions to cure insulin-dependent diabetes. Our assessment of the data presented creates the opportunity for IPITA/TTS to endorse the following broad agenda for specific support by the peer-reviewed agencies.

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