Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency

Kit L. Shaw, Elizabeth Garabedian, Suparna Mishra, Provaboti Barman, Alejandra Davila, Denise Carbonaro, Sally Shupien, Christopher Silvin, Sabine Geiger, Barbara Nowicki, E. Monika Smogorzewska, Berkley Brown, Xiaoyan Wang, Satiro De Oliveira, Yeong Choi, Alan Ikeda, Dayna Terrazas, Pei Yu Fu, Allen Yu, Beatriz Campo Fernandez & 24 others Aaron R. Cooper, Barbara Engel, Greg Podsakoff, Arumugam Balamurugan, Stacie Anderson, Linda Muul, G. Jayashree Jagadeesh, Neena Kapoor, John Tse, Theodore B. Moore, Ken Purdy, Radha Rishi, Kathey Mohan, Suzanne Skoda-Smith, David Buchbinder, Roshini S. Abraham, Andrew Scharenberg, Otto O. Yang, Kenneth Cornetta, David Gjertson, Michael Hershfield, Rob Sokolic, Fabio Candotti, Donald B. Kohn

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

BACKGROUND. Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADAdeficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. METHODS. Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/ progenitor cells. ADA gene expression, and immune reconstitution. RESULTS. With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. CONCLUSION. These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.

Original languageEnglish (US)
Pages (from-to)1689-1699
Number of pages11
JournalJournal of Clinical Investigation
Volume127
Issue number5
DOIs
StatePublished - May 1 2017

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Enzyme Replacement Therapy
Adenosine Deaminase
Stem Cells
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Safety
Genes
Busulfan
Passive Immunization
Autologous Transplantation
Intravenous Immunoglobulins
Lymphocyte Count
Mitogens
Granulocytes
Genetic Therapy
Siblings
Blood Cells
Complementary DNA
Tissue Donors
Transplants

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shaw, K. L., Garabedian, E., Mishra, S., Barman, P., Davila, A., Carbonaro, D., ... Kohn, D. B. (2017). Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. Journal of Clinical Investigation, 127(5), 1689-1699. https://doi.org/10.1172/JCI90367

Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. / Shaw, Kit L.; Garabedian, Elizabeth; Mishra, Suparna; Barman, Provaboti; Davila, Alejandra; Carbonaro, Denise; Shupien, Sally; Silvin, Christopher; Geiger, Sabine; Nowicki, Barbara; Smogorzewska, E. Monika; Brown, Berkley; Wang, Xiaoyan; De Oliveira, Satiro; Choi, Yeong; Ikeda, Alan; Terrazas, Dayna; Fu, Pei Yu; Yu, Allen; Fernandez, Beatriz Campo; Cooper, Aaron R.; Engel, Barbara; Podsakoff, Greg; Balamurugan, Arumugam; Anderson, Stacie; Muul, Linda; Jagadeesh, G. Jayashree; Kapoor, Neena; Tse, John; Moore, Theodore B.; Purdy, Ken; Rishi, Radha; Mohan, Kathey; Skoda-Smith, Suzanne; Buchbinder, David; Abraham, Roshini S.; Scharenberg, Andrew; Yang, Otto O.; Cornetta, Kenneth; Gjertson, David; Hershfield, Michael; Sokolic, Rob; Candotti, Fabio; Kohn, Donald B.

In: Journal of Clinical Investigation, Vol. 127, No. 5, 01.05.2017, p. 1689-1699.

Research output: Contribution to journalArticle

Shaw, KL, Garabedian, E, Mishra, S, Barman, P, Davila, A, Carbonaro, D, Shupien, S, Silvin, C, Geiger, S, Nowicki, B, Smogorzewska, EM, Brown, B, Wang, X, De Oliveira, S, Choi, Y, Ikeda, A, Terrazas, D, Fu, PY, Yu, A, Fernandez, BC, Cooper, AR, Engel, B, Podsakoff, G, Balamurugan, A, Anderson, S, Muul, L, Jagadeesh, GJ, Kapoor, N, Tse, J, Moore, TB, Purdy, K, Rishi, R, Mohan, K, Skoda-Smith, S, Buchbinder, D, Abraham, RS, Scharenberg, A, Yang, OO, Cornetta, K, Gjertson, D, Hershfield, M, Sokolic, R, Candotti, F & Kohn, DB 2017, 'Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency', Journal of Clinical Investigation, vol. 127, no. 5, pp. 1689-1699. https://doi.org/10.1172/JCI90367
Shaw, Kit L. ; Garabedian, Elizabeth ; Mishra, Suparna ; Barman, Provaboti ; Davila, Alejandra ; Carbonaro, Denise ; Shupien, Sally ; Silvin, Christopher ; Geiger, Sabine ; Nowicki, Barbara ; Smogorzewska, E. Monika ; Brown, Berkley ; Wang, Xiaoyan ; De Oliveira, Satiro ; Choi, Yeong ; Ikeda, Alan ; Terrazas, Dayna ; Fu, Pei Yu ; Yu, Allen ; Fernandez, Beatriz Campo ; Cooper, Aaron R. ; Engel, Barbara ; Podsakoff, Greg ; Balamurugan, Arumugam ; Anderson, Stacie ; Muul, Linda ; Jagadeesh, G. Jayashree ; Kapoor, Neena ; Tse, John ; Moore, Theodore B. ; Purdy, Ken ; Rishi, Radha ; Mohan, Kathey ; Skoda-Smith, Suzanne ; Buchbinder, David ; Abraham, Roshini S. ; Scharenberg, Andrew ; Yang, Otto O. ; Cornetta, Kenneth ; Gjertson, David ; Hershfield, Michael ; Sokolic, Rob ; Candotti, Fabio ; Kohn, Donald B. / Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 5. pp. 1689-1699.
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abstract = "BACKGROUND. Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADAdeficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. METHODS. Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/ progenitor cells. ADA gene expression, and immune reconstitution. RESULTS. With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. CONCLUSION. These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.",
author = "Shaw, {Kit L.} and Elizabeth Garabedian and Suparna Mishra and Provaboti Barman and Alejandra Davila and Denise Carbonaro and Sally Shupien and Christopher Silvin and Sabine Geiger and Barbara Nowicki and Smogorzewska, {E. Monika} and Berkley Brown and Xiaoyan Wang and {De Oliveira}, Satiro and Yeong Choi and Alan Ikeda and Dayna Terrazas and Fu, {Pei Yu} and Allen Yu and Fernandez, {Beatriz Campo} and Cooper, {Aaron R.} and Barbara Engel and Greg Podsakoff and Arumugam Balamurugan and Stacie Anderson and Linda Muul and Jagadeesh, {G. Jayashree} and Neena Kapoor and John Tse and Moore, {Theodore B.} and Ken Purdy and Radha Rishi and Kathey Mohan and Suzanne Skoda-Smith and David Buchbinder and Abraham, {Roshini S.} and Andrew Scharenberg and Yang, {Otto O.} and Kenneth Cornetta and David Gjertson and Michael Hershfield and Rob Sokolic and Fabio Candotti and Kohn, {Donald B.}",
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T1 - Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency

AU - Shaw, Kit L.

AU - Garabedian, Elizabeth

AU - Mishra, Suparna

AU - Barman, Provaboti

AU - Davila, Alejandra

AU - Carbonaro, Denise

AU - Shupien, Sally

AU - Silvin, Christopher

AU - Geiger, Sabine

AU - Nowicki, Barbara

AU - Smogorzewska, E. Monika

AU - Brown, Berkley

AU - Wang, Xiaoyan

AU - De Oliveira, Satiro

AU - Choi, Yeong

AU - Ikeda, Alan

AU - Terrazas, Dayna

AU - Fu, Pei Yu

AU - Yu, Allen

AU - Fernandez, Beatriz Campo

AU - Cooper, Aaron R.

AU - Engel, Barbara

AU - Podsakoff, Greg

AU - Balamurugan, Arumugam

AU - Anderson, Stacie

AU - Muul, Linda

AU - Jagadeesh, G. Jayashree

AU - Kapoor, Neena

AU - Tse, John

AU - Moore, Theodore B.

AU - Purdy, Ken

AU - Rishi, Radha

AU - Mohan, Kathey

AU - Skoda-Smith, Suzanne

AU - Buchbinder, David

AU - Abraham, Roshini S.

AU - Scharenberg, Andrew

AU - Yang, Otto O.

AU - Cornetta, Kenneth

AU - Gjertson, David

AU - Hershfield, Michael

AU - Sokolic, Rob

AU - Candotti, Fabio

AU - Kohn, Donald B.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - BACKGROUND. Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADAdeficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. METHODS. Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/ progenitor cells. ADA gene expression, and immune reconstitution. RESULTS. With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. CONCLUSION. These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.

AB - BACKGROUND. Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADAdeficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. METHODS. Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/ progenitor cells. ADA gene expression, and immune reconstitution. RESULTS. With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. CONCLUSION. These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.

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DO - 10.1172/JCI90367

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