Plasmid-Encoded Proinsulin Preserves C-Peptide While Specifically Reducing Proinsulin-Specific CD8+ T Cells in Type 1 Diabetes

Bart O. Roep; Nanette Solvason; Peter A. Gottlieb; Joana R. F. Abreu; Leonard C. Harrison; George S. Eisenbarth; Liping Yu; Michael Leviten; William A. Hagopian; John B. Buse; Matthias von Herrath; Joanne Quan; Robert S. King; William H. Robinson; Paul J. Utz; Hideki Garren; The BHT-3021 Investigators; Lawrence Steinman

doi:10.1126/scitranslmed.3006103

Research ArticleDiabetes

Plasmid-Encoded Proinsulin Preserves C-Peptide While Specifically Reducing Proinsulin-Specific CD8⁺ T Cells in Type 1 Diabetes

Bart O. Roep¹,*,
Nanette Solvason²,³,*,
Peter A. Gottlieb⁴,*,
Joana R. F. Abreu¹,
Leonard C. Harrison⁵,
George S. Eisenbarth⁴,†,
Liping Yu⁴,
Michael Leviten²,
William A. Hagopian⁶,
John B. Buse⁷,
Matthias von Herrath⁸,
Joanne Quan²,
Robert S. King²,
William H. Robinson²,⁹,¹⁰,‡,
Paul J. Utz²,⁹,¹⁰,
Hideki Garren²,¹⁰,
The BHT-3021 Investigators§ and
Lawrence Steinman²,⁹,¹⁰,‡

¹Department for Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
²Bayhill Therapeutics, Palo Alto, CA 94304, USA.
³Foothill College, Los Altos, CA 94022, USA
⁴Barbara Davis Center for Childhood Diabetes, Aurora, CO 80045–6511, USA.
⁵Division of Molecular Medicine, Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria 3052, Australia.
⁶Pacific Northwest Diabetes Research Institute and University of Washington, Seattle, WA 98122, USA.
⁷Diabetes Center for Research, University of North Carolina, Chapel Hill, NC 27599, USA.
⁸La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
⁹Departments of Medicine and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁰Tolerion Inc., 321 Dedalera Drive, Portola Valley, CA, USA.

↵‡Corresponding author. E-mail: steinman{at}stanford.edu (L.S.); wrobins{at}stanford.edu (W.H.R.)

↵* These authors contributed equally to this work.
↵† Deceased.
↵§ United States: P. Gottlieb, Denver, CO; J. Skyler, Miami, FL; R. Hays, Wellington, FL; F. Ovalle, Birmingham, AL; V. Aroda/R. Ratner, Washington, DC; J. Berg/M. Kipnes, San Antonio, TX; L. Zemel, Denver, CO; M. Rendell, Omaha, NE; P. Norwood, Fresno, CA; P. Raskin, Dallas, TX. Australia/New Zealand: P. Colman, Melbourne; M. Gerstman, Victoria; T. Davis, Fremantle; V. Heazlewood, Queensland; J. Baker, Auckland; P. Dunn, Hamilton; R. Scott, Christchurch; J. Krebs, Wellington. ClinicalTrials.gov registration number: NCT00453375.

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Science Translational Medicine 26 Jun 2013:
Vol. 5, Issue 191, pp. 191ra82
DOI: 10.1126/scitranslmed.3006103

Bart O. Roep

Department for Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

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Nanette Solvason

Bayhill Therapeutics, Palo Alto, CA 94304, USA.Foothill College, Los Altos, CA 94022, USA

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Peter A. Gottlieb

Barbara Davis Center for Childhood Diabetes, Aurora, CO 80045–6511, USA.

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Joana R. F. Abreu

Department for Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

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Leonard C. Harrison

Division of Molecular Medicine, Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria 3052, Australia.

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George S. Eisenbarth

Barbara Davis Center for Childhood Diabetes, Aurora, CO 80045–6511, USA.

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Liping Yu

Barbara Davis Center for Childhood Diabetes, Aurora, CO 80045–6511, USA.

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Michael Leviten

Bayhill Therapeutics, Palo Alto, CA 94304, USA.

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William A. Hagopian

Pacific Northwest Diabetes Research Institute and University of Washington, Seattle, WA 98122, USA.

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John B. Buse

Diabetes Center for Research, University of North Carolina, Chapel Hill, NC 27599, USA.

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Matthias von Herrath

La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.

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Joanne Quan

Bayhill Therapeutics, Palo Alto, CA 94304, USA.

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Robert S. King

Bayhill Therapeutics, Palo Alto, CA 94304, USA.

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William H. Robinson

Bayhill Therapeutics, Palo Alto, CA 94304, USA.Departments of Medicine and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.Tolerion Inc., 321 Dedalera Drive, Portola Valley, CA, USA.

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For correspondence: steinman@stanford.edu wrobins@stanford.edu

Paul J. Utz

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Hideki Garren

Bayhill Therapeutics, Palo Alto, CA 94304, USA.Tolerion Inc., 321 Dedalera Drive, Portola Valley, CA, USA.

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Lawrence Steinman

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For correspondence: steinman@stanford.edu wrobins@stanford.edu

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Plasmid-Encoded Proinsulin Preserves C-Peptide While Specifically Reducing Proinsulin-Specific CD8⁺ T Cells in Type 1 Diabetes

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