Michael Steven Hershfield, MD

Professor of Medicine
Professor of Biochemistry
Campus mail 418 Sands Building, Durham, NC 27710
Phone (919) 684-4184
Email address michael.hershfield@duke.edu

Molecular Basis and Therapy of Inherited Disorders of Purine Metabolism
ABSTRACT
We have a longstanding interest in inherited disorders of purine metabolism. Our primary focus has been the combined immunodeficiency disease caused by inherited deficiency of adenosine deaminase (ADA) and purine nucleoisde phosphorylase (PNP). In addition to these rare recessive disorders, we have maintained an interest in gout, the most common purine metabolic disease. We have also investigated the biochemistry, metabolism, and biological effects of nucleoside analogs, including their use for treating neoplastic and viral diseases.

During our first decade at Duke we studied the biochemical mechanisms responsible for immune deficiency caused by ADA and PNP deficiency. We subsequently investigated the operation of these mechanisms in vivo in ADA-deficient patients and in collaboarative studies of ADA knockout mice. We have defined the molecular basis for the interaction between human ADA and CD26/Dipeptidyl Peptidase IV (DPPIV), a cell membrane associated multifunctional glycoprotein, also known as the adenosine deaminase complexing protein. This work has cast doubt on the postulated role of the ADA-DPPIV complex, or "ecto-ADA", in normal immune function.

Twenty-five years ago, in collaboration with Dr. Rebecca Buckley, we initiated, and subsequently played a central role in the clinical development of polyethylene glycol (PEG)-modified adenosine deaminase (PEG-ADA) as replacement therapy for severe combined immunodeficiency disease (SCID) due to ADA deficiency. PEG-ADA was the first PEG-modified therapeutic agent to receive USFDA approval (in 1990), and the first effective form of enzyme replacement therapy for an inherited metabolic disease. We have also collaboarated in evaluating the metabolic efficacy of stem cell transplantation and stem cell gene therapy for treating ADA- SCID. In connection with this work, we have systematically investigated the mutational basis for ADA deficiency, and the relationship between genotype and phenotype. We have written reviews on the treatment of ADA deficiency, and major textbook chapters dealing with ADA and PNP deficiency, and other inherited diseases of purine metabolism. Over the past 3 decades we have continued to serve as a resource for establishing the diagnosis of ADA and PNP deficiency, and to monitor the metabolic effects of PEG-ADA therapy and the immunoe response to PEG-ADA in patients with ADA deficiency in the US and over 20 other countries. 

During the past two decades we have been engaged in translational research to develop a PEGylated recombinant urate oxidase (Pegloticase, Krystexxa) as an Orphan Drug for treating patients with refractory gout and poorly controlled hyperuricemia.  We demonstrated the effectiveness of Pegloticase in preventing uric acid nephropathy in a urate oxidase knockout mouse model, and have participated with John Sundy and other members of the Duke Rheumatology division in the first in-human phase 1 clinical trials of Pegloticase in patients with refractory gout. We subsequently obtained support from the USFDA Office of Orphan Products Development to conduct a Phase II clinical study of Pegloticase in order to optimize dosing and assess the potential effects of profoundly reducing serum uric acid levels on oxidative stress status. In 2010 Pegloticase was one of 21 new drugs to receive FDA approval. We are presently investigating the immune response to Pegloticase, which we have shown to be directed at the PEG polymer rather than the uricase protein.

Keywords: human genetic disease; enzyme replacement therapy; polyethylene glycol modified enzymes; mutation; immune deficiency disease; ADA deficiency; purine nucleoside phosphorylase deficiency; gout

Education and Training

  • Resident, Medicine, University of California School of Medicine, 1974 - 1975
  • M.D., University of Pennsylvania, 1967

Publications

Trotta, L, Martelius, T, Siitonen, T, Hautala, T, Hämäläinen, S, Juntti, H, Taskinen, M, Ilander, M, Andersson, EI, Zavialov, A, Kaustio, M, Keski-Filppula, R, Hershfield, M, Mustjoki, S, Tapiainen, T, Seppänen, M, and Saarela, J. "ADA2 deficiency: Clonal lymphoproliferation in a subset of patients (Accepted)." Journal of Allergy and Clinical Immunology (January 1, 2018).

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Skrabl-Baumgartner, A, Plecko, B, Schmidt, WM, König, N, Hershfield, M, Gruber-Sedlmayr, U, and Lee-Kirsch, MA. "Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation." Pediatric Rheumatology 15, no. 1 (December 2017).

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Hashem, H, Kumar, AR, Müller, I, Babor, F, Bredius, R, Dalal, J, Hsu, AP, Holland, SM, Hickstein, DD, Jolles, S, Krance, R, Sasa, G, Taskinen, M, Koskenvuo, M, Saarela, J, van Montfrans, J, Wilson, K, Bosch, B, Moens, L, Hershfield, M, Meyts, I, and Deficiency of Adenosine Deaminase Type 2 Foundation, . "Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2." Blood 130, no. 24 (December 2017): 2682-2688.

PMID
28974505
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Bucciol, G, Delafontaine, S, Segers, H, Bossuyt, X, Hershfield, MS, Moens, L, and Meyts, I. "Hematopoietic Stem Cell Transplantation in ADA2 Deficiency: Early Restoration of ADA2 Enzyme Activity and Disease Relapse upon Drop of Donor Chimerism." Journal of clinical immunology 37, no. 8 (November 2017): 746-750. (Letter)

PMID
28993957
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Hashem, H, Vatsayan, A, Gupta, A, Nagle, K, Hershfield, M, and Dalal, J. "Successful reduced intensity hematopoietic cell transplant in a patient with deficiency of adenosine deaminase 2." Bone Marrow Transplantation 52, no. 11 (November 2017): 1575-1576.

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Hashem, H, Kelly, SJ, Ganson, NJ, and Hershfield, MS. "Deficiency of Adenosine Deaminase 2 (DADA2), an Inherited Cause of Polyarteritis Nodosa and a Mimic of Other Systemic Rheumatologic Disorders." Current rheumatology reports 19, no. 11 (October 5, 2017): 70-. (Review)

PMID
28983775
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Chang, C-J, Chen, C-H, Chen, B-M, Su, Y-C, Chen, Y-T, Hershfield, MS, Lee, M-TM, Cheng, T-L, Chen, Y-T, Roffler, SR, and Wu, J-Y. "A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol." Nature communications 8, no. 1 (September 12, 2017): 522-.

PMID
28900105
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Schepp, J, Proietti, M, Frede, N, Buchta, M, Hübscher, K, Rojas Restrepo, J, Goldacker, S, Warnatz, K, Pachlopnik Schmid, J, Duppenthaler, A, Lougaris, V, Uriarte, I, Kelly, S, Hershfield, M, and Grimbacher, B. "Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood." Arthritis & rheumatology (Hoboken, N.J.) 69, no. 8 (August 2017): 1689-1700.

PMID
28493328
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Turel, O, Aygun, D, Kardas, M, Torun, E, Hershfield, M, and Camcıoglu, Y. "A case of severe combined immunodeficiency caused by adenosine deaminase deficiency with a new mutation." Pediatrics & Neonatology (July 2017).

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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, P-Y, 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, and Hershfield, M et al. "Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency." The Journal of clinical investigation 127, no. 5 (May 2017): 1689-1699.

PMID
28346229
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