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

Schepp, Johanna, Alla Bulashevska, Wilma Mannhardt-Laakmann, Hongzhi Cao, Fang Yang, Maximilian Seidl, Susan Kelly, Michael Hershfield, and Bodo Grimbacher. “Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency.” J Clin Immunol 36, no. 3 (April 2016): 179–86. https://doi.org/10.1007/s10875-016-0245-x.

PMID
26922074
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Kiykim, A., I. E. Simsek, E. Kiykim, E. Karakoc-Aydiner, S. Baris, A. O. Ozen, M. Aydogan, I. Santisteban, M. Hershfield, and I. Barlan. “Two patients with novel missense mutation in the purine nucleoside phosphorylase gene without serious or recurrent infections.” Clinical and Experimental Neuroimmunology 7, no. 1 (February 1, 2016): 79–82. https://doi.org/10.1111/cen3.12254.

Full Text

Akar, H. H., T. Patiroglu, M. Hershfield, and M. Van Der Burg. “Combined immunodeficiencies: Twenty years experience from a single center in Turkey.” Central European Journal of Immunology 41, no. 1 (January 1, 2016): 107–15. https://doi.org/10.5114/ceji.2015.56168.

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Saito, Y., L. K. Stamp, K. E. Caudle, M. S. Hershfield, E. M. McDonagh, J. T. Callaghan, W. Tassaneeyakul, et al. “Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update.” Clin Pharmacol Ther 99, no. 1 (January 2016): 36–37. https://doi.org/10.1002/cpt.161.

PMID
26094938
Full Text

Tartibi, Hana M., Michael S. Hershfield, and Sami L. Bahna. “A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient.” Pediatrics 137, no. 1 (January 2016). https://doi.org/10.1542/peds.2015-2169.

PMID
26684479
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Qi, Yizhi, Antonina Simakova, Nancy J. Ganson, Xinghai Li, Kelli M. Luginbuhl, Imran Özer, Wenge Liu, Michael S. Hershfield, Krzysztof Matyjaszewski, and Ashutosh Chilkoti. “A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity.” Nat Biomed Eng 1 (2016). https://doi.org/10.1038/s41551-016-0002.

PMID
28989813
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Komarow, Hirsh D., Robert Sokolic, Michael S. Hershfield, Donald B. Kohn, Michael Young, Dean D. Metcalfe, and Fabio Candotti. “Impulse oscillometry identifies peripheral airway dysfunction in children with adenosine deaminase deficiency.” Orphanet J Rare Dis 10 (December 18, 2015): 159. https://doi.org/10.1186/s13023-015-0365-z.

PMID
26682746
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Nakazawa, Yumiko, Toshinao Kawai, Toru Uchiyama, Fumihiro Goto, Nobuyuki Watanabe, Takanobu Maekawa, Akira Ishiguro, et al. “Effects of enzyme replacement therapy on immune function in ADA deficiency patient.” Clin Immunol 161, no. 2 (December 2015): 391–93. https://doi.org/10.1016/j.clim.2015.06.011.

PMID
26122173
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Baffelli, Renata, Lucia D. Notarangelo, Luisa Imberti, Michael S. Hershfield, Federico Serana, Ines Santisteban, Federica Bolda, Fulvio Porta, and Arnalda Lanfranchi. “Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience.” J Clin Immunol 35, no. 7 (October 2015): 624–37. https://doi.org/10.1007/s10875-015-0191-z.

PMID
26376800
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Ombrello, A., D. Stone, P. Hoffmann, A. Jones, B. Barham, K. Barron, W. Flegel, et al. “The deficiency of adenosine deaminase type 2-results of therapeutic intervention.” Pediatric Rheumatology, September 28, 2015. https://doi.org/10.1186/1546-0096-13-S1-O40.

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