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

Hashem, Hasan, Susan J. Kelly, Nancy J. Ganson, and Michael S. Hershfield. “Deficiency of Adenosine Deaminase 2 (DADA2), an Inherited Cause of Polyarteritis Nodosa and a Mimic of Other Systemic Rheumatologic Disorders.” Curr Rheumatol Rep 19, no. 11 (October 5, 2017): 70. https://doi.org/10.1007/s11926-017-0699-8.

PMID
28983775
Full Text

Chang, Chia-Jung, Chien-Hsiun Chen, Bing-Mae Chen, Yu-Cheng Su, Ying-Ting Chen, Michael S. Hershfield, Ming-Ta Michael Lee, et al. “A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol.” Nat Commun 8, no. 1 (September 12, 2017): 522. https://doi.org/10.1038/s41467-017-00622-4.

PMID
28900105
Full Text

Skrabl-Baumgartner, Andrea, Barbara Plecko, Wolfgang M. Schmidt, Nadja König, Michael Hershfield, Ursula Gruber-Sedlmayr, and Min Ae Lee-Kirsch. “Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation.” Pediatr Rheumatol Online J 15, no. 1 (August 22, 2017): 67. https://doi.org/10.1186/s12969-017-0193-x.

PMID
28830446
Full Text

Schepp, Johanna, Michele Proietti, Natalie Frede, Mary Buchta, Katrin Hübscher, Jessica Rojas Restrepo, Sigune Goldacker, et al. “Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood.” Arthritis Rheumatol 69, no. 8 (August 2017): 1689–1700. https://doi.org/10.1002/art.40147.

PMID
28493328
Full Text

Shaw, Kit L., Elizabeth Garabedian, Suparna Mishra, Provaboti Barman, Alejandra Davila, Denise Carbonaro, Sally Shupien, et al. “Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency.” J Clin Invest 127, no. 5 (May 1, 2017): 1689–99. https://doi.org/10.1172/JCI90367.

PMID
28346229
Full Text

Ben-Ami, Tal, Shoshana Revel-Vilk, Rebecca Brooks, Avraham Shaag, Michael S. Hershfield, Susan J. Kelly, Nancy J. Ganson, et al. “Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency.” J Pediatr 177 (October 2016): 316–20. https://doi.org/10.1016/j.jpeds.2016.06.058.

PMID
27514238
Full Text

Hsu, Amy P., Robert R. West, Katherine R. Calvo, Jennifer Cuellar-Rodriguez, Mark Parta, Susan J. Kelly, Nancy J. Ganson, Michael S. Hershfield, Steven M. Holland, and Dennis D. Hickstein. “Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: Successful hematopoietic stem cell transplantation.” J Allergy Clin Immunol 138, no. 2 (August 2016): 628-630.e2. https://doi.org/10.1016/j.jaci.2016.03.016.

PMID
27130863
Full Text

Keer, Nikky, Michael Hershfield, Thomas Caskey, and Sebastian Unizony. “Novel compound heterozygous variants in CECR1 gene associated with childhood onset polyarteritis nodosa and deficiency of ADA2.” Rheumatology (Oxford) 55, no. 6 (June 2016): 1145–47. https://doi.org/10.1093/rheumatology/kew050.

PMID
27069017
Full Text

Ganson, Nancy J., Thomas J. Povsic, Bruce A. Sullenger, John H. Alexander, Steven L. Zelenkofske, Jeffrey M. Sailstad, Christopher P. Rusconi, and Michael S. Hershfield. “Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer.” J Allergy Clin Immunol 137, no. 5 (May 2016): 1610-1613.e7. https://doi.org/10.1016/j.jaci.2015.10.034.

PMID
26688515
Full Text

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
Full Text

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