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

Moreno, Angelo, George A. Pitoc, Nancy J. Ganson, Juliana M. Layzer, Michael S. Hershfield, Alice F. Tarantal, and Bruce A. Sullenger. “Anti-PEG Antibodies Inhibit the Anticoagulant Activity of PEGylated Aptamers..” Cell Chem Biol 26, no. 5 (May 16, 2019): 634-644.e3. https://doi.org/10.1016/j.chembiol.2019.02.001.

PMID
30827937
Full Text

Ombrello, Amanda K., Jing Qin, Patrycja M. Hoffmann, Parag Kumar, Deborah Stone, Anne Jones, Tina Romeo, et al. “Treatment Strategies for Deficiency of Adenosine Deaminase 2..” N Engl J Med 380, no. 16 (April 18, 2019): 1582–84. https://doi.org/10.1056/NEJMc1801927.

PMID
30995379
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Joh, Daniel Y., Zackary Zimmers, Manav Avlani, Jacob T. Heggestad, Hakan B. Aydin, Nancy Ganson, Shourya Kumar, et al. “Architectural Modification of Conformal PEG-Bottlebrush Coatings Minimizes Anti-PEG Antigenicity While Preserving Stealth Properties..” Adv Healthc Mater 8, no. 8 (April 2019). https://doi.org/10.1002/adhm.201801177.

PMID
30908902
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Bursill, David, William J. Taylor, Robert Terkeltaub, Masanari Kuwabara, Tony R. Merriman, Rebecca Grainger, Carlos Pineda, et al. “Gout, Hyperuricemia, and Crystal-Associated Disease Network Consensus Statement Regarding Labels and Definitions for Disease Elements in Gout..” Arthritis Care Res (Hoboken) 71, no. 3 (March 2019): 427–34. https://doi.org/10.1002/acr.23607.

PMID
29799677
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Kohn, Donald B., Michael S. Hershfield, Jennifer M. Puck, Alessandro Aiuti, Annaliesse Blincoe, H Bobby Gaspar, Luigi D. Notarangelo, and Eyal Grunebaum. “Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency..” J Allergy Clin Immunol 143, no. 3 (March 2019): 852–63. https://doi.org/10.1016/j.jaci.2018.08.024.

PMID
30194989
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Moens, Leen, Michael Hershfield, Katrijn Arts, Ivona Aksentijevich, and Isabelle Meyts. “Human adenosine deaminase 2 deficiency: A multi-faceted inborn error of immunity..” Immunol Rev 287, no. 1 (January 2019): 62–72. https://doi.org/10.1111/imr.12722.

PMID
30565235
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Alabbas, Fahad, Ghaleb Elyamany, Omar Alsharif, Michael Hershfield, and Isabelle Meyts. “Childhood Hodgkin Lymphoma: Think DADA2..” J Clin Immunol 39, no. 1 (January 2019): 26–29. https://doi.org/10.1007/s10875-019-0590-7.

PMID
30644014
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Claassen, David, Michelle Boals, Kevin M. Bowling, Gregory M. Cooper, Jennifer Cox, Michael Hershfield, Sara Lewis, Marcin Wlodarski, Mitchell J. Weiss, and Jeremie H. Estepp. “Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia..” Cold Spring Harb Mol Case Stud 4, no. 6 (December 2018). https://doi.org/10.1101/mcs.a003384.

PMID
30559313
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Kisla Ekinci, Rabia Miray, Sibel Balci, Atil Bisgin, Michael Hershfield, Bahriye Atmis, Dilek Dogruel, and Mustafa Yilmaz. “Renal Amyloidosis in Deficiency of Adenosine Deaminase 2: Successful Experience With Canakinumab..” Pediatrics 142, no. 5 (November 2018). https://doi.org/10.1542/peds.2018-0948.

PMID
30377239
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Arts, Katrijn, Jenna R. E. Bergerson, Amanda K. Ombrello, Morgan Similuk, Andrew J. Oler, Anahita Agharahimi, Emily M. Mace, et al. “Warts and DADA2: a Mere Coincidence?.” J Clin Immunol 38, no. 8 (November 2018): 836–43. https://doi.org/10.1007/s10875-018-0565-0.

PMID
30386947
Full Text

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