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

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
Full Text

Lee, Pui Y., Yuelong Huang, Qing Zhou, Oskar Schnappauf, Michael S. Hershfield, Ying Li, Nancy J. Ganson, et al. “Disrupted N-linked glycosylation as a disease mechanism in deficiency of ADA2.” J Allergy Clin Immunol 142, no. 4 (October 2018): 1363-1365.e8. https://doi.org/10.1016/j.jaci.2018.05.038.

PMID
29936104
Full Text

Van Nieuwenhove, Erika, Stephanie Humblet-Baron, Lien Van Eyck, Lien De Somer, James Dooley, Thomas Tousseyn, Michael Hershfield, Adrian Liston, and Carine Wouters. “ADA2 Deficiency Mimicking Idiopathic Multicentric Castleman Disease.” Pediatrics 142, no. 3 (September 2018). https://doi.org/10.1542/peds.2017-2266.

PMID
30139808
Full Text

Cagdas, Deniz, Pınar Gur Cetinkaya, Betül Karaatmaca, Saliha Esenboga, Cagman Tan, Togay Yılmaz, Ersin Gümüş, et al. “ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome.” J Clin Immunol 38, no. 4 (May 2018): 484–93. https://doi.org/10.1007/s10875-018-0496-9.

PMID
29744787
Full Text

Trotta, Luca, Timi Martelius, Timo Siitonen, Timo Hautala, Sari Hämäläinen, Hanna Juntti, Mervi Taskinen, et al. “ADA2 deficiency: Clonal lymphoproliferation in a subset of patients.” J Allergy Clin Immunol 141, no. 4 (April 2018): 1534-1537.e8. https://doi.org/10.1016/j.jaci.2018.01.012.

PMID
29391253
Full Text

Turel, Ozden, Deniz Aygun, Murat Kardas, Emel Torun, Micheal Hershfield, and Yıldız Camcıoglu. “A case of severe combined immunodeficiency caused by adenosine deaminase deficiency with a new mutation.” Pediatr Neonatol 59, no. 1 (February 2018): 97–99. https://doi.org/10.1016/j.pedneo.2016.10.008.

PMID
28823388
Full Text

Barzaghi, Federica, Federica Minniti, Margherita Mauro, Massimiliano De Bortoli, Rita Balter, Elisa Bonetti, Ada Zaccaron, et al. “ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation.” Front Immunol 9 (2018): 2767. https://doi.org/10.3389/fimmu.2018.02767.

PMID
30692987
Full Text

Hashem, Hasan, Ashish R. Kumar, Ingo Müller, Florian Babor, Robbert Bredius, Jignesh Dalal, Amy P. Hsu, et al. “Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2.” Blood 130, no. 24 (December 14, 2017): 2682–88. https://doi.org/10.1182/blood-2017-07-798660.

PMID
28974505
Full Text

Bucciol, Giorgia, Selket Delafontaine, Heidi Segers, Xavier Bossuyt, Michael S. Hershfield, Leen Moens, and Isabelle Meyts. “Hematopoietic Stem Cell Transplantation in ADA2 Deficiency: Early Restoration of ADA2 Enzyme Activity and Disease Relapse upon Drop of Donor Chimerism.” J Clin Immunol 37, no. 8 (November 2017): 746–50. https://doi.org/10.1007/s10875-017-0449-8.

PMID
28993957
Full Text

Hashem, H., A. Vatsayan, A. Gupta, K. Nagle, M. Hershfield, and J. Dalal. “Successful reduced intensity hematopoietic cell transplant in a patient with deficiency of adenosine deaminase 2.” Bone Marrow Transplant 52, no. 11 (November 2017): 1575–76. https://doi.org/10.1038/bmt.2017.173.

PMID
28805790
Full Text

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