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

Komarow, Hirsh, Robert Sokolic, Michael Young, Elizabeth Garabedian, Kenneth N. Olivier, Michael S. Hershfield, Dean D. Metcalfe, and Fabio Candotti. “Impulse Oscillometry (IOS) Reveals Increased Pulmonary Impedence in Children with Adenosine Deaminase-Deficient Severe Combined Immunodeficiency (ADA-SCID).” In Journal of Clinical Immunology, 34:359–359. SPRINGER/PLENUM PUBLISHERS, 2014.

Scholars@Duke

Hershfield, Michael S., Nancy J. Ganson, Susan J. Kelly, Edna L. Scarlett, Denise A. Jaggers, and John S. Sundy. “Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients.” Arthritis Res Ther 16, no. 2 (March 7, 2014): R63. https://doi.org/10.1186/ar4500.

PMID
24602182
Full Text

Hershfield, M. S., N. J. Ganson, S. J. Kelly, E. L. Scarlett, D. A. Jaggers, and J. S. Sundy. “Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients.” Arthritis Research and Therapy 16, no. 2 (March 7, 2014). https://doi.org/10.1186/ar4500.

Full Text

Zhou, Qing, Dan Yang, Amanda K. Ombrello, Andrey V. Zavialov, Camilo Toro, Anton V. Zavialov, Deborah L. Stone, et al. “Early-onset stroke and vasculopathy associated with mutations in ADA2.” N Engl J Med 370, no. 10 (March 6, 2014): 911–20. https://doi.org/10.1056/NEJMoa1307361.

PMID
24552284
Full Text

Lawrence, Monica G., John S. Barber, Robert A. Sokolic, Elizabeth K. Garabedian, Avanti N. Desai, Michelle O’Brien, Nina Jones, et al. “Elevated IgE and atopy in patients treated for early-onset ADA-SCID.” J Allergy Clin Immunol 132, no. 6 (December 2013): 1444–46. https://doi.org/10.1016/j.jaci.2013.05.040.

PMID
23895897
Full Text

Tartibi, H. M., M. S. Hershfield, and S. L. Bahna. “A 22-YEAR REPLACEMENT THERAPY FOR AN ADENOSINE DEAMINASE (ADA) DEFICIENT PATIENT.” In Annals of Allergy Asthma & Immunology, 111:A97–98. ELSEVIER SCIENCE INC, 2013.

Scholars@Duke

Marca, Giancarlo la, Clementina Canessa, Elisa Giocaliere, Francesca Romano, Marzia Duse, Sabrina Malvagia, Francesca Lippi, et al. “Tandem mass spectrometry, but not T-cell receptor excision circle analysis, identifies newborns with late-onset adenosine deaminase deficiency.” J Allergy Clin Immunol 131, no. 6 (June 2013): 1604–10. https://doi.org/10.1016/j.jaci.2012.08.054.

PMID
23280131
Full Text

Sundy, J. S., N. Gansen, S. Kelly, E. Scarlett, D. Jaggers, and M. S. Hershfield. “FRI0390 DUKE-3: A 15-week open-label trial of pegloticase in refractory gout including patients with solid organ transplant or prior pegloticase treatment.” In Annals of the Rheumatic Diseases, 71:446.2-446. BMJ, 2013. https://doi.org/10.1136/annrheumdis-2012-eular.2847.

Full Text

Hershfield, M. S., N. J. Ganson, S. J. Kelly, E. L. Scarlett, D. A. Jaggers, and J. S. Sundy. “FRI0372 Pharmacokinetics and immunogenicity of pegloticase (PL) infused every 3 weeks to treat refractory gout (RG), including in organ transplant recipients (TR).” In Annals of the Rheumatic Diseases, 71:440.1-440. BMJ, 2013. https://doi.org/10.1136/annrheumdis-2012-eular.2829.

Full Text

Borte, Stephan, Jennifer Puck, Fred Lorey, Sean A. McGhee, Michael S. Hershfield, Anders Fasth, Hirokazu Kanegane, Stephan Ehl, and Carsten Speckmann. “KRECs BUT NOT TRECs IDENTIFY PATIENTS WITH DELAYED- ONSET ADENOSINE DEAMINASE (ADA) DEFICIENCY IN NEONATAL SCREENING.” Journal of Clinical Immunology 33, no. 3 (April 1, 2013): 673–673.

Scholars@Duke

Pages