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

Candotti, F., K. L. Shaw, R. Sokolic, D. Carbonaro, L. Muul, S. Mishra, E. Garabedian, et al. “US RESULTS OF GENE THERAPY FOR ADENOSINE DEAMINASE DEFICIENCY.” In Journal of Clinical Immunology, 32:130–130. SPRINGER/PLENUM PUBLISHERS, 2012.

Scholars@Duke

大倉有. 加., 山田雅. 文., 小林一. 郎., I. SANTISTEBAN, G. ARREDONDO-SANTISTEBAN, 善一郎加. 藤., 井口晶. 裕., et al. “ADA酵素蛋白の安定性を相乗的に阻害する"WAZA-ARI"変異を認めたADA欠損症の1例.” 北海道醫學雜誌 = Acta Medica Hokkaidonensia 87, no. 4 (August 1, 2012).

Scholars@Duke

Nakaoka, Hideyuki, Hirokazu Kanegane, Hiromichi Taneichi, Kazushi Miya, Xi Yang, Keiko Nomura, Shunichiro Takezaki, et al. “Delayed onset adenosine deaminase deficiency associated with acute disseminated encephalomyelitis.” Int J Hematol 95, no. 6 (June 2012): 692–96. https://doi.org/10.1007/s12185-012-1055-4.

PMID
22447032
Full Text

Sokolic, Robert, Linda Muul, Elizabeth Garabedian, Kit Shaw, Michael S. Hershfield, Alan S. Wayne, Donald B. Kohn, and Fabio Candotti. “Systemic Effects of PEG-ADA Withdrawal with or Without Chemotherapy (CHTX) and Cytotherapy (CTX) in Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA-SCID).” In Journal of Clinical Immunology, 32:404–404. SPRINGER/PLENUM PUBLISHERS, 2012.

Scholars@Duke

Moncada-Vélez, M., A. Vélez-Ortega, J. Orrego, I. Santisteban, J. Jagadeesh, M. Olivares, N. Olaya, M. Hershfield, F. Candotti, and J. Franco. “Somatic mosaicism caused by monoallelic reversion of a mutation in T cells of a patient with ADA-SCID and the effects of enzyme replacement therapy on the revertant phenotype.” Scand J Immunol 74, no. 5 (November 2011): 471–81. https://doi.org/10.1111/j.1365-3083.2011.02593.x.

PMID
21671975
Full Text

Sokolic, Robert, Irina Maric, Chimene Kesserwan, Elizabeth Garabedian, I Celine Hanson, Margaret Dodds, Rebecca Buckley, et al. “Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency.” Blood 118, no. 10 (September 8, 2011): 2688–94. https://doi.org/10.1182/blood-2011-01-329359.

PMID
21725047
Full Text

Okura, Yuka, Masafumi Yamada, Ichiro Kobayashi, Ines Santisteban, Gabriella Arredondo-Santisteban, Zenichiro Kato, Akihiro Iguchi, et al. “ADA-SCID with 'WAZA-ARI' mutations that synergistically abolished ADA protein stability.” Br J Haematol 153, no. 5 (June 2011): 675–76. https://doi.org/10.1111/j.1365-2141.2011.08640.x.

PMID
21410451
Full Text

Denoble, Anna E., Kim M. Huffman, Thomas V. Stabler, Susan J. Kelly, Michael S. Hershfield, Gary E. McDaniel, R Edward Coleman, and Virginia B. Kraus. “Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.” Proc Natl Acad Sci U S A 108, no. 5 (February 1, 2011): 2088–93. https://doi.org/10.1073/pnas.1012743108.

PMID
21245324
Full Text

Hershfield, Michael S., L Jackson Roberts, Nancy J. Ganson, Susan J. Kelly, Ines Santisteban, Edna Scarlett, Denise Jaggers, and John S. Sundy. “Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo.” Proc Natl Acad Sci U S A 107, no. 32 (August 10, 2010): 14351–56. https://doi.org/10.1073/pnas.1001072107.

PMID
20660758
Full Text

Artac, Hasibe, Bahar Göktürk, Sefika Elmas Bozdemir, Hatice Toy, Mirjam van der Burg, Ines Santisteban, Michael Hershfield, and Ismail Reisli. “Late-onset adenosine deaminase deficiency presenting with Heck's disease.” Eur J Pediatr 169, no. 8 (August 2010): 1033–36. https://doi.org/10.1007/s00431-009-1131-9.

PMID
20039061
Full Text

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