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

Otsu, Makoto, Masafumi Yamada, Satoru Nakajima, Miyuki Kida, Yoshihiro Maeyama, Norikazu Hatano, Nariaki Toita, et al. “Outcomes in two Japanese adenosine deaminase-deficiency patients treated by stem cell gene therapy with no cytoreductive conditioning.” J Clin Immunol 35, no. 4 (May 2015): 384–98. https://doi.org/10.1007/s10875-015-0157-1.

PMID
25875699
Full Text

Shaw, Kit L., Elizabeth Garabedian, Rob Sokolic, Provaboti Barman, Alejandra Davila, Christopher Silvin, Satiro de Oliveira, et al. “30. Phase II Clinical Trial of Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA-SCID) Using a γ-Retroviral Vector.” In Molecular Therapy, 23:S13–14. Elsevier BV, 2015. https://doi.org/10.1016/s1525-0016(16)33634-6.

Full Text

Celmeli, Fatih, Doga Turkkahraman, Vedat Uygun, Giancarlo la Marca, Michael Hershfield, and Akif Yesilipek. “A successful unrelated peripheral blood stem cell transplantation with reduced intensity-conditioning regimen in a patient with late-onset purine nucleoside phosphorylase deficiency.” Pediatr Transplant 19, no. 2 (March 2015): E47–50. https://doi.org/10.1111/petr.12413.

PMID
25514831
Full Text

Van Eyck, Lien, Michael S. Hershfield, Diana Pombal, Susan J. Kelly, Nancy J. Ganson, Leen Moens, Glynis Frans, et al. “Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency.” J Allergy Clin Immunol 135, no. 1 (January 2015): 283-7.e5. https://doi.org/10.1016/j.jaci.2014.10.010.

PMID
25457153
Full Text

Van Eyck, L., M. S. Hershfield, D. Pombal, S. J. Kelly, N. J. Ganson, L. Moens, G. Frans, et al. “HSCT Rescues the Immunological and Vascular Phenotype of ADA2-Deficiency.” In Journal of Clinical Immunology, 34:S196–97. SPRINGER/PLENUM PUBLISHERS, 2014.

Scholars@Duke

Celmeli, Fatih, Giancarlo la Marca, Ines Santisteban, and Michael S. Hershfield. “LATE-ONSET PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY WITH SPASTIC PARAPLEGIA.” In Journal of Clinical Immunology, 34:717–18. SPRINGER/PLENUM PUBLISHERS, 2014.

Scholars@Duke

Celmeli, Fatih, Giancarlo la Marca, Ines Santisteban, and Michael S. Hershfield. “LATE-ONSET PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY WITH SPASTIC PARAPLEGIA.” In Journal of Clinical Immunology, 34:717–18. SPRINGER/PLENUM PUBLISHERS, 2014.

Scholars@Duke

Marca, Giancarlo la, Clementina Canessa, Elisa Giocaliere, Francesca Romano, Sabrina Malvagia, Silvia Funghini, Maria Moriondo, et al. “Diagnosis of immunodeficiency caused by a purine nucleoside phosphorylase defect by using tandem mass spectrometry on dried blood spots.” J Allergy Clin Immunol 134, no. 1 (July 2014): 155–59. https://doi.org/10.1016/j.jaci.2014.01.040.

PMID
24767876
Full Text

Shaw, Kit L., Robert Sokolic, Alejandra Davila, Christopher Silvin, Elizabeth Garabedian, Satiro de Oliveira, Provaboti Barman, et al. “Phase II Clinical Trial of Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA-SCID).” In Molecular Therapy, 22:S107–S107. NATURE PUBLISHING GROUP, 2014.

Scholars@Duke

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