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

Reinhardt, Bryanna, Omar Habib, Kit L. Shaw, Elizabeth Garabedian, Denise A. Carbonaro-Sarracino, Dayna Terrazas, Beatriz Campo Fernandez, et al. “Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency.” In Blood, 138:1304–16, 2021. https://doi.org/10.1182/blood.2020010260.

PMID
33974038
Full Text

Baloh, Carolyn H., Samiksha A. Borkar, Kai-Fen Chang, Jiqiang Yao, Michael S. Hershfield, Suhag H. Parikh, Donald B. Kohn, Maureen M. Goodenow, John W. Sleasman, and Li Yin. “Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy.” Journal of Clinical Immunology 41, no. 7 (October 2021): 1597–1606. https://doi.org/10.1007/s10875-021-01034-2.

PMID
34184208
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Hashem, Hasan, Giorgia Bucciol, Seza Ozen, Sule Unal, Ikbal Ok Bozkaya, Nurten Akarsu, Mervi Taskinen, et al. “Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.” J Clin Immunol 41, no. 7 (October 2021): 1633–47. https://doi.org/10.1007/s10875-021-01098-0.

PMID
34324127
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Ferriani, Mariana P. L., Elvis T. Valera, Graziella R. de Sousa, Paula Sandrin-Garcia, Ronald R. de Moura, Michel S. Hershfield, and Luciana M. de Carvalho. “ADA2 deficiency (DADA2) associated with Evans syndrome and a severe ADA2 genotype.” Rheumatology (Oxford) 60, no. 7 (July 1, 2021): e237–39. https://doi.org/10.1093/rheumatology/keab011.

PMID
33493352
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Kohn, Donald B., Claire Booth, Kit L. Shaw, Jinhua Xu-Bayford, Elizabeth Garabedian, Valentina Trevisan, Denise A. Carbonaro-Sarracino, et al. “Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.” N Engl J Med 384, no. 21 (May 27, 2021): 2002–13. https://doi.org/10.1056/NEJMoa2027675.

PMID
33974366
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Jee, Hyuk, Zhengping Huang, Samantha Baxter, Yuelong Huang, Maria L. Taylor, Lauren A. Henderson, Sofia Rosenzweig, et al. “Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach.” J Allergy Clin Immunol, May 15, 2021. https://doi.org/10.1016/j.jaci.2021.04.034.

PMID
34004258
Full Text

Brooks, Joel P., Andrew J. Rice, Weizhen Ji, Stephen M. Lanahan, Monica Konstantino, Jasmeen Dara, Michael S. Hershfield, et al. “Uncontrolled Epstein-Barr Virus as an Atypical Presentation of Deficiency in ADA2 (DADA2).” J Clin Immunol 41, no. 3 (April 2021): 680–83. https://doi.org/10.1007/s10875-020-00940-1.

PMID
33394316
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Schnappauf, Oskar, Natalia Sampaio Moura, Ivona Aksentijevich, Monique Stoffels, Amanda K. Ombrello, Patrycja Hoffmann, Karyl Barron, et al. “Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2.” Arthritis Rheumatol 73, no. 3 (March 2021): 512–19. https://doi.org/10.1002/art.41549.

PMID
33021335
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Betrains, A., F. Staels, L. Moens, S. Delafontaine, M. S. Hershfield, D. Blockmans, A. Liston, et al. “Diagnosis of deficiency of adenosine deaminase type 2 in adulthood.” Scand J Rheumatol, February 25, 2021, 1–4. https://doi.org/10.1080/03009742.2021.1881156.

PMID
33627040
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Sharma, Aman, Gsrsnk Naidu, Vikas Sharma, Saket Jha, Aaadhar Dhooria, Varun Dhir, Prateek Bhatia, et al. “Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.” Arthritis Rheumatol 73, no. 2 (February 2021): 276–85. https://doi.org/10.1002/art.41500.

PMID
32892503
Full Text

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