Michael S. Hershfield, MD

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• Rheumatology and Immunology

Department / Division:
Medicine / Rheumatology and Immunology

Address:
DUMC 3049
Durham, NC 27710

Office Telephone:
(919) 684-4184

Fax Telephone:
(919) 684-4168

• M.D., University of Pennsylvania, 1967

• Internal Medicine, University of California, 1974-1975
• Rheumatology, University of California, 1972-1976

Clinical Interests:
Inherited disorders of purine metabolism; gout

Research Interests:
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 patients and in collaboarative studies of knockout mice.In the past five years we have examined the molecular basis for the interaction between ADA and the cell membrane associated multifunctional glycoprotein, Dipeptidyl Peptidase IV (DPPIV), also known as the adenosine deaminase complexing protein. Our work has shed light on the postulated essential role of the ecto-ADA formed by the ADA-DPPIV complex for normal immune function.

More than 15 years ago we initiated, and have 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, and the first effective form of enzyme replacement therapy for an inherited metabolic disease. We currently monitor the metabolic effects of PEG-ADA therapy and the immunologic response to the PEG-modified enzyme in patients with ADA deficiency in the US and over 15 other countries. We have collaborated in defining the ontogeny of immune reconstitution during enzyme replacement. We have also collaboarated in evaluating combined PEG-ADA/umbilical cord stem cell gene therapy for ADA deficiency. Becasue of the relatively large number of patients with this rare disorder whom we diagnose and monitor, we have been able to systematically investigate the mutational basis for ADA deficiency, and the relationship between genotype and phenotype. We have written several reviews on the treatment of ADA deficiency, and major textbook chapters dealing with ADA and PNP deficiency, and other inherited diseases of purine metabolism.

For the past decade we have been engaged in translational research to develop a PEG-modified urate oxidase as an Orphan Drug for treating patients with refractory gout and poorly controlled hyperuricemia. We demonstrated the effectiveness of PEG-uricase therapy in preventing uric acid nephropathy in a urate oxidase knockout mouse model, and have participated with other members of the Duke Rheumatology division in two phase I clinical trials of PEG-uricase in subjects with refractory gout. We are now involved in a Phase II clinical study of PEG-uricase in patients with refractory gout that is supported by a grant from the USFDA Office of Orphan Products Development. In connection with this study we are evaluating a method for determining the effect of PEG-uricase therapy on uric acid pool size.


Keywords: human genetic disease; enzyme replacement therapy; polyethylene glycol modified enzymes; mutation; immune deficiency disease; ADA deficiency; purine nucleoside phosphorylase deficiency; gout

Representative Publications:
Thompson LF, Van de Wiele CJ, Laurent AB, Hooker SW, Vaughn JG, Jiang H, Khare K, Kellems RE, Blackburn MR, Hershfield MS, Resta R. Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase-deficient fetal thymic organ cultures. J Clin Invest. 2000 Nov;106(9):1149-57. (2000) Abstract

Hershfield MS. Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy. Semin Hematol. 1998 Oct;35(4):291-8. (1998) Abstract

Hershfield MS. On the role of deoxyribonucleic acid polymerase in determining mutation rates. Characterization of the defect in the T4 deoxyribonucleic acid polymerase caused by the ts L88 mutation. J Biol Chem. 1973 Feb 25;248(4):1417-23. (1973) Abstract

Migchielsen AA, Knaän-Schanzer S, Breuer ML, Hershfield MS, Valerio D. Generation of normal lymphocyte populations following transplantation of adenosine-deaminase-deficient fetal liver cells. Bone Marrow Transplant. 1997 Jun;19(11):1137-43. (1997) Abstract

Hershfield MS, Kredich NM. S-Adenosylhomocysteine metabolism in adenosine deaminase deficient cells. Adv Exp Med Biol. 1980;122A:421-5. (1980) Abstract

Hershfield MS. Apparent suicide inactivation of human lymphoblast S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine and adenine arabinoside. A basis for direct toxic effects of analogs of adenosine. J Biol Chem. 1979 Jan 10;254(1):22-5. (1979) Abstract

Hershfield MS, Nossal NG. In vitro characterization of a mutator T4 DNA polymerase. Genetics. 1973 Apr;73:Suppl 73:131-6. (1973) Abstract

Hershfield MS, Francke U. The human genes for S-adenosylhomocysteine hydrolase and adenosine deaminase are syntenic on chromosome 20. Science. 1982 May 14;216(4547):739-42. (1982) Abstract

Kredich NM, Hershfield MS. Perturbations in S-adenosylhomocysteine and S-adenosylmethionine metabolism: effects on transmethylation. Adv Enzyme Regul. 1980;18:181-91. (1980) Abstract

Hershfield MS, Snyder FF, Seegmiller JE. Adenine and adenosine are toxic to human lymphoblast mutants defective in purine salvage enzymes. Science. 1977 Sep 23;197(4310):1284-7. (1977) Abstract

Greenberg ML, Chaffee S, Hershfield MS. Basis for resistance to 3-deazaaristeromycin, an inhibitor of S-adenosylhomocysteine hydrolase, in human B-lymphoblasts. J Biol Chem. 1989 Jan 15;264(2):795-803. (1989) Abstract

Coulter-Karis DE, Hershfield MS. Sequence of full length cDNA for human S-adenosylhomocysteine hydrolase. Ann Hum Genet. 1989 May;53 ( Pt 2):169-75. (1989) Abstract

Kohn DB, Weinberg KI, Nolta JA, Heiss LN, Lenarsky C, Crooks GM, Hanley ME, Annett G, Brooks JS, el-Khoureiy A, Hershfield MS, et al. Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency.  Nature Medicine.  1995 Oct;1(10):1017-23. (1995) Abstract

Nossal NG, Hershfield MS. Nuclease activity in a fragment of bacteriophage T4 deoxyribonucleic acid polymerase induced by the amber mutant am B22. J Biol Chem. 1971 Sep 10;246(17):5414-26. (1971) Abstract

Hershfield MS, Fetter JE, Small WC, Bagnara AS, Williams SR, Ullman B, Martin DW Jr, Wasson DB, Carson DA. Effects of mutational loss of adenosine kinase and deoxycytidine kinase on deoxyATP accumulation and deoxyadenosine toxicity in cultured CEM human T-lymphoblastoid cells. J Biol Chem. 1982 Jun 10;257(11):6380-6. (1982) Abstract

Hershfield MS, Krodich NM. S-adenosylhomocysteine hydrolase is an adenosine-binding protein: a target for adenosine toxicity. Science. 1978 Nov 17;202(4369):757-60. (1978) Abstract

Kurtzberg J, Hershfield MS. Determinants of deoxyadenosine toxicity in hybrids between human T- and B- lymphoblasts as a model for the development of drug resistance in T-cell acute lymphoblastic leukemia. Cancer Res. 1985 Apr;45(4):1579-86. (1985) Abstract

Kohn DB, Hershfield MS, Carbonaro D, Shigeoka A, Brooks J, Smogorzewska EM, Barsky LW, Chan R, Burotto F, Annett G, Nolta JA, Crooks G, Kapoor N, Elder M, Wara D, Bowen T, Madsen E, Snyder FF, Bastian J, Muul L, Blaese RM, Weinberg K, Parkman R. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nat Med. 1998 Jul;4(7):775-80. (1998) Abstract

Hershfield MS, Kurtzberg J, Harden E, Moore JO, Whang-Peng J, Haynes BF. Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin. Proc Natl Acad Sci U S A. 1984 Jan;81(1):253-7. (1984) Abstract

Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS. Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet. 1998 Oct;63(4):1049-59. (1998) Abstract

Kelly SJ, Delnomdedieu M, Oliverio MI, Williams LD, Saifer MG, Sherman MR, Coffman TM, Johnson GA, Hershfield MS. Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase. J Am Soc Nephrol. 2001 May;12(5):1001-9. (2001) Abstract

Kredich NM, Hershfield MS. S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. Proc Natl Acad Sci U S A. 1979 May;76(5):2450-4. (1979) Abstract

Chua CC, Greenberg ML, Viau AT, Nucci M, Brenckman WD Jr, Hershfield MS. Use of polyethylene glycol-modified uricase (PEG-uricase) to treat hyperuricemia in a patient with non-Hodgkin lymphoma. Ann Intern Med. 1988 Jul 15;109(2):114-7. (1988) Abstract

Bagnara AS, Hershfield MS. Mechanism of deoxyadenosine-induced catabolism of adenine ribonucleotides in adenosine deaminase-inhibited human T lymphoblastoid cells. Proc Natl Acad Sci U S A. 1982 Apr;79(8):2673-7. (1982) Abstract

Ariga T, Oda N, Sanstisteban I, Arredondo-Vega FX, Shioda M, Ueno H, Terada K, Kobayashi K, Hershfield MS, Sakiyama Y. Molecular basis for paradoxical carriers of adenosine deaminase (ADA) deficiency that show extremely low levels of ADA activity in peripheral blood cells without immunodeficiency. J Immunol. 2001 Feb 1;166(3):1698-702. (2001) Abstract

Hershfield MS, Chaffee S, Sorensen RU. Enzyme replacement therapy with polyethylene glycol-adenosine deaminase in adenosine deaminase deficiency: overview and case reports of three patients, including two now receiving gene therapy. Pediatr Res. 1993 Jan;33(1 Suppl):S42-7; discussion S47-8. (1993) Abstract

Levy Y, Hershfield MS, Fernandez-Mejia C, Polmar SH, Scudiery D, Berger M, Sorensen RU. Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycol-modified adenosine deaminase. J Pediatr. 1988 Aug;113(2):312-7. (1988) Abstract

Weinberg K, Hershfield MS, Bastian J, Kohn D, Sender L, Parkman R, Lenarsky C. T lymphocyte ontogeny in adenosine deaminase-deficient severe combined immune deficiency after treatment with polyethylene glycol-modified adenosine deaminase. J Clin Invest. 1993 Aug;92(2):596-602. (1993) Abstract

Hershfield MS, Seegmiller JE. Regulation of de novo purine biosynthesis in human lymphoblasts. Coordinate control of proximal (rate-determining) steps and the inosinic acid branch point. J Biol Chem. 1976 Dec 10;251(23):7348-54. (1976) Abstract

Blackburn MR, Aldrich M, Volmer JB, Chen W, Zhong H, Kelly S, Hershfield MS, Datta SK, Kellems RE. The use of enzyme therapy to regulate the metabolic and phenotypic consequences of adenosine deaminase deficiency in mice. Differential impact on pulmonary and immunologic abnormalities. J Biol Chem. 2000 Oct 13;275(41):32114-21. (2000) Abstract

Kurtzberg J, Waldmann TA, Davey MP, Bigner SH, Moore JO, Hershfield MS, Haynes BF. CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells. Blood. 1989 Feb;73(2):381-90. (1989) Abstract

Arredondo-Vega FX, Santisteban I, Richard E, Bali P, Koleilat M, Loubser M, Al-Ghonaium A, Al-Helali M, Hershfield MS. Adenosine deaminase deficiency with mosaicism for a "second-site suppressor" of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy. Blood. 2002 Feb 1;99(3):1005-13. (2002) Abstract

Ariga T, Oda N, Yamaguchi K, Kawamura N, Kikuta H, Taniuchi S, Kobayashi Y, Terada K, Ikeda H, Hershfield MS, Kobayashi K, Sakiyama Y. T-cell lines from 2 patients with adenosine deaminase (ADA) deficiency showed the restoration of ADA activity resulted from the reversion of an inherited mutation. Blood. 2001 May 1;97(9):2896-9. (2001) Abstract

Hershfield MS, Buckley RH, Greenberg ML, Melton AL, Schiff R, Hatem C, Kurtzberg J, Markert ML, Kobayashi RH, Kobayashi AL. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N Engl J Med. 1987 Mar 5;316(10):589-96. (1987) Abstract

Hershfield MS, Kredich NM. Resistance of an adenosine kinase-deficient human lymphoblastoid cell line to effects of deoxyadenosine on growth, S-adenosylhomocysteine hydrolase inactivation, and dATP accumulation. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4292-6. (1980) Abstract

Van De Wiel CJ, Hooker SW, Laurent AB, Vaughn JG, Blackburn MR, Kellems RE, Hershfield MS, Thompson LF. Inhibition of fetal thymic caspases abrogates the consequences of adenosine deaminase deficiency. Adv Exp Med Biol. 2000;486:65-70. (2000) Abstract

Otsu M, Hershfield MS, Tuschong LM, Muul LM, Onodera M, Ariga T, Sakiyama Y, Candotti F. Flow cytometry analysis of adenosine deaminase (ADA) expression: a simple and reliable tool for the assessment of ADA-deficient patients before and after gene therapy. Hum Gene Ther. 2002 Feb 10;13(3):425-32. (2002) Abstract

Greenberg ML, Hershfield MS. A radiochemical-high-performance liquid chromatographic assay for urate oxidase in human plasma. Anal Biochem. 1989 Feb 1;176(2):290-3. (1989) Abstract

Hershfield MS, Chaffee S, Koro-Johnson L, Mary A, Smith AA, Short SA. Use of site-directed mutagenesis to enhance the epitope-shielding effect of covalent modification of proteins with polyethylene glycol. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7185-9. (1991) Abstract

Hershfield MS, Kredich NM, Koller CA, Mitchell BS, Kurtzberg J, Kinney TR, Falletta JM. S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine. Cancer Res. 1983 Jul;43(7):3451-8. (1983) Abstract

Richard E, Alam SM, Arredondo-Vega FX, Patel DD, Hershfield MS. Clustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing protein CD26/dipeptidyl peptidase IV. J Biol Chem. 2002 May 31;277(22):19720-6. (2002) Abstract

Hershfield MS, Nossal NG. Hydrolysis of template and newly synthesized deoxyribonucleic acid by the 3' to 5' exonuclease activity of the T4 deoxyribonucleic acid polymerase. J Biol Chem. 1972 Jun 10;247(11):3393-404. (1972) Abstract

Kurtzberg J, Bigner SH, Hershfield MS. Establishment of the DU.528 human lymphohemopoietic stem cell line. J Exp Med. 1985 Nov 1;162(5):1561-78. (1985) Abstract

Migchielsen AA, Breuer ML, van Roon MA, te Riele H, Zurcher C, Ossendorp F, Toutain S, Hershfield MS, Berns A, Valerio D. Adenosine-deaminase-deficient mice die perinatally and exhibit liver-cell degeneration, atelectasis and small intestinal cell death. Nat Genet. 1995 Jul;10(3):279-87. (1995) Abstract

Richard E, Arredondo-Vega FX, Santisteban I, Kelly SJ, Patel DD, Hershfield MS. The binding site of human adenosine deaminase for CD26/Dipeptidyl peptidase IV: the Arg142Gln mutation impairs binding to cd26 but does not cause immune deficiency. J Exp Med. 2000 Nov 6;192(9):1223-36. (2000) Abstract

Arredondo-Vega FX, Santisteban I, Kelly S, Schlossman CM, Umetsu DT, Hershfield MS. Correct splicing despite mutation of the invariant first nucleotide of a 5' splice site: a possible basis for disparate clinical phenotypes in siblings with adenosine deaminase deficiency. Am J Hum Genet. 1994 May;54(5):820-30. (1994) Abstract

Vihinen M, Arredondo-Vega FX, Casanova JL, Etzioni A, Giliani S, Hammarström L, Hershfield MS, Heyworth PG, Hsu AP, Lähdesmäki A, Lappalainen I, Notarangelo LD, Puck JM, Reith W, Roos D, Schumacher RF, Schwarz K, Vezzoni P, Villa A, Väliaho J, Smith CI. Primary immunodeficiency mutation databases. Adv Genet. 2001;43:103-88. (2001) Abstract

Finger LR, Kagan J, Christopher G, Kurtzberg J, Hershfield MS, Nowell PC, Croce CM. Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5039-43. (1989) Abstract

Hershfield MS, Aiyar VN, Premakumar R, Small WC. S-Adenosylhomocysteine hydrolase from human placenta. Affinity purification and characterization. Biochem J. 1985 Aug 15;230(1):43-52. (1985) Abstract

Hershfield MS, Kredich NM, Ownby DR, Ownby H, Buckley R. In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients. J Clin Invest. 1979 Apr;63(4):807-11. (1979) Abstract

Santisteban I, Arredondo-Vega FX, Kelly S, Mary A, Fischer A, Hummell DS, Lawton A, Sorensen RU, Stiehm ER, Uribe L, Weinberg K, Hershfield MS. Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype.  J Clin Invest.  1993 Nov;92(5):2291-302. (1993) Abstract

Hershfield MS. Genotype is an important determinant of phenotype in adenosine deaminase deficiency. Curr Opin Immunol. 2003 Oct;15(5):571-7. (2003) Abstract

Blanchet F, Cardona A, Letimier FA, Hershfield MS, Acuto O. CD28 costimulatory signal induces protein arginine methylation in T cells. J Exp Med. 2005 Aug 1;202(3):371-7. (2005) Abstract

Chan B, Wara D, Bastian J, Hershfield MS, Bohnsack J, Azen CG, Parkman R, Weinberg K, Kohn DB. Long-term efficacy of enzyme replacement therapy for Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (SCID). Clin Immunol. 2005 Aug 19. (2005) Abstract

Hershfield MS. Combined immune deficiencies due to purine enzyme defects, in: Stiehm ER, Ochs HD, Winkelstein J, (eds). Immunologic Disorders in Infants and Children. 5th ed. Philadelphia: W.B. Saunders, 2004, 480-504 (2004)

Hershfield MS, Mitchell BS: Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency, in: Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2585-2625, 2001 (2001)