Dr. Andrea Amalfitano

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Michigan State University
College of Osteopathic Medicine
Microbiology and Molecular Genetics and Pediatrics
Osteopathic Heritage Foundation Endowed ChairAppointed: 2005
Professional Headshot of Andrea Amalfitano

Mailing Address

4194 Biomedical and Physical Sciences Bldg
Michigan State University
East Lansing, Michigan 48824
United States

Contact Information

Phone: (517) 355-6463, ext. 1537
Fax: (517) 355-8147
amalfit1@msu.edu

Qualifications

D.O., Michigan State University, Osteopathic Medicine, 1990.
Ph.D., Michigan State University, Microbiology, 1989.
B.S., Michigan State University, Microbiology, 1984.

Expertise and Research Interests

Dr. Andrea Amalfitano is a physician/scientist, and is currently The Osteopathic Heritage Foundation Professor in the Departments of Microbiology and Molecular Genetics and Department of Pediatrics at Michigan State University. He has established himself as an independent investigator, his efforts have focused upon the human adenovirus (Ad), and its potential for use in the genetic therapy of several pediatric diseases.
I. Modification of Ad based vectors:
Adenovirus based vectoring systems have a number of positive attributes. First generation, [E1-] Ad vectors can persist in a variety of terminally differentiated tissues, and are one of the most efficient means of transducing genes into large numbers of cells in vivo. Ad vectors have been approved for human use and are currently being utilized in a variety of human gene therapy clinical trials (~260 as of this date). It is however very clear that Ad based vectors have several major limitations; namely the inability to persist long-term, as well as having significant toxicities in vivo. Our group reasoned that [E1-]Ad vectors were limited because of their continued expression of a number of Ad genes still resident in the [E1-] Ad vector genomes. Our working hypothesis has been that novel Ad vector modifications would result in an improved and safer vector for potential use in pediatric disease gene therapy trials.
For example, our group was the first to describe the generation of a new series of multiply deleted [E1-,E2b-]Ad vectors. Our co-deletion of the Ad E1 and E2b genes was predicted to significantly improve overall Ad vector performance, by blocking the vectors from replicating in vivo. Our recently published results has in fact confirmed the hypothesis, and allowed for long term efficacy to be demonstrated in animal models of human pediatric diseases.
II. Utilization of modified Ad vectors in specific genetic disease models:
Our studies have demonstrated that [E1-,E2b-]Ad vectors exhibit significantly diminished hepatoxicity, and can persist long term when utilized in vivo. We have capitalized upon these benefits, by investigating the potential of [E1-,E2b-]Ad mediated genetic therapy for babies/adults affected by glycogen storage disease Type II (GSD Type II). GSD Type II (a.k.a.: Pompe disease) is caused by lack of intra-lysosomal acid alpha glucosidase (AAG) activity, resulting in a progressive myopathy. We recently demonstrated in a murine model of GSD-II that a single intravenous administration of an [E1-,E2b-]Ad vector encoding AAG resulted in rapid correction of the glycogen accumulations in a variety of muscle tissues, with efficacy being demonstrated for at least 6 months. Future studies will investigate long term ramifications and immunological consequences of this unique form of therapy both in the mouse model and a quail model of GSD Type II. Finally, formal collaborations are actively underway to investigate the potential of our current classes of modified Ad vectors for transfer of a variety of genes into a number of animal models of pediatric disease.

Other Expertise

Medical Genetics-Clinical
Metabolic Genetics
Molecular Biology
Genetic Engineering
Gene Therapy
ABMG certified Medical Geneticist

Future Research

Vaccine Development utilizing Adenovirus based vectors
Cancer vaccine development utilizing Adenovirus based vectors
Development of safer gene therapy vectors

Industrial Relevance

-"Adenovirus Vectors"-United States Patent. #6,063,622: Issue date:5/16/2000.
-"Deleted Adenovirus vectors and Methods of Making and Administering the Same".
United States Patent: #6,328,958 Issue date: 12/11/2001.
-"Helper Adenovirus Vectors" US Patent #6,451,596: Issue Date: Sep. 17, 2002
-"Deleted Adenovirus vectors and Methods of Making and Administering the Same".
United States Patent: #6,797,265: Issue date 9/28/2004.
-"Replicating Adenovirus Vectors" US Patent #6,946,126: Issue date: Sep. 20, 2005.

-Numerous Patents awarded or pending via overseas PTO in reference to above US patent

Keywords

COS Keywords:

Gene Therapy, Human Genome, Medical Genetics, Pediatrics.

Memberships

American Society of Gene Therapy
American Society of Human Genetics
American Society of Microbiology

Honors and Awards

2001-2001, 2001 Michigan State University College of Osteopathic Medicine Alumni of the Year Award, Michigan State University College of Osteopathic Medicine, Michigan State University
1997-1998, James Shannon Award, NIH, Duke University, Adenovirus vectors for Gene Therapy
1996, Diplomate, American Board of Medical Genetics, Clinical Geneticist, 1996, American Board of Medical Genetics, Clinical Genetics

Previous Positions

1996-2006, Associate Professor, Duke University, Medical Center
1996-2005, Acting Chief, Duke University, Duke University Medical Center, Pediatrics, Medical Genetics

Funding Received

  • National Institutes of Health (NIH): Complement and Adenovirus, 2005 to 2008.
  • National Institutes of Health (NIH): Adoptive Immunotherapy with Adenovirus Vectors, 2004 to 2009.

Publications

  • Hartman ZC, Appledorn DM, Amalfitano A (Nov 2007) Adenovirus vector induced innate immune responses: Impact upon efficacy and toxicity in gene therapy and vaccine applications. Abstract
  • Hensley SE, Amalfitano A (Aug 2007) Toll-like receptors impact on safety and efficacy of gene transfer vectors., Molecular therapy : the journal of the American Society of Gene Therapy, 15 (8), 1417-22 Abstract
  • Kiang A, Amalfitano A (Jul 2007) Progress and problems when considering gene therapy for GSD-II., Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases, 26 (1), 49-52 Abstract
  • McColl BW, McGregor AL, Wong A, Harris JD, Amalfitano A, Magnoni S, Baker AH, Dickson G, Horsburgh K (Mar 2007) APOE epsilon3 gene transfer attenuates brain damage after experimental stroke., Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 27 (3), 477-87 Abstract
  • Hartman ZC, Black EP, Amalfitano A (Feb 2007) Adenoviral infection induces a multi-faceted innate cellular immune response that is mediated by the toll-like receptor pathway in A549 cells., Virology, 358 (2), 357-72 Abstract
  • Hartman ZC, Kiang A, Everett RS, Serra D, Yang XY, Clay TM, Amalfitano A (Feb 2007) Adenovirus infection triggers a rapid, MyD88-regulated transcriptome response critical to acute-phase and adaptive immune responses in vivo., Journal of virology, 81 (4), 1796-812 Abstract
  • Kiang A, Hartman ZC, Everett RS, Serra D, Jiang H, Frank MM, Amalfitano A (Oct 2006) Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system., Molecular therapy : the journal of the American Society of Gene Therapy, 14 (4), 588-98 Abstract
  • Kishnani PS, Nicolino M, Voit T, Rogers RC, Tsai AC, Waterson J, Herman GE, Amalfitano A, Thurberg BL, Richards S, Davison M, Corzo D, Chen YT (Jul 2006) Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease., The Journal of pediatrics, 149 (1), 89-97 Abstract
  • Li H, Li JZ, Pittman DD, Amalfitano A, Hankins GR, Helm GA (2006) Comparison of osteogenic potentials of human rat BMP4 and BMP6 gene therapy using [E1-] and [E1-,E2b-] adenoviral vectors., International journal of medical sciences, 3 (3), 97-105 Abstract
  • Xu F, Serra D, Amalfitano A (2006) Applications of adenoviral vector-mediated gene transfer in cardiovascular research., Methods in molecular medicine, 129, 209-39 Abstract
  • An Y, Young SP, Kishnani PS, Millington DS, Amalfitano A, Corz D, Chen YT (Aug 2005) Glucose tetrasaccharide as a biomarker for monitoring the therapeutic response to enzyme replacement therapy for Pompe disease., Molecular Genetics and Metabolism, 85 (4), 247-54 Abstract
  • Peppel K, Zhang L, Orman ES, Hagen PO, Amalfitano A, Brian L, Freedman NJ (Feb 2005) Activation of vascular smooth muscle cells by TNF and PDGF: overlapping and complementary signal transduction mechanisms., Cardiovascular Research, 65 (3), 674-82 Abstract
  • Xu F, Ding E, Migone F, Serra D, Schneider A, Chen YT, Amalfitano A (Feb 2005) Glycogen storage in multiple muscles of old GSD-II mice can be rapidly cleared after a single intravenous injection with a modified adenoviral vector expressing hGAA., The Journal of Gene Medicine, 7 (2), 171-8 Abstract
  • Sun B, Zhang H, Franco LM, Young SP, Schneider A, Bird A, Amalfitano A, Chen YT, Koeberl DD (Jan 2005) Efficacy of an adeno-associated virus 8-pseudotyped vector in glycogen storage disease type II., Molecular Therapy : the Journal of the American Society of Gene Therapy, 11 (1), 57-65 Abstract
  • Jiang H, Wang Z, Serra D, Frank MM, Amalfitano A (Dec 2004) Recombinant adenovirus vectors activate the alternative complement pathway, leading to the binding of human complement protein C3 independent of anti-ad antibodies., Molecular Therapy : the Journal of the American Society of Gene Therapy, 10 (6), 1140-2 Abstract
  • Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, Geleoc GS, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS (Dec 2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells., Nature, 432 (7018), 723-30 Abstract
  • Xu F, Ding E, Liao SX, Migone F, Dai J, Schneider A, Serra D, Chen YT, Amalfitano A (Nov 2004) Improved efficacy of gene therapy approaches for Pompe disease using a new, immune-deficient GSD-II mouse model., Gene Therapy, 11 (21), 1590-8 Abstract
  • Hunley TE, Corzo D, Dudek M, Kishnani P, Amalfitano A, Chen YT, Richards SM, Phillips JA 3rd, Fogo AB, Tiller GE (Oct 2004) Nephrotic syndrome complicating alpha-glucosidase replacement therapy for Pompe disease., Pediatrics, 114 (4), e532-5 Abstract
  • Amalfitano A (Jun 2004) Utilization of adenovirus vectors for multiple gene transfer applications., Methods (san Diego, Calif.), 33 (2), 173-8 Abstract
  • Everett RS, Hodges BL, Ding EY, Xu F, Serra D, Amalfitano A (Dec 2003) Liver toxicities typically induced by first-generation adenoviral vectors can be reduced by use of E1, E2b-deleted adenoviral vectors., Human Gene Therapy, 14 (18), 1715-26 Abstract
  • Amalfitano A (Aug 2003) Use of multiply deleted adenovirus vectors to probe adenovirus vector performance and toxicities., Current Opinion in Molecular Therapeutics, 5 (4), 362-6 Abstract
  • McVie-Wylie AJ, Ding EY, Lawson T, Serra D, Migone FK, Pressley D, Mizutani M, Kikuchi T, Chen YT, Amalfitano A (May 2003) Multiple muscles in the AMD quail can be "cross-corrected" of pathologic glycogen accumulation after intravenous injection of an [E1-, polymerase-] adenovirus vector encoding human acid-alpha-glucosidase., The Journal of Gene Medicine, 5 (5), 399-406 Abstract
  • Dode C, Levilliers J, Dupont JM, , Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP, Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome, Nature Genetics, 33(4), 463-5, April 2003 Abstract
  • Sun B, Chen YT, Bird A, Xu F, Hou YX, Amalfitano A, Koeberl DD (Apr 2003) Packaging of an AAV vector encoding human acid alpha-glucosidase for gene therapy in glycogen storage disease type II with a modified hybrid adenovirus-AAV vector., Molecular Therapy : the Journal of the American Society of Gene Therapy, 7 (4), 467-77 Abstract
  • Amalfitano A, Parks RJ, Separating fact from fiction: assessing the potential of modified adenovirus vectors for use in human gene therapy, Current Gene Therapy, 2(2), 111-33, May 2002 Abstract
  • Amalfitano A, Parks RJ (May 2002) Separating fact from fiction: assessing the potential of modified adenovirus vectors for use in human gene therapy., Current Gene Therapy, 2 (2), 111-33 Abstract
  • Dhar S, Bitting RL, Rylova SN, Jansen PJ, Lockhart E, Koeberl DD, Amalfitano A, Boustany RM, Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons, Annals of Neurology, 51(4), 448-66, April 2002 Abstract
  • Ding E, Hu H, Hodges BL, Migone F, Serra D, Xu F, Chen YT, Amalfitano A, Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction, Molecular Therapy : the Journal of the American Society of Gene Therapy, 5(4), 436-46, April 2002 Abstract
  • Ding E, Hu H, Hodges BL, Migone F, Serra D, Xu F, Chen YT, Amalfitano A (Apr 2002) Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction., Molecular Therapy : the Journal of the American Society of Gene Therapy, 5 (4), 436-46 Abstract
  • Rylova SN, Amalfitano A, Persaud-Sawin DA, Guo WX, Chang J, Jansen PJ, Proia AD, Boustany RM, The CLN3 gene is a novel molecular target for cancer drug discovery, Cancer Research, 62(3), 801-8, February 2002 Abstract
  • Harris JD, Graham IR, Schepelmann S, Stannard AK, Roberts ML, Hodges BL, Hill V, Amalfitano A, Hassall DG, Owen JS, Dickson G (Jan 2002) Acute regression of advanced and retardation of early aortic atheroma in immunocompetent apolipoprotein-E (apoE) deficient mice by administration of a second generation [E1(-), E3(-), polymerase(-)] adenovirus vector expressing human apo, Human Molecular Genetics, 11 (1), 43-58 Abstract
  • Gilbert R, Nalbantoglu J, Howell JM, Davies L, Fletcher S, Amalfitano A, Petrof BJ, Kamen A, Massie B, Karpati G, Dystrophin expression in muscle following gene transfer with a fully deleted ('gutted') adenovirus is markedly improved by trans-acting adenoviral gene products, Human Gene Therapy, 12(14), 1741-55, September 2001 Abstract
  • Gilbert R, Nalbantoglu J, Howell JM, Davies L, Fletcher S, Amalfitano A, Petrof BJ, Kamen A, Massie B, Karpati G (Sep 2001) Dystrophin expression in muscle following gene transfer with a fully deleted ("gutted") adenovirus is markedly improved by trans-acting adenoviral gene products., Human Gene Therapy, 12 (14), 1741-55 Abstract
  • Hodges BL, Evans HK, Everett RS, Ding EY, Serra D, Amalfitano A, Adenovirus vectors with the 100K gene deleted and their potential for multiple gene therapy applications, Journal of Virology, 75(13), 5913-20, July 2001 Abstract
  • Luebke AE, Steiger JD, Hodges BL, Amalfitano A, A modified adenovirus can transfect cochlear hair cells in vivo without compromising cochlear function, Gene Therapy, 8(10), 789-94, May 2001 Abstract
  • Ding EY, Hodges BL, Hu H, McVie-Wylie AJ, Serra D, Migone FK, Pressley D, Chen YT, Amalfitano A, Long-term efficacy after [E1-, polymerase-] adenovirus-mediated transfer of human acid-alpha-glucosidase gene into glycogen storage disease type II knockout mice, Human Gene Therapy, 12(8), 955-65, May 2001 Abstract
  • Ding EY, Hodges BL, Hu H, McVie-Wylie AJ, Serra D, Migone FK, Pressley D, Chen YT, Amalfitano A (May 2001) Long-term efficacy after [E1-, polymerase-] adenovirus-mediated transfer of human acid-alpha-glucosidase gene into glycogen storage disease type II knockout mice., Human Gene Therapy, 12 (8), 955-65 Abstract
  • Amalfitano A, Bengur AR, Morse RP, Majure JM, Case LE, Veerling DL, Mackey J, Kishnani P, Smith W, McVie-Wylie A, Sullivan JA, Hoganson GE, Phillips JA 3rd, Schaefer GB, Charrow J, Ware RE, Bossen EH, Chen YT, Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial, Genetics in Medicine : Official Journal of the American College of Medical Genetics., 3(2), 132-8, 2001 Abstract
  • Amalfitano A, Bengur AR, Morse RP, Majure JM, Case LE, Veerling DL, Mackey J, Kishnani P, Smith W, McVie-Wylie A, Sullivan JA, Hoganson GE, Phillips JA 3rd, Schaefer GB, Charrow J, Ware RE, Bossen EH, Chen YT (Mar-Apr 2001) Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial., Genetics in Medicine : Official Journal of the American College of Medical Genetics., 3 (2), 132-8 Abstract
  • Ahmad A, Brinson M, Hodges BL, Chamberlain JS, Amalfitano A, Mdx mice inducibly expressing dystrophin provide insights into the potential of gene therapy for duchenne muscular dystrophy, Human Molecular Genetics, 9(17), 2507-15, October 2000 Abstract
  • Hodges BL, Serra D, Hu H, Begy CA, Chamberlain JS, Amalfitano A, Multiply deleted [E1, polymerase-, and pTP-] adenovirus vector persists despite deletion of the preterminal protein, The Journal of Gene Medicine, 2(4), 250-9, 2000 Abstract
  • Chen YT, Amalfitano A, Towards a molecular therapy for glycogen storage disease type II (Pompe disease), Molecular Medicine Today, 6(6), 245-51, June 2000 Abstract
  • Chen YT, Amalfitano A (Jun 2000) Towards a molecular therapy for glycogen storage disease type II (Pompe disease)., Molecular Medicine Today, 6 (6), 245-51 Abstract
  • Amalfitano A, Next-generation adenoviral vectors: new and improved, Gene Therapy, 6(10), 1643-5, October 1999 Abstract
  • Ahmad A, Amalfitano A, Chen YT, Kishnani PS, Miller C, Kelley R, Dubowitz syndrome: a defect in the cholesterol biosynthetic pathway?, American Journal of Medical Genetics, 86(5), 503-4, October 1999 Abstract
  • Amalfitano A, Next-generation adenoviral vectors: new and improved., Gene Therapy, 6(10), 1643-5, Oct 1999 Abstract
  • Ahmad A, Amalfitano A, Chen YT, Kishnani PS, Miller C, Kelley R, Dubowitz syndrome: a defect in the cholesterol biosynthetic pathway?, American Journal of Medical Genetics, 86(5), 503-4, Oct 1999 Abstract
  • Hartigan-O'Connor D, Amalfitano A, Chamberlain JS, Improved production of gutted adenovirus in cells expressing adenovirus preterminal protein and DNA polymerase, Journal of Virology, 73(9), 7835-41, September 1999 Abstract
  • Amalfitano A, McVie-Wylie AJ, Hu H, Dawson TL, Raben N, Plotz P, Chen YT, Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-alpha-glucosidase., Proceedings of the National Academy of Sciences (USA), 96(16), 8861-6, 3 Aug 1999 Abstract
  • Amalfitano A, McVie-Wylie AJ, Hu H, Dawson TL, Raben N, Plotz P, Chen YT (Aug 1999) Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-alpha-glucosidase., Proceedings of the National Academy of Sciences of the United States of America., 96 (16), 8861-6 Abstract
  • Hu H, Serra D, Amalfitano A, Persistence of an [E1-, polymerase-] adenovirus vector despite transduction of a neoantigen into immune-competent mice., Human Gene Therapy, 10(3), 355-64, 10 Feb 1999 Abstract
  • Amalfitano A, Hauser M A, Hu H, Serra D, Begy C R, Chamberlain J S, Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes deleted., Journal of Virology, 72(2), 926-33, February 1998 Abstract
  • Hauser M A, Amalfitano A, Kumar-Singh R, Hauschka S D, Chamberlain J S, Improved adenoviral vectors for gene therapy of Duchenne muscular dystrophy., Neuromuscular Disorders, 7(5), 277-83, July 1997 Abstract
  • Amalfitano A, Chamberlain J S, Isolation and characterization of packaging cell lines that coexpress the adenovirus E1, DNA polymerase, and preterminal proteins: implications for gene therapy., Gene Therapy, 4(3), 258-63, March 1997 Abstract
  • Amalfitano A, Chamberlain J S, The mdx-amplification-resistant mutation system assay, a simple and rapid polymerase chain reaction-based detection of the mdx allele., Muscle and Nerve, 19(12), 1549-53, December 1996 Abstract
  • Amalfitano A, Begy C R, Chamberlain J S, Improved adenovirus packaging cell lines to support the growth of replication-defective gene-delivery vectors., Proceedings of the National Academy of Sciences (USA), 93(8), 3352-6, 16 Apr 1996 Abstract
  • Amalfitano A, Martin LG, Fluck MM, Different roles for two enhancer domains in the organ- and age-specific pattern of polyomavirus replication in the mouse, Molecular and Cellular Biology, 12(8), 3628-35, August 1992 Abstract

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Last Updated: 2/4/2008

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