ROLAND HERZOG

Summary

Affiliation: University of Florida
Country: USA

Publications

  1. pmc Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B
    Sushrusha Nayak
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida Gainesville, FL, USA
    Front Microbiol 2:244. 2011
  2. pmc Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies
    David M Markusic
    Department of Pediatrics, University of Florida, Gainesville, FL, USA
    EMBO Mol Med 5:1698-709. 2013
  3. pmc Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy
    Brandon K Sack
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, Florida, United States of America
    PLoS ONE 7:e37671. 2012
  4. doi request reprint Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B
    Geoffrey L Rogers
    Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, Florida, USA
    J Transl Med 12:25. 2014
  5. ncbi request reprint Immune responses to AAV capsid: are mice not humans after all?
    Roland W Herzog
    Division of Molecular and Cellular Therapy, University of Florida, Cancer and Genetics Research Complex, Gainesville, Florida 32610, USA
    Mol Ther 15:649-50. 2007
  6. ncbi request reprint Gene therapy for treatment of inherited haematological disorders
    Roland W Herzog
    Department of Pediatrics, University of Florida, Cellular and Molecular Therapy, Alachua, FL 32615, USA
    Expert Opin Biol Ther 6:509-22. 2006
  7. pmc Two decades of clinical gene therapy--success is finally mounting
    Roland W Herzog
    Department of Pediatrics, University of Florida College of Medicine, 2033 Mowry Road, Gainesville, Florida 32610, USA
    Discov Med 9:105-11. 2010
  8. ncbi request reprint Substantial immune suppression required in gene therapy for muscular dystrophy?
    Roland W Herzog
    Department of Pediatrics, University of Florida, Gainesville, FL, USA
    Neuromuscul Disord 18:83-4. 2008
  9. ncbi request reprint Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1
    Valder R Arruda
    Department of Pediatrics, University of Pennsylvani Medical Center, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 103:85-92. 2004
  10. pmc Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells
    Eric Dobrzynski
    Department of Pediatrics, The Children s Hospital of Philadelphia and University of Pennsylvania Medical School, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 103:4592-7. 2006

Research Grants

  1. Immunology of Factor IX Gene Transfer to Liver
    Roland W Herzog; Fiscal Year: 2010
  2. Bioencapsulated Factor IX for Oral Tolerance in Hemophilia B
    ROLAND HERZOG; Fiscal Year: 2007
  3. Immunology of Factor IX Gene Transfer to Liver
    ROLAND HERZOG; Fiscal Year: 2006
  4. Immunology of Factor IX Gene Transfer to Liver
    Roland W Herzog; Fiscal Year: 2011

Collaborators

Detail Information

Publications44

  1. pmc Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B
    Sushrusha Nayak
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida Gainesville, FL, USA
    Front Microbiol 2:244. 2011
    ..When combined with intravenous antigen administration, oral delivery of rapamycin had to be performed daily in order to induce Treg, which were suppressive and phenotypically comparable to natural Treg...
  2. pmc Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies
    David M Markusic
    Department of Pediatrics, University of Florida, Gainesville, FL, USA
    EMBO Mol Med 5:1698-709. 2013
    ..Together, these data suggest that hepatic gene transfer-based ITI provides a safe and effective alternative to eradicate inhibitors. This strategy may be broadly applicable to reversal of antibodies in different genetic diseases...
  3. pmc Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy
    Brandon K Sack
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, Florida, United States of America
    PLoS ONE 7:e37671. 2012
    ..Therefore, anti-CD20 may be beneficial in preventing vector-induced immune priming to FVIII, but higher levels of liver-restricted expression are preferred for tolerance...
  4. doi request reprint Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B
    Geoffrey L Rogers
    Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, Florida, USA
    J Transl Med 12:25. 2014
    ..However, recent reports have suggested that scAAV vectors are more immunogenic than ssAAV. In this study, we investigated the effects of a self-complementary genome during gene therapy with a therapeutic protein, human factor IX (hF.IX)...
  5. ncbi request reprint Immune responses to AAV capsid: are mice not humans after all?
    Roland W Herzog
    Division of Molecular and Cellular Therapy, University of Florida, Cancer and Genetics Research Complex, Gainesville, Florida 32610, USA
    Mol Ther 15:649-50. 2007
  6. ncbi request reprint Gene therapy for treatment of inherited haematological disorders
    Roland W Herzog
    Department of Pediatrics, University of Florida, Cellular and Molecular Therapy, Alachua, FL 32615, USA
    Expert Opin Biol Ther 6:509-22. 2006
    ..In general, long-term follow-up will be important for assessment of the safety of all existing gene therapy strategies...
  7. pmc Two decades of clinical gene therapy--success is finally mounting
    Roland W Herzog
    Department of Pediatrics, University of Florida College of Medicine, 2033 Mowry Road, Gainesville, Florida 32610, USA
    Discov Med 9:105-11. 2010
    ..While immune responses and insertional mutagenesis pose obstacles for this novel form of molecular medicine, continuous progress suggests that a wider range of diseases can be treated with gene therapy in the future...
  8. ncbi request reprint Substantial immune suppression required in gene therapy for muscular dystrophy?
    Roland W Herzog
    Department of Pediatrics, University of Florida, Gainesville, FL, USA
    Neuromuscul Disord 18:83-4. 2008
  9. ncbi request reprint Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1
    Valder R Arruda
    Department of Pediatrics, University of Pennsylvani Medical Center, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 103:85-92. 2004
    ..ix...
  10. pmc Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells
    Eric Dobrzynski
    Department of Pediatrics, The Children s Hospital of Philadelphia and University of Pennsylvania Medical School, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 103:4592-7. 2006
    ..This result suggests that augmentation of regulatory T cell activation should provide new means to avoid destructive immune responses in gene transfer...
  11. ncbi request reprint Emerging role of regulatory T cells in gene transfer
    Ou Cao
    Department Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, FL 32610, USA
    Curr Gene Ther 7:381-90. 2007
    ..This review seeks to provide an overview of these data and their implications for gene therapy...
  12. pmc Tolerance induction by viral in vivo gene transfer
    Eric Dobrzynski
    Department of Pediatrics, University of Pennsylvania Medical Center, Philadelphia, USA
    Clin Med Res 3:234-40. 2005
    ..Taken together, these data indicate the potential for viral in vivo gene transfer not only to provide sustained systemic expression, but moreover to induce immunological hypo-responsiveness to the therapeutic gene product...
  13. pmc Improved induction of immune tolerance to factor IX by hepatic AAV-8 gene transfer
    Mario Cooper
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA
    Hum Gene Ther 20:767-76. 2009
    ..IX largely independent of genetic factors. A comparison with other studies suggests that additional parameters besides plateau levels of F.IX expression contributed to the improved success rate of tolerance induction...
  14. ncbi request reprint Therapeutic levels of factor IX expression using a muscle-specific promoter and adeno-associated virus serotype 1 vector
    Yi Lin Liu
    Department of Pediatrics, Children s Hospital of Philadelphia and University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA
    Hum Gene Ther 15:783-92. 2004
    ..IX transgene product in mice with F.IX gene deletion, indicating that the risk of humoral immune responses remains in the context of an immunologically unfavorable mutation...
  15. ncbi request reprint Muscle as a target for supplementary factor IX gene transfer
    Brad E Hoffman
    Department of Pediatrics and Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
    Hum Gene Ther 18:603-13. 2007
    ..IX gene transfer to skeletal muscle does not break tolerance achieved by liver-derived expression. The approach is efficacious, if the vector for muscle gene transfer does not express immunogenic viral proteins...
  16. pmc Evading the immune response upon in vivo gene therapy with viral vectors
    Brandon K Sack
    University of Florida, Department of Pediatrics, Cancer and Genetic Research Center, Gainesville, FL 32610, USA
    Curr Opin Mol Ther 11:493-503. 2009
    ....
  17. ncbi request reprint AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B
    Catherine S Manno
    Department of Pediatrics, University of Pennsylvania and The Children s Hospital of Philadelphia, PA, 19104, USA
    Blood 101:2963-72. 2003
    ....
  18. pmc Improved hepatic gene transfer by using an adeno-associated virus serotype 5 vector
    Federico Mingozzi
    Department of Pediatrics, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA
    J Virol 76:10497-502. 2002
    ..The subpopulations of hepatocytes transduced with either vector widely overlap, with the AAV-5 vector transducing additional hepatocytes and showing a wider area of transgene expression throughout the liver parenchyma...
  19. pmc Impact of the underlying mutation and the route of vector administration on immune responses to factor IX in gene therapy for hemophilia B
    Ou Cao
    Department of Pediatrics, University of Florida, Gainesville, Florida 32610, USA
    Mol Ther 17:1733-42. 2009
    ..Therefore, endogenous expression prevented T-cell responses more effectively than antibody formation, and immune responses varied substantially depending on the protocol and the underlying mutation...
  20. pmc Optimized adeno-associated virus (AAV)-protein phosphatase-5 helper viruses for efficient liver transduction by single-stranded AAV vectors: therapeutic expression of factor IX at reduced vector doses
    Giridhara R Jayandharan
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32611 3633, USA
    Hum Gene Ther 21:271-83. 2010
    ..The strategy presented here should be adaptable to any ssAAV transgene cassette and, specifically, liver-directed applications of ssAAV2 vectors containing larger genes that cannot be encapsidated in scAAV vectors...
  21. pmc Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer
    Ou Cao
    Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, USA
    Blood 110:1132-40. 2007
    ..Our study reveals a crucial role of CD4(+)CD25(+) T(regs) in preventing immune responses to the transgene product in gene transfer...
  22. ncbi request reprint Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene
    Denise E Sabatino
    Department of Pediatrics, Graduate Program in Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, USA
    Blood 104:2767-74. 2004
    ..These new mouse models faithfully mimic the mutations causing human disease, and will prove useful for testing novel therapies for hemophilia...
  23. ncbi request reprint Treatment of human disease by adeno-associated viral gene transfer
    Kenneth H Warrington
    Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32615 9586, USA
    Hum Genet 119:571-603. 2006
    ..Treatments of genetic disorders, cancer, and other acquired diseases are summarized in this review. Vector development, results in animals, early clinical experience, as well as potential hurdles and challenges are discussed...
  24. pmc Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer
    Federico Mingozzi
    Department of Pediatrics, The Children s Hospital of Philadelphia, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA
    J Clin Invest 111:1347-56. 2003
    ..With a strain-dependent rate of success, tolerance to murine F.IX was induced in mice with a large F.IX gene deletion, supporting the relevance of these data for treatment of hemophilia B and other genetic diseases...
  25. ncbi request reprint AAV-mediated gene transfer to skeletal muscle
    Roland W Herzog
    Department of Pediatrics, Univeristy of Pennsylvania Medical Center and the Children s Hospital of Philadelphia, Philadelphia, PA, USA
    Methods Mol Biol 246:179-94. 2004
    ..IX deficiency), muscular dystrophy, obesity, age-related atrophy, and beta-thalassemia (8,12,13,15,17,18,20-25)...
  26. pmc Tyrosine-phosphorylation of AAV2 vectors and its consequences on viral intracellular trafficking and transgene expression
    Li Zhong
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA
    Virology 381:194-202. 2008
    ..These studies provide new insights into the role of tyrosine-phosphorylation of AAV capsids in various steps in the virus life cycle, which has implications in the optimal use of recombinant AAV vectors in human gene therapy...
  27. pmc Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses
    Li Zhong
    Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA
    Proc Natl Acad Sci U S A 105:7827-32. 2008
    ..These studies have led to the development of AAV vectors that are capable of high-efficiency transduction at lower doses, which has important implications in their use in human gene therapy...
  28. pmc Systemic protein delivery by muscle-gene transfer is limited by a local immune response
    Lixin Wang
    Department of Pediatrics, University of Pennsylvania Medical Center and Children s Hospital of Philadelphia, Abramson Research Center, 302 34th St and Civic Center Blvd, Philadelphia, PA 19104, USA
    Blood 105:4226-34. 2005
    ..This study documents that a local immune response limits sustained expression of a secreted protein in muscle gene transfer, a finding that may have consequences for design of clinical protocols...
  29. pmc Hepatic gene transfer as a means of tolerance induction to transgene products
    Paul A LoDuca
    Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, FL 32610, USA
    Curr Gene Ther 9:104-14. 2009
    ....
  30. pmc Tolerance induction to cytoplasmic beta-galactosidase by hepatic AAV gene transfer: implications for antigen presentation and immunotoxicity
    Ashley T Martino
    Department of Pediatrics, University of Florida, Gainesville, FL, USA
    PLoS ONE 4:e6376. 2009
    ..This study addresses the question of whether AAV gene transfer can induce tolerance to a cytoplasmic protein...
  31. pmc Immune deviation by mucosal antigen administration suppresses gene-transfer-induced inhibitor formation to factor IX
    Ou Cao
    Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Alachua, 32615, USA
    Blood 108:480-6. 2006
    ..This was achieved through immune deviation to a T-helper-cell response with increased IL-10 and TGF-beta production and activation of regulatory CD4(+)CD25(+) T cells...
  32. ncbi request reprint Immune implications of gene therapy for hemophilia
    Roland W Herzog
    Department of Pediatrics, University of Pennsylvania Medical Center and The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Semin Thromb Hemost 30:215-26. 2004
    ..Recent studies provide evidence for tolerance induction to coagulation factor antigens by viral hepatic or neonatal in vivo gene transfer, by in utero gene delivery, and by oral or nasal administration of protein or peptides...
  33. ncbi request reprint Gene therapy approaches to induce tolerance in autoimmunity by reshaping the immune system
    Clive H Wasserfall
    University of Florida, Department Pathology, Immunology, and Laboratory Medicine, 1600 SW Archer Road, Gainesville, FL 32610, USA
    Curr Opin Investig Drugs 10:1143-50. 2009
    ....
  34. pmc Coaxing the liver into preventing autoimmune disease in the brain
    Brad E Hoffman
    Department of Pediatrics, University of Florida, Gainesville, Florida, USA
    J Clin Invest 118:3271-3. 2008
    ..These findings suggest that the introduction of antigens to the liver may have potential as a preventative or therapeutic intervention for autoimmune disease...
  35. ncbi request reprint Factor IX variants improve gene therapy efficacy for hemophilia B
    Joerg Schuettrumpf
    The Children s Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104, USA
    Blood 105:2316-23. 2005
    ..IX variants did not trigger antibody formation to F.IX in mice tolerant to F.IX-WT. These studies demonstrate that F.IX variants provide a promising strategy to improve the efficacy for a variety of gene-based therapies for hemophilia B...
  36. ncbi request reprint Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy
    Roland W Herzog
    Department of Pediatrics and Pathology, University of Pennsylvania Medical Center and Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Hum Gene Ther 13:1281-91. 2002
    ..IX antigen, indicating a helper T cell-dependent mechanism. Anti-cF.IX formation is likely influenced by the extent of local antigen presentation and may be avoided by limited vector doses or by transient immune modulation...
  37. ncbi request reprint AAV-mediated gene transfer for treatment of hemophilia
    Lixin Wang
    Dept Pediatrics, University of Pennsylvania Medical Center, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Curr Gene Ther 5:349-60. 2005
    ..Taken together, these studies provide much encouragement for the possibility of future clinical success, but also point out hurdles that still have to be overcome...
  38. ncbi request reprint Gene therapy and the immune system
    Roland W Herzog
    Curr Gene Ther 7:296. 2007
  39. ncbi request reprint Update on gene therapy for hereditary hematological disorders
    Roland W Herzog
    The Children s Hospital of Philadelphia, Abramson Research Center, PA 19104, USA
    Expert Rev Cardiovasc Ther 1:215-32. 2003
    ..Efficient lentiviral gene transfer to HSC in murine models of beta-thalassemia and sickle cell disease demonstrated sustained phenotypic correction...
  40. ncbi request reprint Recent advances in hepatic gene transfer: more efficacy and less immunogenicity
    Roland W Herzog
    The Children s Hospital of Philadelphia, Abramson Research Center 302, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA
    Curr Opin Drug Discov Devel 8:199-206. 2005
    ..Equally importantly, hepatic gene transfer has been demonstrated to induce immune tolerance to therapeutic transgene products...
  41. ncbi request reprint Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer
    Eric Dobrzynski
    The Children s Hospital of Philadelphia, Abramson Research Center 302, 34th St and Civic Center Blvd, Philadelphia, PA 19104, USA
    Blood 104:969-77. 2004
    ..These data provide direct evidence that transgene expression following in vivo viral gene transfer can induce CD4+ T-cell tolerance to the transgene product, involving anergy and deletion mechanisms...
  42. pmc TLR3 signaling does not affect organ-specific immune responses to factor IX in AAV gene therapy
    Ou Cao
    Blood 112:910-1. 2008
  43. ncbi request reprint Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy
    Jane D Mount
    Scott Ritchey Research Center and Department of Clinical Sciences, College of Veterinary Sciences, Auburn University, AL, USA
    Blood 99:2670-6. 2002
    ..This study demonstrates that hepatic AAV gene transfer can result in sustained therapeutic expression in a large animal model characterized by increased risk of a neutralizing anti-FIX response...
  44. pmc Regional intravascular delivery of AAV-2-F.IX to skeletal muscle achieves long-term correction of hemophilia B in a large animal model
    Valder R Arruda
    The Children s Hospital of Philadelphia, 3615 Civic Center Blvd, 302 Abramson Research Center, Philadelphia, PA 19104, USA
    Blood 105:3458-64. 2005
    ..These findings also have immediate relevance for gene transfer in patients with muscular dystrophy...

Research Grants12

  1. Immunology of Factor IX Gene Transfer to Liver
    Roland W Herzog; Fiscal Year: 2010
    ..Therefore, superior immune tolerance protocols are highly desirable. ..
  2. Bioencapsulated Factor IX for Oral Tolerance in Hemophilia B
    ROLAND HERZOG; Fiscal Year: 2007
    ..In future studies, the oral tolerance protocol will be further optimized and adapted to prevention of inhibitors to factor VIII in treatment of hemophilia A. ..
  3. Immunology of Factor IX Gene Transfer to Liver
    ROLAND HERZOG; Fiscal Year: 2006
    ..Taken together, these studies will provide a detailed analysis of transgene product-specific T cell responses following AAV-mediated hepatic gene transfer. ..
  4. Immunology of Factor IX Gene Transfer to Liver
    Roland W Herzog; Fiscal Year: 2011
    ..Therefore, superior immune tolerance protocols are highly desirable. ..