GENE THERAPY FOR HEMOPHILIA

Summary

Principal Investigator: Katherine A High
Abstract: DESCRIPTION (provided by applicant): This is the second competitive renewal application for a Program Project Grant (PPG) entitled Gene Therapy for Hemophilia. The PPG consists of 3 projects and 3 cores. All three projects are continued from the previous PPG. Project 1, directed by Dr. Valder Arruda, will take advantage of a novel Factor (F.) IX variant (F.IX Padua, R338L) that has 10-fold the activity of wild type F.IX. Dr. Arruda will study F.IX Padua's efficacy and potential side-effects in the canine hemophilia 8 models as well as study the molecular basis for F.IX Padua's increased specific activity. Project 2, directed by Dr. Katherine High, will examine the safety and efficacy of continuous expression of Factor VIla after intravascular delivery to skeletal muscle of an AAVFVIIa vector in hemophilic dogs;she will also develop an inducible Vila vector that can be regulated by doxycycline. Project 3, directed by Dr. l\/lortimer Poncz, will continue his successful work of the previous funding period to understand the details of thrombus development by platelet-delivered F.VIII and to develop strategies to avoid observed clot instability while retaining platelet F.VIII activity in the presence of inhibitors in both hemophilia A mice and dogs. These 3 projects will be supported by three cores: Core A, the Administrative Core, will support and co-ordinate scientific interactions among the group. Core B, the Vector Core, will provide research grade AAV and lentiviral vectors for the investigators. Finally, Core C, the Large Animal Models Core at UNC-Chapel Hill, will provide access to hemophilic dogs and will provide expertise in coagulation testing and in vivo clotting models in these animals. This PPG presents three highly innovative projects to advance the care of patients with inherited bleeding disorders, including hemophilia A, hemophilia B, and patients with inhibitors to F.VIII or F.IX. The three projects investigate therapeutic strategies that utilize skeletal muscle or hematopoietic cells as targets for gene transfer, and thus are feasible for clinical translation even for those with liver disease due to viral hepatitis, which includes a large fraction of adults with severe hemophilia. The projects are highly interactive, and all three take full advantage of the proposed cores.
Funding Period: 2000-02-22 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response
    Catherine S Manno
    The Children s Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA
    Nat Med 12:342-7. 2006
  2. ncbi Immune responses to AAV in clinical trials
    Federico Mingozzi
    Children s Hospital of Philadelphia, PA 19104, USA
    Curr Gene Ther 11:321-30. 2011
  3. pmc In vivo genome editing restores haemostasis in a mouse model of haemophilia
    Hojun Li
    Division of Hematology, CTRB 5000, Children s Hospital of Philadelphia, 3501 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
    Nature 475:217-21. 2011
  4. pmc Animal models of hemophilia
    Denise E Sabatino
    Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Prog Mol Biol Transl Sci 105:151-209. 2012
  5. pmc Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer
    George Buchlis
    Division of Hematology and Center for Cellular and Molecular Therapeutics, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 119:3038-41. 2012
  6. pmc The gene therapy journey for hemophilia: are we there yet?
    Katherine A High
    Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 120:4482-7. 2012
  7. pmc The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy
    Jonathan D Finn
    Children s Hospital of Philadelphia, Philadelphia, PA, USA
    Blood 120:4521-3. 2012
  8. ncbi The gene therapy journey for hemophilia: are we there yet?
    Katherine A High
    Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Hematology Am Soc Hematol Educ Program 2012:375-81. 2012
  9. pmc Minimal modification in the factor VIII B-domain sequence ameliorates the murine hemophilia A phenotype
    Joshua I Siner
    Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 121:4396-403. 2013
  10. pmc Treatment of diabetes and long-term survival after insulin and glucokinase gene therapy
    David Callejas
    Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma Barcelona, Bellaterra, Spain
    Diabetes 62:1718-29. 2013

Research Grants

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  2. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
  3. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
  4. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
  5. Interactions Between Inflammation, Oxidant Stress and Cardiovascular Disease
    David G Harrison; Fiscal Year: 2013
  6. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
  7. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
  8. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
  9. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
  10. Lung Endothelial Cell Phenotypes
    Troy Stevens; Fiscal Year: 2013

Detail Information

Publications32

  1. ncbi Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response
    Catherine S Manno
    The Children s Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA
    Nat Med 12:342-7. 2006
    ..We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression...
  2. ncbi Immune responses to AAV in clinical trials
    Federico Mingozzi
    Children s Hospital of Philadelphia, PA 19104, USA
    Curr Gene Ther 11:321-30. 2011
    ....
  3. pmc In vivo genome editing restores haemostasis in a mouse model of haemophilia
    Hojun Li
    Division of Hematology, CTRB 5000, Children s Hospital of Philadelphia, 3501 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
    Nature 475:217-21. 2011
    ..Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease...
  4. pmc Animal models of hemophilia
    Denise E Sabatino
    Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Prog Mol Biol Transl Sci 105:151-209. 2012
    ....
  5. pmc Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer
    George Buchlis
    Division of Hematology and Center for Cellular and Molecular Therapeutics, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 119:3038-41. 2012
    ..This is the longest reported transgene expression to date from a parenterally administered AAV vector, with broad implications for the future of muscle-directed gene transfer...
  6. pmc The gene therapy journey for hemophilia: are we there yet?
    Katherine A High
    Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 120:4482-7. 2012
    ..Efforts to extend AAV-mediated gene therapy to hemophilia A, and alternate approaches that may be useful for persons with severe liver disease, who may not be candidates for gene transfer to liver, are also discussed...
  7. pmc The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy
    Jonathan D Finn
    Children s Hospital of Philadelphia, Philadelphia, PA, USA
    Blood 120:4521-3. 2012
    Studies on gene therapy for hemophilia B (HB) using adeno-associated viral (AAV) vectors showed that the safety of a given strategy is directly related to the vector dose...
  8. ncbi The gene therapy journey for hemophilia: are we there yet?
    Katherine A High
    Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Hematology Am Soc Hematol Educ Program 2012:375-81. 2012
    ..Efforts to extend AAV-mediated gene therapy to hemophilia A, and alternate approaches that may be useful for persons with severe liver disease, who may not be candidates for gene transfer to liver, are also discussed...
  9. pmc Minimal modification in the factor VIII B-domain sequence ameliorates the murine hemophilia A phenotype
    Joshua I Siner
    Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 121:4396-403. 2013
    ..Thus, FVIII-RH is an attractive bioengineered molecule for improving efficacy without increased immunogenicity and may be suitable for both protein- and gene-based strategies for HA...
  10. pmc Treatment of diabetes and long-term survival after insulin and glucokinase gene therapy
    David Callejas
    Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma Barcelona, Bellaterra, Spain
    Diabetes 62:1718-29. 2013
    ..This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes...
  11. pmc Immune responses to AAV vectors: overcoming barriers to successful gene therapy
    Federico Mingozzi
    Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Blood 122:23-36. 2013
    ....
  12. pmc Cellular localization and characterization of cytosolic binding partners for Gla domain-containing proteins PRRG4 and PRRG2
    Mustafa N Yazicioglu
    Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 288:25908-14. 2013
    ..Several of the PRRG-interacting proteins we identified are essential for a variety of physiologic processes. Our findings indicate possible novel and previously unidentified functions for PRRG proteins. ..
  13. pmc Robust ZFN-mediated genome editing in adult hemophilic mice
    Xavier M Anguela
    Division of Hematology and Center for Cellular and Molecular Therapeutics, Children s Hospital of Philadelphia, Philadelphia, PA
    Blood 122:3283-7. 2013
    ..These results broaden the therapeutic potential of AAV/ZFN-mediated genome editing in the liver and could expand this strategy to other nonreplicating cell types. ..
  14. pmc Characterization of naturally-occurring humoral immunity to AAV in sheep
    Joseph Tellez
    Department of Animal Biotechnology, University of Nevada, Reno, Nevada, United States of America
    PLoS ONE 8:e75142. 2013
    ....
  15. ncbi Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges
    Federico Mingozzi
    Center for Cellular and Molecular Therapeutics, The Children s Hospital of Philadelphia, 3501 Civic Center Boulevard, 5th Floor CTRB, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Genet 12:341-55. 2011
    ..Recent exciting results have raised hopes for the treatment of many other diseases. As we discuss here, the prospects and challenges for AAV gene therapy are to a large extent dependent on the target tissue and the specific disease...
  16. pmc In vivo efficacy of platelet-delivered, high specific activity factor VIII variants
    Teshell K Greene
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Blood 116:6114-22. 2010
    ....
  17. ncbi Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial
    Joerg Schuettrumpf
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Mol Ther 13:1064-73. 2006
    ..We conclude that AAV2 presents minimal germline transmission risk for humans...
  18. ncbi Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B
    Haiyan Jiang
    Avigen, Inc, Alameda, CA 94502, USA
    Mol Ther 14:452-5. 2006
    ..These results demonstrate, for the first time, multiyear FIX expression by AAV2 vector in humans and suggest that improved muscle delivery provides effective treatment for protein deficiencies or muscle-specific diseases...
  19. ncbi Persistent expression of hF.IX After tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice
    Denise E Sabatino
    Department of Hematology, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    Mol Ther 15:1677-85. 2007
    ..IX expression. This supports the concept of a narrow "window of opportunity" for tolerance induction...
  20. ncbi Prolonged susceptibility to antibody-mediated neutralization for adeno-associated vectors targeted to the liver
    Samuel L Murphy
    Department of Pediatrics, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Mol Ther 16:138-45. 2008
    ..These studies characterize the in vivo clearance rates of AAV vectors for the first time and guide the development of future strategies for the avoidance of antibody-mediated AAV vector neutralization...
  21. ncbi Immune responses to AAV in clinical trials
    Federico Mingozzi
    Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Curr Gene Ther 7:316-24. 2007
    ....
  22. ncbi Platelet-delivered factor VIII provides limited resistance to anti-factor VIII inhibitors
    J Gewirtz
    Division of Hematology, Children s Hospital of Philadelphia, Philadelphia, PA 190104, USA
    J Thromb Haemost 6:1160-6. 2008
    ..Among these is that platelet (p) FVIII may be effective in the presence of circulating anti-FVIII inhibitors...
  23. pmc Analysis of the spatial and temporal characteristics of platelet-delivered factor VIII-based clots
    Michael Neyman
    Division of Hematology, Children s Hospital of Philadelphia, PA 19104, USA
    Blood 112:1101-8. 2008
    ..These observations may not only have implications for the use of pFVIII in gene therapy for hemophilia A, but may also have physiologic consequences, explaining why many procoagulant factors are delivered ..
  24. pmc Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy
    Glenn P Niemeyer
    Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA
    Blood 113:797-806. 2009
    ..and initial clinical trials have documented the feasibility of adenoassociated virus (AAV)-mediated gene therapy for hemophilia B...
  25. pmc Diverse IgG subclass responses to adeno-associated virus infection and vector administration
    Samuel L Murphy
    Center for Cell and Molecular Therapeutics, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 4318, USA
    J Med Virol 81:65-74. 2009
    ..Analysis of IgG subclass distribution of anti-AAV capsid antibodies indicates a complex, non-uniform pattern of responses to this viral antigen. J. Med. Virol. 81:65-74, 2009. (c) 2008 Wiley-Liss, Inc...
  26. pmc Successful treatment of canine hemophilia by continuous expression of canine FVIIa
    Paris Margaritis
    Division of Hematology, Children s Hospital of Philadelphia, PA 19104, USA
    Blood 113:3682-9. 2009
    ....
  27. ncbi High AAV vector purity results in serotype- and tissue-independent enhancement of transduction efficiency
    E Ayuso
    Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Autonoma de Barcelona, Bellaterra, Spain
    Gene Ther 17:503-10. 2010
    ....
  28. pmc Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B
    Valder R Arruda
    University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Blood 115:4678-88. 2010
    ..Collectively, these results demonstrate the feasibility of this approach for treatment of HB and highlight the importance of IS to prevent immune responses to the FIX transgene product...
  29. pmc Safety of AAV factor IX peripheral transvenular gene delivery to muscle in hemophilia B dogs
    Virginia Haurigot
    Division of Hematology and Center for Cellular and Molecular Therapeutics, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    Mol Ther 18:1318-29. 2010
    ..In summary, this study in a large animal model of HB demonstrates that therapeutic levels of gene transfer can be safely achieved using a novel route of intravascular gene transfer to muscle...
  30. ncbi Gene therapy in haemophilia--going for cure?
    P Margaritis
    Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Haemophilia 16:24-8. 2010
    ....
  31. pmc High-level transgene expression in induced pluripotent stem cell-derived megakaryocytes: correction of Glanzmann thrombasthenia
    Spencer K Sullivan
    Division of Hematology
    Blood 123:753-7. 2014
    ..Our findings demonstrate a novel approach to studying human megakaryocyte biology as well as functional correction of the GT defect, offering a potential therapeutic strategy for patients with diseases that affect platelet function. ..

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  3. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
    ..Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world. ..
  4. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  5. Interactions Between Inflammation, Oxidant Stress and Cardiovascular Disease
    David G Harrison; Fiscal Year: 2013
    ..Overall, these studies will promote our understanding of the interplay between inflammation, oxidant stress and cardiovascular disease. ..
  6. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
    ..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
  7. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  8. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  9. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  10. Lung Endothelial Cell Phenotypes
    Troy Stevens; Fiscal Year: 2013
    ..abstract_text> ..
  11. Protein-glycan Interactions in the Vascular System
    Lijun Xia; Fiscal Year: 2013
    ..This information may suggest new approaches to treat heart attacks, strokes, and other cardiovascular disorders. ..
  12. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..