Gene therapy for hemophilia

Hemophilia A and B are X‐chromosome linked recessive bleeding disorders that result from a deficiency in factor VIII (FVIII) and factor IX (FIX) respectively. Though factor substitution therapy has greatly improved the lives of hemophiliac patients, there are still limitations to the current treatment that have triggered interest in alternative treatments by gene therapy. Significant progress has recently been made in the development of gene therapy for the treatment of hemophilia A and B. These advances parallel the technical improvements of existing vector systems including MoMLV‐based retroviral, adenoviral and AAV vectors, and the development of new delivery methods such as lentiviral vectors, helper‐dependent adenoviral vectors and improved non‐viral gene delivery methods. Therapeutic and physiologic levels of FVIII and FIX could be achieved in FVIII‐ and FIX‐deficient mice and hemophilia dogs by different gene therapy approaches. Long‐term correction of the bleeding disorders and in some cases a permanent cure has been realized in these preclinical studies. However, the induction of neutralizing antibodies often precludes stable phenotypic correction. Another complication is that certain promoters are prone to transcriptional inactivation in vivo, precluding long‐term FVIII or FIX expression. Several gene therapy phase I clinical trials are currently ongoing in patients suffering from severe hemophilia A or B. No significant adverse side‐effects were reported, and semen samples were negative for vector sequences by sensitive PCR assays. Most importantly, some subjects report fewer bleeding episodes and occasionally have very low levels of clotting factor activity detected. The results from the extensive preclinical studies in normal and hemophilic animal models and encouraging preliminary clinical data indicate that the simultaneous development of different strategies is likely to bring a permanent cure for hemophilia one step closer to reality. Copyright © 2001 John Wiley & Sons, Ltd.

[1]  M. Chuah,et al.  Viral vector-mediated gene therapy for hemophilia. , 2001, Current gene therapy.

[2]  R. Morgan,et al.  Lentiviral-mediated gene transfer into human lymphocytes: role of HIV-1 accessory proteins. , 2000, Blood.

[3]  M. Kay,et al.  Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver. , 2000, Blood.

[4]  L. Ailles,et al.  Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences , 2000, Nature Genetics.

[5]  M. Kay,et al.  Inclusion of the hepatic locus control region, an intron, and untranslated region increases and stabilizes hepatic factor IX gene expression in vivo but not in vitro. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[6]  M. Kay,et al.  Somatic integration and long-term transgene expression in normal and haemophilic mice using a DNA transposon system , 2000, Nature Genetics.

[7]  H. Kazazian,et al.  Correction of the coagulation defect in hemophilia A mice through factor VIII expression in skin. , 2000, Blood.

[8]  Theresa A. Storm,et al.  Nonrandom Transduction of Recombinant Adeno-Associated Virus Vectors in Mouse Hepatocytes In Vivo: Cell Cycling Does Not Influence Hepatocyte Transduction , 2000, Journal of Virology.

[9]  H. Kazazian,et al.  Partial correction of murine hemophilia A with neo-antigenic murine factor VIII. , 2000, Human gene therapy.

[10]  T. VandenDriessche,et al.  Long-term persistence of human bone marrow stromal cells transduced with factor VIII-retroviral vectors and transient production of therapeutic levels of human factor VIII in nonmyeloablated immunodeficient mice. , 2000, Human gene therapy.

[11]  H. Ertl,et al.  Role of vector in activation of T cell subsets in immune responses against the secreted transgene product factor IX. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[12]  Alan McClelland,et al.  Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector , 2000, Nature Genetics.

[13]  A. Bruce,et al.  Sustained expression of human factor VIII in mice using a parvovirus-based vector. , 2000, Blood.

[14]  G. White,et al.  Gene therapy for hemophilia: a step closer to reality. , 2000, Molecular Therapy.

[15]  I. Verma,et al.  Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  C. Balagué,et al.  Sustained high-level expression of full-length human factor VIII and restoration of clotting activity in hemophilic mice using a minimal adenovirus vector. , 2000, Blood.

[17]  R. Morgan,et al.  Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity. , 1999, Blood.

[18]  H. Kazazian,et al.  Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Douar,et al.  Therapeutic plasma concentrations of human factor IX in mice after gene delivery into the amniotic cavity: a model for the prenatal treatment of haemophilia B , 1999, The journal of gene medicine.

[20]  A. Beaudet,et al.  Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Mitchell,et al.  Coexpression of factor VIII heavy and light chain adeno-associated viral vectors produces biologically active protein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Samulski,et al.  Persistent expression of canine factor IX in hemophilia B canines , 1999, Gene Therapy.

[23]  S. Snyder,et al.  Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization , 1999, Nature Medicine.

[24]  R. Kaufman.  Advances toward gene therapy for hemophilia at the millennium. , 1999, Human gene therapy.

[25]  C. Steer,et al.  Correction of the UDP-glucuronosyltransferase gene defect in the gunn rat model of crigler-najjar syndrome type I with a chimeric oligonucleotide. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. VandenDriessche,et al.  Long-term expression of human coagulation factor VIII and correction of hemophilia A after in vivo retroviral gene transfer in factor VIII-deficient mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  K. High,et al.  Gene therapy for the hemophilias. , 1999, Advances in veterinary medicine.

[28]  D. Jolly,et al.  Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency , 1999, Thrombosis and Haemostasis.

[29]  C. Balagué,et al.  Development And Application Of A Minimal-Adenoviral Vector System For Gene Therapy Of Hemophilia A , 1999, Thrombosis and Haemostasis.

[30]  A. Beaudet,et al.  Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors. , 1999, Human gene therapy.

[31]  D. Kayda,et al.  In vivo evaluation of an adenoviral vector encoding canine factor VIII: high-level, sustained expression in hemophiliac mice. , 1999, Human gene therapy.

[32]  E. Waller,et al.  Expression of Factor VIII by Murine Liver Sinusoidal Endothelial Cells* , 1999, The Journal of Biological Chemistry.

[33]  M. Kay,et al.  Isolation of Recombinant Adeno-Associated Virus Vector-Cellular DNA Junctions from Mouse Liver , 1999, Journal of Virology.

[34]  J. Wolff,et al.  High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. , 1999, Human gene therapy.

[35]  P. Chang,et al.  Persistent delivery of factor IX in mice: gene therapy for hemophilia using implantable microcapsules. , 1999, Human gene therapy.

[36]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[37]  S. Bidlingmaier,et al.  Sustained correction of bleeding disorder in hemophilia B mice by gene therapy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. Morgan,et al.  The rhesus macaque as an animal model for hemophilia B gene therapy. , 1999, Blood.

[39]  R. Kaufman,et al.  Evaluation of an Adenoviral Vector Encoding Full-Length Human Factor VIII in Hemophiliac Mice , 1999, Thrombosis and Haemostasis.

[40]  J. Jesty,et al.  Human factor VIII can be packaged and functionally expressed in an adeno‐associated virus background: applicability to haemophilia A gene therapy , 1999, British journal of haematology.

[41]  Tal Kafri,et al.  A Packaging Cell Line for Lentivirus Vectors , 1999, Journal of Virology.

[42]  M. Alison.  Liver stem cells: a two compartment system. , 1998, Current opinion in cell biology.

[43]  R. Morgan,et al.  Ex vivo fibroblast transduction in rabbits results in long-term (>600 days) factor IX expression in a small percentage of animals. , 1998, Human gene therapy.

[44]  D. Trono,et al.  A Third-Generation Lentivirus Vector with a Conditional Packaging System , 1998, Journal of Virology.

[45]  P. Matzinger,et al.  An innate sense of danger. , 1998, Seminars in immunology.

[46]  N. Sarvetnick,et al.  Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[47]  M. Kay,et al.  Hepatocyte growth factor induces hepatocyte proliferation in vivo and allows for efficient retroviral‐mediated gene transfer in mice , 1998, Hepatology.

[48]  T. VandenDriessche,et al.  Gene therapy for hemophilia: hopes and hurdles , 1998 .

[49]  K. Kurachi,et al.  Targeted inactivation of the coagulation factor IX gene causes hemophilia B in mice. , 1998, Blood.

[50]  R. Morgan,et al.  Genetic induction of immune tolerance to human clotting factor VIII in a mouse model for hemophilia A. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[51]  B. Trapnell,et al.  Sustained phenotypic correction of murine hemophilia A by in vivo gene therapy. , 1998, Blood.

[52]  E. Canning,et al.  A triploblast origin for Myxozoa? , 1998, Nature.

[53]  C. Steer,et al.  In vivo site-directed mutagenesis of the factor IX gene by chimeric RNA/DNA oligonucleotides , 1998, Nature Medicine.

[54]  H. Brems,et al.  Bone marrow stromal cells as targets for gene therapy of hemophilia A. , 1998, Human gene therapy.

[55]  A. Giles,et al.  The Canine Factor VIII cDNA and 5’ Flanking Sequence , 1998, Thrombosis and Haemostasis.

[56]  S. Kung,et al.  Human factor IX corrects the bleeding diathesis of mice with hemophilia B. , 1998, Blood.

[57]  S. Bidlingmaier,et al.  Optimization of the human factor VIII complementary DNA expression plasmid for gene therapy of hemophilia A. , 1997, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[58]  D. Peterson,et al.  Sustained expression of genes delivered directly into liver and muscle by lentiviral vectors , 1997, Nature Genetics.

[59]  M. Zoppè,et al.  A factor IX-deficient mouse model for hemophilia B gene therapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[60]  L Naldini,et al.  Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector , 1997, Journal of virology.

[61]  Luigi Naldini,et al.  Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo , 1997, Nature Biotechnology.

[62]  R. Morgan,et al.  Gut epithelial cells as targets for gene therapy of hemophilia. , 1997, Human gene therapy.

[63]  G. Brownlee,et al.  An ex vivo keratinocyte model for gene therapy of hemophilia B. , 1997, The Journal of investigative dermatology.

[64]  S. Woo,et al.  Viral Vector-Mediated Gene Therapy for Hemophilia B , 1997, Thrombosis and Haemostasis.

[65]  A. Gown,et al.  Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors , 1997, Nature Genetics.

[66]  J. Kaplan,et al.  Transient immunosuppression with deoxyspergualin improves longevity of transgene expression and ability to readminister adenoviral vector to the mouse lung. , 1997, Human gene therapy.

[67]  R. Gregory,et al.  Antibody to CD40 ligand inhibits both humoral and cellular immune responses to adenoviral vectors and facilitates repeated administration to mouse airway , 1997, Gene Therapy.

[68]  James M. Wilson,et al.  Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[69]  C. Lindley,et al.  Extravascular Administration of Factor IX: Potential for Replacement Therapy of Canine and Human Hemophilia B , 1997, Thrombosis and Haemostasis.

[70]  D. Farson,et al.  Persistent transgene expression in mouse liver following in vivo gene transfer with a ΔE1/ΔE4 adenovirus vector , 1997, Gene Therapy.

[71]  A. Gown,et al.  Transient immunomodulation with anti-CD40 ligand antibody and CTLA4Ig enhances persistence and secondary adenovirus-mediated gene transfer into mouse liver. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[72]  E. Berntorp.  Second Generation, B-Domain Deleted Recombinant Factor VIII , 1997, Thrombosis and Haemostasis.

[73]  R. Morgan,et al.  In vivo retrovirus-mediated gene transfer into multiple hematopoietic lineages in rabbits without preconditioning. , 1997, Human gene therapy.

[74]  D. Prockop.  Marrow Stromal Cells as Stem Cells for Nonhematopoietic Tissues , 1997, Science.

[75]  F. Graham,et al.  A helper-dependent system for adenovirus vector production helps define a lower limit for efficient DNA packaging , 1997, Journal of virology.

[76]  S. Kochanek,et al.  Persistence in muscle of an adenoviral vector that lacks all viral genes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[77]  M. Kay,et al.  Liver regeneration: prospects for therapy based on new technologies. , 1997, Molecular medicine today.

[78]  G. Yeoh,et al.  The oval-shaped cell as a candidate for a liver stem cell in embryonic, neonatal and precancerous liver: identification based on morphology and immunohistochemical staining for albumin and pyruvate kinase isoenzyme expression , 1997, Histochemistry and Cell Biology.

[79]  D. Russell,et al.  Persistent expression of human clotting factor IX from mouse liver after intravenous injection of adeno-associated virus vectors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[80]  T. Galanopoulos,et al.  Systemic delivery of human growth hormone or human factor IX in dogs by reintroduced genetically modified autologous bone marrow stromal cells. , 1997, Human gene therapy.

[81]  B. Davidson,et al.  Proliferation induced by keratinocyte growth factor enhances in vivo retroviral-mediated gene transfer to mouse hepatocytes. , 1996, The Journal of clinical investigation.

[82]  J. Wilson,et al.  Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy , 1996, Journal of virology.

[83]  G. Brownlee,et al.  Recombinant factor IX secreted by transduced human keratinocytes is biologically active , 1996, British journal of haematology.

[84]  M. Kay,et al.  Recombinant adenoviruses with large deletions generated by Cre-mediated excision exhibit different biological properties compared with first-generation vectors in vitro and in vivo , 1996, Journal of virology.

[85]  B. Carter.  The promise of adeno-associated virus vectors , 1996, Nature Biotechnology.

[86]  M. Rudnicki,et al.  A helper-dependent adenovirus vector system: removal of helper virus by Cre-mediated excision of the viral packaging signal. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[87]  M. Kaleko,et al.  Complete short-term correction of canine hemophilia A by in vivo gene therapy. , 1996, Blood.

[88]  H. Kazazian,et al.  Further characterization of factor VIII-deficient mice created by gene targeting: RNA and protein studies. , 1996, Blood.

[89]  K. Campbell,et al.  In vivo muscle gene transfer of full-length dystrophin with an adenoviral vector that lacks all viral genes. , 1996, Gene therapy.

[90]  R. Samulski,et al.  Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector , 1996, Journal of virology.

[91]  J. Yang,et al.  Implantation of autologous skin fibroblast genetically modified to secrete clotting factor IX partially corrects the hemorrhagic tendencies in two hemophilia B patients. , 1996, Chinese medical journal.

[92]  R. Mulligan,et al.  A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[93]  F. Gage,et al.  Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[94]  R. Hoeben,et al.  Gene therapy for the hemophilias , 1996, Current opinion in hematology.

[95]  A. van der Eb,et al.  The human clotting factor VIII cDNA contains an autonomously replicating sequence consensus- and matrix attachment region-like sequence that binds a nuclear factor, represses heterologous gene expression, and mediates the transcriptional effects of sodium butyrate , 1996, Molecular and cellular biology.

[96]  A. Al-Hendy,et al.  Delivery of human factor IX in mice by encapsulated recombinant myoblasts: a novel approach towards allogeneic gene therapy of hemophilia B. , 1996, Blood.

[97]  C. Caskey,et al.  A new adenoviral vector: Replacement of all viral coding sequences with 28 kb of DNA independently expressing both full-length dystrophin and beta-galactosidase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[98]  M. Kaleko,et al.  Sustained expression of therapeutic levels of human factor VIII in mice. , 1996, Blood.

[99]  M. Kaleko,et al.  Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector. , 1996, Gene therapy.

[100]  J. Leiden,et al.  Immune responses to transgene–encoded proteins limit the stability of gene expression after injection of replication–defective adenovirus vectors , 1996, Nature Medicine.

[101]  F. Gage,et al.  In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector , 1996, Science.

[102]  D. Kohn,et al.  Expression levels by retroviral vectors based upon the N2 and the MFG backbones. , 1996, Gene therapy.

[103]  K. Kurachi,et al.  Loss of expression of a retrovirus-transduced gene in human keratinocytes. , 1996, The Journal of investigative dermatology.

[104]  D. Bellinger,et al.  Lack of persistence of E1- recombinant adenoviral vectors containing a temperature-sensitive E2A mutation in immunocompetent mice and hemophilia B dogs. , 1996, Gene therapy.

[105]  M. Kaleko,et al.  High-level tissue-specific expression of functional human factor VIII in mice. , 1996, Human gene therapy.

[106]  C. Porter,et al.  Sensitization of cells and retroviruses to human serum by (αl-3) galactosyltransferase , 1996, Nature.

[107]  M. Perricaudet,et al.  Efficient dual transcomplementation of adenovirus E1 and E4 regions from a 293-derived cell line expressing a minimal E4 functional unit , 1996, Journal of virology.

[108]  R. C. Johnson,et al.  Neovascularization of synthetic membranes directed by membrane microarchitecture. , 1995, Journal of biomedical materials research.

[109]  Y Takeuchi,et al.  High-titer packaging cells producing recombinant retroviruses resistant to human serum , 1995, Journal of virology.

[110]  Q. Wang,et al.  A packaging cell line for propagation of recombinant adenovirus vectors containing two lethal gene-region deletions. , 1995, Gene therapy.

[111]  R. Morgan,et al.  Development and analysis of retroviral vectors expressing human factor VIII as a potential gene therapy for hemophilia A. , 1995, Human gene therapy.

[112]  G. Gahrton,et al.  Retroviral‐mediated gene transfer into human bone marrow stromal cells: Studies of efficiency and in vivo survival in SCID mice , 1995, European journal of haematology.

[113]  G. Prince,et al.  Characterization of an adenovirus gene transfer vector containing an E4 deletion. , 1995, Human gene therapy.

[114]  A. Gown,et al.  Long–term hepatic adenovirus–mediated gene expression in mice following CTLA4Ig administration , 1995, Nature Genetics.

[115]  Theodore A G Smith.  Section Review: Biologicals & Immunologicals: Gene therapy for haemophilia , 1995 .

[116]  M. Kay,et al.  Gene therapy for hemophilia B: host immunosuppression prolongs the therapeutic effect of adenovirus-mediated factor IX expression. , 1995, Human gene therapy.

[117]  A. Gown,et al.  A modified urokinase plasminogen activator induces liver regeneration without bleeding. , 1995, Human gene therapy.

[118]  P. Malik,et al.  Expression of biologically active human factor IX in human hematopoietic cells after retroviral vector-mediated gene transduction. , 1995, Human gene therapy.

[119]  A. van der Eb,et al.  Expression of the blood-clotting factor-VIII cDNA is repressed by a transcriptional silencer located in its coding region. , 1995, Blood.

[120]  S. Antonarakis,et al.  Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A , 1995, Nature Genetics.

[121]  C. Caskey,et al.  Rescue, propagation, and partial purification of a helper virus-dependent adenovirus vector. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[122]  A. Krumm,et al.  Sequences within the coding regions of clotting factor VIII and CFTR block transcriptional elongation. , 1995, Human gene therapy.

[123]  R. Crystal,et al.  Modulation of gene expression after replication-deficient, recombinant adenovirus-mediated gene transfer by the product of a second adenovirus vector. , 1995, Gene therapy.

[124]  R. Hoeben.  Gene therapy for the haemophilias: current status. , 1995, Biologicals : journal of the International Association of Biological Standardization.

[125]  N. Sarvetnick,et al.  Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[126]  A. Berns,et al.  Gene therapy for hemophilia A: production of therapeutic levels of human factor VIII in vivo in mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[127]  M. Kaleko,et al.  In vivo gene delivery and expression of physiological levels of functional human factor VIII in mice. , 1995, Human gene therapy.

[128]  R. Kotin.  Prospects for the use of adeno-associated virus as a vector for human gene therapy. , 1994, Human gene therapy.

[129]  James M. Wilson,et al.  Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis , 1994, Nature Genetics.

[130]  A. Dorner,et al.  The levels of endoplasmic reticulum proteins and ATP affect folding and secretion of selective proteins. , 1994, Biologicals : journal of the International Association of Biological Standardization.

[131]  K. Zatloukal,et al.  In vivo production of human factor VII in mice after intrasplenic implantation of primary fibroblasts transfected by receptor-mediated, adenovirus-augmented gene delivery. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[132]  D. Kohn,et al.  Sustained human hematopoiesis in immunodeficient mice by cotransplantation of marrow stroma expressing human interleukin-3: analysis of gene transduction of long-lived progenitors. , 1994, Blood.

[133]  M. Kay,et al.  In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[134]  D. Curiel,et al.  Efficient transfection of primary cells in a canine hemophilia B model using adenovirus-polylysine-DNA complexes. , 1994, Human gene therapy.

[135]  K. Kurachi,et al.  Primary myoblast-mediated gene transfer: persistent expression of human factor IX in mice. , 1994, Gene therapy.

[136]  M. W. Flye,et al.  Liver-directed gene therapy: quantitative evaluation of promoter elements by using in vivo retroviral transduction. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[137]  J. Lozier,et al.  Gene therapy and the hemophilias. , 1994, JAMA.

[138]  B. Trapnell,et al.  Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice , 1993, Nature Genetics.

[139]  Lu Da-ru,et al.  Long-term expression of human factor IX cDNA in rabbits. , 1993 .

[140]  Lu Da-ru,et al.  Stage I Clinical Trial of Gene Therapy for Hemophilia B , 1993 .

[141]  M. Kay,et al.  In vivo gene therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. , 1993, Science.

[142]  A. Giles,et al.  Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII. , 1993, Blood.

[143]  A. Miller,et al.  Sequences in the coding region of clotting factor VIII act as dominant inhibitors of RNA accumulation and protein production. , 1993, Human gene therapy.

[144]  R. Moen,et al.  Report to the NIH Recombinant DNA Advisory Committee on murine replication-competent retrovirus (RCR) assays (February 17, 1993). , 1993, Human gene therapy.

[145]  A. van der Eb,et al.  Toward gene therapy for hemophilia A: long-term persistence of factor VIII-secreting fibroblasts after transplantation into immunodeficient mice. , 1993, Human gene therapy.

[146]  F. Watt,et al.  Towards gene therapy for haemophilia B using primary human keratinocytes , 1993, Nature Genetics.

[147]  A. Giles,et al.  The Development of Homologous (Canine/Anti-Canine) Antibodies in Dogs with Haemophilia A (Factor VIII Deficiency): A Ten-Year Longitudinal Study , 1993, Thrombosis and Haemostasis.

[148]  R. Naviaux,et al.  Gene therapy via primary myoblasts: long-term expression of factor IX protein following transplantation in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[149]  K. Kurachi,et al.  Biology of factor IX. , 1992, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[150]  M. Raffeld,et al.  Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer , 1992, The Journal of experimental medicine.

[151]  R. Naviaux,et al.  Circulating human or canine factor IX from retrovirally transduced primary myoblasts and established myoblast cell lines grafted into murine skeletal muscle , 1992, Somatic cell and molecular genetics.

[152]  K. Kurachi,et al.  Expression of human factor IX in mice after injection of genetically modified myoblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[153]  A. van der Eb,et al.  Toward Gene Therapy in Haemophilia A: Retrovirus-Mediated Transfer of a Factor VIII Gene into Murine Haematopoietic Progenitor Cells , 1992, Thrombosis and Haemostasis.

[154]  K. Kurachi,et al.  Deficiencies in factors IX and VIII: what is now known. , 1992, Hospital practice.

[155]  K. Kurachi,et al.  Expression of human factor IX in rat capillary endothelial cells: toward somatic gene therapy for hemophilia B. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[156]  A. Thompson.  Status of Gene Transfer for Hemophilia A and B , 1991, Thrombosis and Haemostasis.

[157]  R. Scharfmann,et al.  Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[158]  A. van der Eb,et al.  Inactivation of the Moloney murine leukemia virus long terminal repeat in murine fibroblast cell lines is associated with methylation and dependent on its chromosomal position , 1991, Journal of virology.

[159]  R. Palmiter,et al.  Heterologous introns can enhance expression of transgenes in mice. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[160]  G. Darlington,et al.  Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: potential for gene therapy of hemophilia B. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[161]  M. Goossens,et al.  Haemophilia B: database of point mutations and short additions and deletions, 7th edition , 1990, Nucleic Acids Res..

[162]  I. Verma,et al.  Phenotypic correction of factor IX deficiency in skin fibroblasts of hemophilic dogs. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[163]  A. van der Eb,et al.  Expression of functional factor VIII in primary human skin fibroblasts after retrovirus-mediated gene transfer. , 1990, The Journal of biological chemistry.

[164]  R. Kaufman,et al.  Retroviral-mediated transfer and amplification of a functional human factor VIII gene. , 1990, Blood.

[165]  G. Brayer,et al.  Canine hemophilia B resulting from a point mutation with unusual consequences. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[166]  R. Kaufman,et al.  Structure-Function Relationships of Factor VIII Elucidated through Recombinant DNA Technology , 1989, Thrombosis and Haemostasis.

[167]  K. Berkner.  Development of adenovirus vectors for the expression of heterologous genes. , 1988, BioTechniques.

[168]  A. Dorner,et al.  Synthesis, processing, and secretion of recombinant human factor VIII expressed in mammalian cells. , 1988, The Journal of biological chemistry.

[169]  S. Leahy.  Eight ‘Musts’ for Biotechnology , 1988, Bio/Technology.

[170]  I. Verma,et al.  An alternative approach to somatic cell gene therapy. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[171]  I. Verma,et al.  Towards gene therapy for hemophilia B. , 1987, Molecular biology & medicine.

[172]  R. Kaufman,et al.  A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[173]  B. Keyt,et al.  Structure of human factor VIII , 1984, Nature.

[174]  E. Chen,et al.  Characterization of the human factor VIII gene , 1984, Nature.

[175]  B. Keyt,et al.  Expression of active human factor VIII from recombinant DNA clones , 1984, Nature.

[176]  G. Knutson,et al.  Molecular cloning of a cDNA encoding human antihaemophilic factor , 1984, Nature.

[177]  A. Giles,et al.  Development of factor VIII:C antibodies in dogs with hemophilia A (factor VIII:C deficiency) , 1984 .

[178]  K. Kurachi,et al.  Isolation and characterization of a cDNA coding for human factor IX. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[179]  P. Leder,et al.  Splicing and the formation of stable RNA , 1979, Cell.

[180]  M. Kay,et al.  Efficient lentiviral transduction of liver requires cell cycling in vivo , 2000, Nature Genetics.

[181]  R. Samulski,et al.  Site-specific targeting of DNA plasmids to chromosome 19 using AAV cis and trans sequences. , 2000, Methods in molecular biology.

[182]  Katherine A. High,et al.  Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector , 1999, Nature Medicine.

[183]  M. Kay,et al.  Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors , 1999, Nature Medicine.

[184]  R. Samulski,et al.  Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia , 1998, Gene Therapy.

[185]  R. C. Johnson,et al.  Transplantation of cells in an immunoisolation device for gene therapy. , 1997, Methods in molecular biology.

[186]  J. Arnout,et al.  Factor VIII Inhibitors in Previously Treated Haemophilia A Patients with a Double Virus-inactivated Plasma Derived Factor VIII Concentrate , 1997, Thrombosis and Haemostasis.

[187]  G. Lenoir,et al.  Molecular cloning and mapping of a human cDNA (PA2G4) that encodes a protein highly homologous to the mouse cell cycle protein p38-2G4. , 1997, Cytogenetics and cell genetics.

[188]  M Vapalahti,et al.  [Human gene therapy]. , 1996, Duodecim; laaketieteellinen aikakauskirja.

[189]  C. Porter,et al.  Sensitization of cells and retroviruses to human serum by (alpha 1-3) galactosyltransferase. , 1996, Nature.

[190]  A. J. Gerrard.  Towards Gene Therapy for Haemophilia B , 1996 .

[191]  M. Baru,et al.  Retroviral-mediated in vivo gene transfer into muscle cells and synthesis of human factor IX in mice. , 1995, Intervirology.

[192]  Donald W. Pfaff,et al.  Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain , 1994, Nature Genetics.

[193]  G. Anton.  Retroviral vectors. , 1994, Revue roumaine de virologie.

[194]  Daniel G. Miller,et al.  Use of retroviral vectors for gene transfer and expression. , 1993, Methods in enzymology.

[195]  X. Wang,et al.  Stage I clinical trial of gene therapy for hemophilia B. , 1993, Science in China. Series B, Chemistry, life sciences & earth sciences.

[196]  J. M. Zhou,et al.  Long-term expression of human factor IX cDNA in rabbits. , 1993, Science in China. Series B, Chemistry, life sciences & earth sciences.

[197]  O. Gan,et al.  Gene therapy model for stromal precursor cells of hematopoietic microenvironment. , 1992, Leukemia.

[198]  K. Cornetta,et al.  Safety issues related to retroviral-mediated gene transfer in humans. , 1991, Human gene therapy.

[199]  R. Herzog,et al.  Skeletal Actin/cmv Hybrid Enhancer/promoter Improved Muscle-derived Expression of Human Coagulation Factor Ix from A , 2022 .