Gene therapy: therapeutic applications and relevance to pathology

Summary This review discusses gene therapy as a new treatment paradigm where genetic material is introduced into cells for therapeutic benefit. The genetic material is the ‘drug’. It can have a transient or ongoing effect depending on whether or not the introduced genetic material becomes part of the host cell DNA. Different delivery and gene technologies are chosen by investigators to maximise gene delivery to, and expression within, the target cells appropriate for the disease indication. The presence and expression of the introduced genetic material is monitored by molecular means so that treatment efficacy can be assessed via changes in surrogate and/or actual markers of disease. Of interest to the pathologist will be the approaches being developed for the disease indications highlighted and the monitoring of treatment efficacy.

[1]  G. Margison,et al.  Lentivirus-mediated expression of mutant MGMTP140K protects human CD34+ cells against the combined toxicity of O6-benzylguanine and 1,3-bis(2-chloroethyl)-nitrosourea or temozolomide. , 2004, Human gene therapy.

[2]  E. Simons.  Gene Therapy of X-Linked Severe Combined Immunodeficiency by Use of a Pseudotyped Gammaretroviral Vector , 2006, Pediatrics.

[3]  J. Rasko,et al.  Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response , 2006, Nature Medicine.

[4]  A. Rabinowitz,et al.  Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Frederic D. Bushman,et al.  Efficacy of gene therapy for X-linked severe combined immunodeficiency. , 2010, The New England journal of medicine.

[6]  Christof von Kalle,et al.  A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. , 2003, The New England journal of medicine.

[7]  Yang Du,et al.  Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1 , 2006, Nature Medicine.

[8]  G. Both.  Gene-directed enzyme prodrug therapy for cancer: a glimpse into the future? , 2009, Discovery medicine.

[9]  I. Graham,et al.  Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study , 2009, The Lancet Neurology.

[10]  P. Russell,et al.  Relative efficiency of tumor cell killing in vitro by two enzyme-prodrug systems delivered by identical adenovirus vectors. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  M. Wiles,et al.  Hematopoietic commitment during embryonic stem cell differentiation in culture. , 1993, Molecular and cellular biology.

[12]  A. Manzur,et al.  Glucocorticoid corticosteroids for Duchenne muscular dystrophy. , 2004, The Cochrane database of systematic reviews.

[13]  Ravi A. Desai,et al.  Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid , 2006, Nature Medicine.

[14]  S. Ponnazhagan,et al.  Lack of site-specific integration of the recombinant adeno-associated virus 2 genomes in human cells. , 1997, Human gene therapy.

[15]  G. van Ommen,et al.  Systemic administration of PRO051 in Duchenne's muscular dystrophy. , 2011, The New England journal of medicine.

[16]  John J. Rossi,et al.  Foamy Combinatorial Anti-HIV Vectors with MGMTP140K Potently Inhibit HIV-1 and SHIV Replication and Mediate Selection In Vivo , 2009, Gene Therapy.

[17]  I. Graham,et al.  Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. , 2007, Human gene therapy.

[18]  P. Russell,et al.  Gene‐directed enzyme prodrug therapy for prostate cancer in a mouse model that imitates the development of human disease , 2004, The journal of gene medicine.

[19]  Christof von Kalle,et al.  Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. , 2009, Nature medicine.

[20]  Kevin M Flanigan,et al.  The Muscular Dystrophies , 1999, Seminars in Neurology.

[21]  R W Veltri,et al.  Implication of cell kinetic changes during the progression of human prostatic cancer. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  G. V. Ommen,et al.  The risks of therapeutic misconception and individual patient (n =1) “trials” in rare diseases such as Duchenne dystrophy , 2011, Neuromuscular Disorders.

[23]  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.

[24]  N. James,et al.  A phase I/II clinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954 [correction of CB1984]. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[25]  A. Mortellaro,et al.  Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning , 2002, Science.

[26]  R. Griggs,et al.  Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids 2–4 April 2004, Naarden, The Netherlands , 2004, Neuromuscular Disorders.

[27]  Hans Martin,et al.  Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease , 2010, Nature Medicine.

[28]  J. Zack,et al.  Phase I/II Clinical Trials Using Gene-Modified Adult Hematopoietic Stem Cells for HIV: Lessons Learnt , 2011, Stem cells international.

[29]  L. Notarangelo,et al.  Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement , 2002, Nature Medicine.

[30]  H. Herschman,et al.  The influence of innate and pre‐existing immunity on adenovirus therapy , 2009, Journal of cellular biochemistry.

[31]  P. Russell,et al.  Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines , 2009, Clinical Cancer Research.

[32]  G. Symonds,et al.  The use of cell-delivered gene therapy for the treatment of HIV/AIDS , 2010, Immunologic research.

[33]  S. Rosenberg,et al.  Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes , 2006, Science.

[34]  B. Movsas,et al.  Prostate cancer gene therapy clinical trials. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[35]  A. Monaco,et al.  An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. , 1988, Genomics.

[36]  D. Russell,et al.  Foamy virus vectors , 1996, Journal of virology.

[37]  J. Mendell,et al.  Aminoglycoside-induced mutation suppression (stop codon readthrough) as a therapeutic strategy for Duchenne muscular dystrophy , 2010, Therapeutic advances in neurological disorders.

[38]  F. Baas,et al.  Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients. , 2003, Human molecular genetics.

[39]  J. Mendell,et al.  Molecular Therapeutic Strategies Targeting Duchenne Muscular Dystrophy , 2010, Journal of child neurology.

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

[41]  A. Rabinowitz,et al.  Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology , 2006, Nature Medicine.

[42]  A. Dutra,et al.  The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Amado,et al.  Gene therapy for HIV/AIDS: the potential for a new therapeutic regimen , 2003, The journal of gene medicine.

[44]  M. Branca.  Gene therapy: cursed or inching towards credibility? , 2005, Nature Biotechnology.

[45]  C. Mann,et al.  Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse , 2003, Nature Medicine.

[46]  A. Thrasher,et al.  Gene therapy for severe combined immunodeficiencies , 2005, Expert opinion on biological therapy.

[47]  J. Mendell,et al.  Somatic reversion/suppression in Duchenne muscular dystrophy (DMD): evidence supporting a frame-restoring mechanism in rare dystrophin-positive fibers. , 1992, American journal of human genetics.

[48]  J. Rasko,et al.  Gene Therapy for Hemophilia: Clinical Trials and Technical Tribulations , 2009, Seminars in thrombosis and hemostasis.

[49]  G. van Ommen,et al.  New insights in gene‐derived therapy: the example of Duchenne muscular dystrophy , 2010, Annals of the New York Academy of Sciences.

[50]  Clelia Di Serio,et al.  Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration , 2006, Nature Biotechnology.

[51]  Akinori Nakamura,et al.  Efficacy of systemic morpholino exon‐skipping in duchenne dystrophy dogs , 2009, Annals of neurology.

[52]  Geoffrey Kemball-Cook,et al.  Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. , 2006, Blood.

[53]  Stephen L. Brown,et al.  Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[54]  A. Schambach,et al.  Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[55]  A. Aiuti,et al.  Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency , 2010, Current opinion in allergy and clinical immunology.

[56]  J. Wilson,et al.  Efficacy and safety of adeno‐associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy , 2006, Journal of thrombosis and haemostasis : JTH.

[57]  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.

[58]  C. Mann,et al.  Improved antisense oligonucleotide induced exon skipping in the mdx mouse model of muscular dystrophy , 2002, The journal of gene medicine.

[59]  C. Mann,et al.  Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Jamel Chelly,et al.  Transcription of the dystrophin gene in human muscle and non-muscle tissues , 1988, Nature.

[61]  F. Deist,et al.  Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. , 2000, Science.

[62]  D. Persons,et al.  Solving the problem of γ-retroviral vectors containing long terminal repeats. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[63]  Johan T den Dunnen,et al.  Local dystrophin restoration with antisense oligonucleotide PRO051. , 2007, The New England journal of medicine.

[64]  A. Fischer,et al.  Treatment of an infant with X-linked severe combined immunodeficiency ( SCID-X 1 ) by gene therapy in Australia , 2000 .

[65]  A. Giles,et al.  Aberrant Splicing and Premature Termination of Transcription of the FVIII Gene as a Cause of Severe Canine Hemophilia A: Similarities with the Intron 22 Inversion Mutation in Human Hemophilia , 2002, Thrombosis and Haemostasis.

[66]  Kathleen A. Marshall,et al.  Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial , 2009, The Lancet.

[67]  Jérôme Larghero,et al.  Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia , 2010, Nature.

[68]  Lindsay J. Georgopoulos,et al.  Adenovirus-derived vectors for prostate cancer gene therapy. , 2010, Human gene therapy.

[69]  Colin Chandler,et al.  Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation , 2002, Neuromuscular Disorders.

[70]  S. Cole,et al.  Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1-infected patients. , 2004, Human gene therapy.

[71]  S. Wilton,et al.  Morpholino antisense oligonucleotide induced dystrophin exon 23 skipping in mdx mouse muscle. , 2003, Human molecular genetics.

[72]  G. Both.  Recent progress in gene-directed enzyme prodrug therapy: an emerging cancer treatment. , 2009, Current opinion in molecular therapeutics.

[73]  Manfred Schmidt,et al.  Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy , 2009, Science.

[74]  S. Wilton,et al.  Antisense oligonucleotide-induced exon skipping across the human dystrophin gene transcript. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[75]  G. Both.  Ovine atadenovirus: a review of its biology, biosafety profile and application as a gene delivery vector , 2004, Immunology and cell biology.

[76]  L. Couto,et al.  Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. , 2006, Blood.

[77]  G. Symonds,et al.  Gene-expressed RNA as a therapeutic: issues to consider, using ribozymes and small hairpin RNA as specific examples. , 2006, Handbook of experimental pharmacology.

[78]  D. Baltimore.  Gene therapy. Intracellular immunization. , 1988, Nature.

[79]  Stephen L. Brown,et al.  Phase I trial of replication-competent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[80]  Jon Cohen,et al.  Building an HIV-Proof Immune System , 2007, Science.

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

[82]  P. Iversen,et al.  Morpholino oligomer-mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[83]  G. van Ommen,et al.  In vivo comparison of 2′‐O‐methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping , 2009, The journal of gene medicine.

[84]  Christine Kinnon,et al.  Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. , 2008, The Journal of clinical investigation.

[85]  J. H. Kim,et al.  Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization. , 2000, Human gene therapy.

[86]  K. Cornetta,et al.  Certification assays for HIV-1-based vectors: frequent passage of gag sequences without evidence of replication-competent viruses. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[87]  R. Herzog,et al.  Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. , 2002, Blood.

[88]  J. Mendell,et al.  Gentamicin‐induced readthrough of stop codons in duchenne muscular dystrophy , 2010, Annals of neurology.

[89]  K. High,et al.  Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges , 2011, Nature Reviews Genetics.

[90]  B. Smart.  Stem-Cell Gene Therapy for the Wiskott-Aldrich Syndrome , 2011, Pediatrics.

[91]  J. Sommer,et al.  Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[92]  D. Kaufman,et al.  Multilineage Differentiation from Human Embryonic Stem Cell Lines , 2001, Stem cells.

[93]  S. Rosenberg,et al.  T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years , 1995, Science.

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

[95]  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.

[96]  T. Vulliamy,et al.  Exon skipping and translation in patients with frameshift deletions in the dystrophin gene. , 1993, American journal of human genetics.

[97]  Marcela V Maus,et al.  CD8+ T-cell responses to adeno-associated virus capsid in humans , 2007, Nature Medicine.

[98]  T. Friedmann.  Gene therapy of cancer through restoration of tumor‐suppressor functions? , 1992, Cancer.

[99]  S. Wilton,et al.  Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide , 2006, The journal of gene medicine.

[100]  J. Peabody,et al.  Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. , 2003, Cancer research.

[101]  P. Russell,et al.  Purine nucleoside phosphorylase and fludarabine phosphate gene‐directed enzyme prodrug therapy suppresses primary tumour growth and pseudo‐metastases in a mouse model of prostate cancer , 2004, The journal of gene medicine.

[102]  S. Tapscott,et al.  Gene therapy in large animal models of muscular dystrophy. , 2009, ILAR journal.

[103]  P. Russell,et al.  Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus , 2004, Gene Therapy.

[104]  M. Robb.  Failure of the Merck HIV vaccine: an uncertain step forward , 2008, The Lancet.

[105]  N. Wade.  Gene therapy caught in more entanglements. , 1981, Science.

[106]  N. James,et al.  A Phase I/II Clinical Trial in Localized Prostate Cancer of an Adenovirus Expressing Nitroreductase with CB1984. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[107]  Steve D Wilton,et al.  Splice modification to restore functional dystrophin synthesis in Duchenne muscular dystrophy. , 2010, Current pharmaceutical design.

[108]  P. Iversen,et al.  Antisense oligonucleotide-induced exon skipping restores dystrophin expression in vitro in a canine model of DMD , 2006, Gene Therapy.

[109]  S. Agrawal,et al.  Specific removal of the nonsense mutation from the mdx dystrophin mRNA using antisense oligonucleotides , 1999, Neuromuscular Disorders.

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

[111]  Thomas W Prior,et al.  Experience and strategy for the molecular testing of Duchenne muscular dystrophy. , 2005, The Journal of molecular diagnostics : JMD.

[112]  K. Davies,et al.  Prevention of dystrophic pathology in severely affected dystrophin/utrophin-deficient mice by morpholino-oligomer-mediated exon-skipping. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[113]  F. Muntoni,et al.  Immunohistological intensity measurements as a tool to assess sarcolemma‐associated protein expression , 2009, Neuropathology and applied neurobiology.

[114]  P. Miura,et al.  Utrophin upregulation for treating Duchenne or Becker muscular dystrophy: how close are we? , 2006, Trends in molecular medicine.

[115]  W. Gerlach,et al.  Long‐term survival and concomitant gene expression of ribozyme‐transduced CD4+ T‐lymphocytes in HIV‐infected patients , 2005, The journal of gene medicine.

[116]  A. Fischer,et al.  20 years of gene therapy for SCID , 2010, Nature Immunology.

[117]  L. Popplewell,et al.  Gene therapy for muscular dystrophy: current progress and future prospects , 2009, Expert opinion on biological therapy.