Gene therapy returns to centre stage

Recent clinical trials of gene therapy have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver 'cures' for some otherwise terminal or severely disabling conditions. Behind these advances lie improved vector designs that enable the safe delivery of therapeutic genes to specific cells. Technologies for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.

[1]  T. Schumacher,et al.  Neoantigens in cancer immunotherapy , 2015, Science.

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

[3]  Hojun Li,et al.  Assessing the potential for AAV vector genotoxicity in a murine model. , 2011, Blood.

[4]  Christof von Kalle,et al.  The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. , 2009, The Journal of clinical investigation.

[5]  A. Shapiro,et al.  Modern haemophilia care , 2012, The Lancet.

[6]  L. Notarangelo,et al.  Primary immunodeficiencies. , 2010, The Journal of allergy and clinical immunology.

[7]  S. Kemp,et al.  See Blockindiscussions, Blockinstats, Blockinand Blockinauthor Blockinprofiles Blockinfor Blockinthis Blockinpublication X-linked Blockinadrenoleukodystrophy: Blockinclinical, Metabolic, Blockingenetic Blockinand Blockinpathophysiological Aspects Article Blockin Blockinin Blockin Blockinbiochimica B , 2022 .

[8]  A. Fischer,et al.  Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy. , 2012, Methods in Enzymology.

[9]  R. Herzog,et al.  Progress and prospects: immune responses to viral vectors , 2010, Gene Therapy.

[10]  R. Barker,et al.  Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial , 2014, The Lancet.

[11]  S. Rosenberg,et al.  Adoptive cell transfer as personalized immunotherapy for human cancer , 2015, Science.

[12]  L. Naldini,et al.  Liver-directed lentiviral gene therapy in a dog model of hemophilia B , 2015, Science Translational Medicine.

[13]  Rodney Rothstein,et al.  Repair of strand breaks by homologous recombination. , 2013, Cold Spring Harbor perspectives in biology.

[14]  Paolo Melillo,et al.  Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. , 2013, Ophthalmology.

[15]  K. High,et al.  Immune responses to AAV vectors: overcoming barriers to successful gene therapy. , 2013, Blood.

[16]  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.

[17]  Hojun Li,et al.  In vivo genome editing restores hemostasis in a mouse model of hemophilia , 2011, Nature.

[18]  S. Bicciato,et al.  IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. , 2013, Blood.

[19]  D. Lavillette,et al.  Baboon envelope pseudotyped LVs outperform VSV-G-LVs for gene transfer into early-cytokine-stimulated and resting HSCs. , 2014, Blood.

[20]  H. Ertl,et al.  Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. , 2013, Blood.

[21]  M. Cavazzana‐Calvo,et al.  A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. , 2010, Blood.

[22]  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.

[23]  Alessandro Aiuti,et al.  Gene therapy for immunodeficiency due to adenosine deaminase deficiency. , 2009, The New England journal of medicine.

[24]  L. Pani,et al.  Regulatory evaluation of Glybera in Europe — two committees, one mission , 2013, Nature Reviews Drug Discovery.

[25]  Christof von Kalle,et al.  and insertional genotoxicity Cell culture assays reveal the importance of retroviral vector design for , 2006 .

[26]  L. Gattinoni.  Memory T cells officially join the stem cell club. , 2014, Immunity.

[27]  L. Naldini,et al.  Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. , 2006, The Journal of clinical investigation.

[28]  Michael Rothe,et al.  Gene Therapy for Wiskott-Aldrich Syndrome—Long-Term Efficacy and Genotoxicity , 2014, Science Translational Medicine.

[29]  David V. Schaffer,et al.  Engineering adeno-associated viruses for clinical gene therapy , 2014, Nature Reviews Genetics.

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

[31]  John T. Gray,et al.  Mouse Transplant Models for Evaluating the Oncogenic Risk of a Self-Inactivating XSCID Lentiviral Vector , 2013, PloS one.

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

[33]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

[34]  Margherita Neri,et al.  Site-specific integration and tailoring of cassette design for sustainable gene transfer , 2011, Nature Methods.

[35]  Jean Bennett,et al.  Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[36]  David V Schaffer,et al.  The AAV Vector Toolkit: Poised at the Clinical Crossroads. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[37]  P. Sharma,et al.  The future of immune checkpoint therapy , 2015, Science.

[38]  M. Raffeld,et al.  Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes , 2002, Science.

[39]  Christof von Kalle,et al.  Fanconi anemia gene editing by the CRISPR/Cas9 system. , 2015, Human gene therapy.

[40]  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.

[41]  I. Weissman,et al.  The road to purified hematopoietic stem cell transplants is paved with antibodies. , 2012, Current opinion in immunology.

[42]  U. Modlich,et al.  Concise Review: Managing Genotoxicity in the Therapeutic Modification of Stem Cells , 2011, Stem cells.

[43]  D. Lillicrap,et al.  Current status of haemophilia gene therapy , 2014, Haemophilia : the official journal of the World Federation of Hemophilia.

[44]  Sadik H. Kassim,et al.  A Pilot Trial Using Lymphocytes Genetically Engineered with an NY-ESO-1–Reactive T-cell Receptor: Long-term Follow-up and Correlates with Response , 2014, Clinical Cancer Research.

[45]  Pamela A Shaw,et al.  Chimeric antigen receptor T cells for sustained remissions in leukemia. , 2014, The New England journal of medicine.

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

[47]  Troyen A. Brennan,et al.  The special case of gene therapy pricing , 2014, Nature Biotechnology.

[48]  C. von Kalle,et al.  Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy , 2013, Science.

[49]  T. Nägele,et al.  Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort , 2013, Bone Marrow Transplantation.

[50]  Luigi Naldini,et al.  A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. , 2012, Blood.

[51]  L. Naldini.  Ex vivo gene transfer and correction for cell-based therapies , 2011, Nature Reviews Genetics.

[52]  Daniel G. Anderson,et al.  Genome editing with Cas 9 in adult mice corrects a disease mutation and phenotype Citation , 2014 .

[53]  C. Di Serio,et al.  Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation , 2012, Proceedings of the National Academy of Sciences.

[54]  Gianluigi Zanetti,et al.  Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. , 2011, Blood.

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

[56]  A. Wright.  Long-term effects of retinal gene therapy in childhood blindness. , 2015, The New England journal of medicine.

[57]  Wei-Ting Hwang,et al.  Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. , 2014, The New England journal of medicine.

[58]  S. Rosenberg,et al.  Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[59]  Matthew C. Canver,et al.  An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level , 2013, Science.

[60]  Feng Zhang,et al.  CRISPR germline engineering—the community speaks , 2015, Nature Biotechnology.

[61]  L. Naldini,et al.  Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters , 2005, Nature Biotechnology.

[62]  D. Shera,et al.  Long-Term Follow-Up After Gene Therapy for Canavan Disease , 2012, Science Translational Medicine.

[63]  Kathryn L. Parsley,et al.  Long-Term Persistence of a Polyclonal T Cell Repertoire After Gene Therapy for X-Linked Severe Combined Immunodeficiency , 2011, Science Translational Medicine.

[64]  Lei Zhang,et al.  Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. , 2015, Blood.

[65]  Christopher Baum,et al.  A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. , 2014, The New England journal of medicine.

[66]  J. Doudna,et al.  The new frontier of genome engineering with CRISPR-Cas9 , 2014, Science.

[67]  Frederic D Bushman,et al.  Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. , 2015, JAMA.

[68]  J. Church.  Vectored Immunoprophylaxis Protects Humanized Mice From Mucosal HIV Transmission , 2014, Pediatrics.

[69]  Aaron R Cooper,et al.  Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. , 2012, Blood.

[70]  J. F. Wright,et al.  Overcoming Preexisting Humoral Immunity to AAV Using Capsid Decoys , 2013, Science Translational Medicine.

[71]  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.

[72]  S. Rosenberg,et al.  Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. , 2009, Blood.

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

[74]  Sadik H. Kassim,et al.  Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[75]  Jianhong Cao,et al.  Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. , 2008, The New England journal of medicine.

[76]  Z. Modrušan,et al.  Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing , 2014, Nature.

[77]  M. van der Burg,et al.  Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells , 2014, Nature.

[78]  A. Elkahloun,et al.  Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. , 2015, The Journal of clinical investigation.

[79]  C. von Kalle,et al.  Insertion sites in engrafted cells cluster within a limited repertoire of genomic areas after gammaretroviral vector gene therapy. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[80]  A. Ballabio,et al.  Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. , 2014 .

[81]  D. Kohn.  Gene therapy outpaces haplo for SCID-X1. , 2015, Blood.

[82]  Seth M Steinberg,et al.  T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial , 2015, The Lancet.

[83]  Yong Huang,et al.  Promoterless gene targeting without nucleases ameliorates haemophilia B in mice , 2014, Nature.

[84]  R. Cattaneo,et al.  New viruses for cancer therapy: meeting clinical needs , 2013, Nature Reviews Microbiology.

[85]  A. Fischer,et al.  Primary immunodeficiencies: 2009 update. , 2009, The Journal of allergy and clinical immunology.

[86]  Edward Wright,et al.  A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA. , 2015, The New England journal of medicine.

[87]  J. Grieger,et al.  Adeno-associated virus vectorology, manufacturing, and clinical applications. , 2012, Methods in enzymology.

[88]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[89]  M. Kay,et al.  Selection and evaluation of clinically relevant AAV variants in a xenograft liver model , 2013, Nature.

[90]  L. Naldini,et al.  Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. , 2004, The Journal of clinical investigation.

[91]  C. Breitbach,et al.  Going viral with cancer immunotherapy , 2014, Nature Reviews Cancer.

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

[93]  Randall J. Platt,et al.  Therapeutic genome editing: prospects and challenges , 2015, Nature Medicine.

[94]  Luigi Naldini,et al.  Targeted gene therapy and cell reprogramming in Fanconi anemia , 2014, EMBO molecular medicine.

[95]  Maxim N. Artyomov,et al.  Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens , 2014, Nature.

[96]  A. J. Roman,et al.  Improvement and decline in vision with gene therapy in childhood blindness. , 2015, The New England journal of medicine.

[97]  Michael Recht,et al.  Long-term safety and efficacy of factor IX gene therapy in hemophilia B. , 2014, The New England journal of medicine.

[98]  D. Kuhns,et al.  Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. , 2010, Blood.

[99]  I. Krägeloh-Mann,et al.  Metachromatic Leukodystrophy – An Update , 2010, Neuropediatrics.

[100]  J. Stockman.  Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome , 2012 .

[101]  A. Fischer,et al.  Immune deficiencies , infection , and systemic immune disorders Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe : Entering a new century , do we do better ? , 2010 .

[102]  Edward A Copelan,et al.  Hematopoietic stem-cell transplantation. , 2006, The New England journal of medicine.

[103]  A. Nicosia,et al.  Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults , 2015, Science Translational Medicine.

[104]  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.

[105]  Qing He,et al.  CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia , 2013, Science Translational Medicine.

[106]  C. von Kalle,et al.  Retroviral gene therapy for X-linked chronic granulomatous disease: results from phase I/II trial. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[107]  Jennifer A. Doudna,et al.  A prudent path forward for genomic engineering and germline gene modification , 2015, Science.

[108]  Ton N. Schumacher,et al.  Adoptive cellular therapy: A race to the finish line , 2015, Science Translational Medicine.

[109]  F. Bushman,et al.  Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. , 2008, The Journal of clinical investigation.

[110]  Lei Zhang,et al.  Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer , 2012, Nature Medicine.

[111]  A. Schambach,et al.  Physiological promoters reduce the genotoxic risk of integrating gene vectors. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[112]  Jennifer A. Doudna,et al.  The new frontier of genome engineering with CRISPR-Cas 9 GENOME , 2014 .

[113]  Martin J. Aryee,et al.  GUIDE-Seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases , 2014, Nature Biotechnology.

[114]  J. Gern,et al.  Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients With Wiskott-Aldrich Syndrome , 2014, Pediatrics.

[115]  Mark Ende,et al.  Hematopoietic stem-cell transplantation. , 2006, The New England journal of medicine.

[116]  Jessica Zucman-Rossi,et al.  Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas , 2015, Nature Genetics.

[117]  Kathryn L. Parsley,et al.  Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase–Deficient Severe Combined Immunodeficiency Leads to Long-Term Immunological Recovery and Metabolic Correction , 2011, Science Translational Medicine.

[118]  Elisa Laurenti,et al.  Hematopoiesis: a human perspective. , 2012, Cell stem cell.

[119]  B. Levine,et al.  Adoptive immunotherapy for cancer or viruses. , 2014, Annual review of immunology.

[120]  Jeffrey C. Miller,et al.  An unbiased genome-wide analysis of zinc-finger nuclease specificity , 2011, Nature Biotechnology.

[121]  David A. Scott,et al.  In vivo genome editing using Staphylococcus aureus Cas9 , 2015, Nature.

[122]  C. Morrison.  $1-million price tag set for Glybera gene therapy , 2015, Nature Biotechnology.

[123]  P. Gregory,et al.  Genomic Editing of the HIV-1 Coreceptor CCR5 in Adult Hematopoietic Stem and Progenitor Cells Using Zinc Finger Nucleases , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[124]  C. Bordignon,et al.  Improving the safety of cell therapy with the TK-suicide gene , 2015, Front. Pharmacol..