Gene Therapy pp 139-281 | Cite as

Clinical Applications of Gene Therapy

  • Mauro Giacca


Since 1989, the year of the first gene therapy clinical trial (cf. section on ‘Genes as Drugs’), over 1500 clinical studies have been conducted involving several tens of thousands of patients. If objectively evaluated, the overall clinical success of these trials has been modest so far. With some remarkable exceptions, most of the trials have encountered unanticipated technological and biological problems. In this evaluation, however, it should be taken into account that the vast majority of the diseases faced by gene therapy are life-threatening conditions, for which no conventional medical therapy exists, and that gene therapy is a completely new discipline, both conceptually and technically. Indeed, 20 years after the first application, the possibility of success of gene therapy now appears much closer. This is a consequence of the significant improvements made in the development of both in vivo and ex vivo systems for gene delivery and the identification of novel classes of therapeutic genes. The recent results obtained by gene therapy of inherited blindness and of some neurodegenerative disorders, as well as the progress made in several other clinical trials, now encourage informed and firm optimism on the eventual success of this discipline.


Gene Therapy Major Histocompatibility Complex Class Duchenne Muscular Dystrophy Spinal Muscular Atrophy Simian Immunodeficiency Virus 


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4.1 Clinical Applications of Gene Therapy: General Considerations

Further Reading

  1. Alexander BL, Ali RR, Alton EW et al (2007) Progress and prospects: gene therapy clinical trials (part 1). Gene Ther 14:1439–1447PubMedGoogle Scholar
  2. Alton E, Ferrari S, Griesenbach U (2007) Progress and prospects: gene therapy clinical trials (part 2). Gene Ther 14:1555–1563PubMedGoogle Scholar
  3. Edelstein ML, Abedi MR, Wixon J (2007) Gene therapy clinical trials worldwide to 2007: an update. J Gene Med 9:833–842PubMedGoogle Scholar
  4. Edelstein ML, Abedi MR, Wixon J, Edelstein RM (2004) Gene therapy clinical trials worldwide 1989–2004: an overview. J Gene Med 6:597–602PubMedGoogle Scholar
  5. Fischer A, Cavazzana-Calvo M (2008) Gene therapy of inherited diseases. Lancet 371:2044–2047PubMedGoogle Scholar
  6. Porteus MH, Connelly JP, Pruett SM (2006) A look to future directions in gene therapy research for monogenic diseases. PLoS Genet 2:e133PubMedGoogle Scholar
  7. Relph K, Harrington K, Pandha H (2004) Recent developments and current status of gene therapy using viral vectors in the United Kingdom. BMJ 329:839–842PubMedGoogle Scholar
  8. Schenk-Braat EA, van Mierlo MM, Wagemaker G et al (2007) An inventory of shedding data from clinical gene therapy trials. J Gene Med 9:910–921PubMedGoogle Scholar

Gene Therapy of Hematopoietic Stem Cells Further Reading

  1. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22:7468–7485PubMedGoogle Scholar
  2. Baker SJ, Rane SG, Reddy EP (2007) Hematopoietic cytokine receptor signaling. Oncogene 26:6724–6737PubMedGoogle Scholar
  3. Cavazzana-Calvo M, Fischer A (2007) Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest 117:1456–1465PubMedGoogle Scholar
  4. Cavazzana-Calvo M, Lagresle C, Hacein-Bey-Abina S, Fischer A (2005) Gene therapy for severe combined immunodeficiency. Annu Rev Med 56:585–602PubMedGoogle Scholar
  5. Greenberger JS (2008) Gene therapy approaches for stem cell protection. Gene Ther 15:100–108PubMedGoogle Scholar
  6. Hawley RG, Sobieski DA (2002) Of mice and men: the tale of two therapies. Stem Cells 20:275–278PubMedGoogle Scholar
  7. Hossle JP, Seger RA, Steinhoff D (2002) Gene therapy of hematopoietic stem cells: strategies for improvement. News Physiol Sci 17:87–92PubMedGoogle Scholar
  8. Licht T, Herrmann F, Gottesman MM, Pastan I (1997) In vivo drug-selectable genes: a new concept in gene therapy. Stem Cells 15:104–111PubMedGoogle Scholar
  9. Nienhuis AW (2008) Development of gene therapy for blood disorders. Blood 111:4431–4444PubMedGoogle Scholar
  10. Sands MS, Davidson BL (2006) Gene therapy for lysosomal storage diseases. Mol Ther 13:839–849PubMedGoogle Scholar
  11. Tey SK, Brenner MK (2007) The continuing contribution of gene marking to cell and gene therapy. Mol Ther 15:666–676PubMedGoogle Scholar
  12. Thrasher AJ, Gaspar HB, Baum C et al (2006) Gene therapy: X-SCID transgene leukaemogenicity. Nature 443:E5–6; discussion E6–7Google Scholar
  13. Zielske SP, Braun SE (2004) Cytokines: value-added products in hematopoietic stem cell gene therapy. Mol Ther 10:211–219PubMedGoogle Scholar

Selected Bibliography

  1. Aiuti A, Cattaneo F, Galimberti S et al (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360:447–458PubMedGoogle Scholar
  2. Aiuti A, Slavin S, Aker M et al (2002) Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296:2410–2413PubMedGoogle Scholar
  3. Aiuti A, Vai S, Mortellaro A et al (2002) Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med 8:423–425PubMedGoogle Scholar
  4. Alexander IE, Cunningham SC, Logan GJ, Christodoulou J (2008) Potential of AAV vectors in the treatment of metabolic disease. Gene Ther 15:831–839PubMedGoogle Scholar
  5. Baum C, von Kalle C, Staal FJ et al (2004) Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther 9:5–13PubMedGoogle Scholar
  6. Beck M (2007) New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet 121:1–22PubMedGoogle Scholar
  7. Biffi A, Naldini L (2005) Gene therapy of storage disorders by retroviral and lentiviral vectors. Hum Gene Ther 16:1133–1142PubMedGoogle Scholar
  8. Bonini C, Bondanza A, Perna SK et al (2007) The suicide gene therapy challenge: how to improve a successful gene therapy approach. Mol Ther 15:1248–1252PubMedGoogle Scholar
  9. Brenner MK (1996) Gene marking. Gene Ther 3:278–279PubMedGoogle Scholar
  10. Cattoglio C, Facchini G, Sartori D et al (2007) Hot spots of retroviral integration in human CD34+ hematopoietic cells. Blood 110:1770–1778PubMedGoogle Scholar
  11. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G et al (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288:669–672PubMedGoogle Scholar
  12. Cheng SH, Smith AE (2003) Gene therapy progress and prospects: gene therapy of lysosomal storage disorders. Gene Ther 10:1275–1281PubMedGoogle Scholar
  13. Dave UP, Jenkins NA, Copeland NG (2004) Gene therapy insertional mutagenesis insights. Science 303:333PubMedGoogle Scholar
  14. Deisseroth AB, Zu Z, Claxton D et al (1994) Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML. Blood 83:3068–3076PubMedGoogle Scholar
  15. Dinauer MC, Orkin SH (1992) Chronic granulomatous disease. Annu Rev Med 43:117–124PubMedGoogle Scholar
  16. Gaspar HB, Bjorkegren E, Parsley K et al (2006) Successful reconstitution of immunity in ADASCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning. Mol Ther 14:505–513PubMedGoogle Scholar
  17. Gaspar HB, Parsley KL, Howe S et al (2004) Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364:2181–2187PubMedGoogle Scholar
  18. Hacein-Bey-Abina S, von Kalle C, Schmidt M et al (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 348:255–256PubMedGoogle Scholar
  19. Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419PubMedGoogle Scholar
  20. Hodges BL, Cheng SH (2006) Cell and gene-based therapies for the lysosomal storage diseases. Curr Gene Ther 6:227–241PubMedGoogle Scholar
  21. Kohn DB, Sadelain M, Glorioso JC (2003) Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer 3:477–488PubMedGoogle Scholar
  22. Muul LM, Tuschong LM, Soenen SL et al (2003) Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial. Blood 101:2563–2569PubMedGoogle Scholar
  23. Ott MG, Schmidt M, Schwarzwaelder K et al (2006) Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med 12:401–409PubMedGoogle Scholar
  24. Schwarzwaelder K, Howe SJ, Schmidt M et al (2007) Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo. J Clin Invest 117:2241–2249PubMedGoogle Scholar
  25. Shou Y, Ma Z, Lu T, Sorrentino BP (2006) Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy. Proc Natl Acad Sci U S A 103:11730–11735PubMedGoogle Scholar
  26. Woods NB, Bottero V, Schmidt M et al (2006) Gene therapy: therapeutic gene causing lymphoma. Nature 440:1123PubMedGoogle Scholar

Gene Therapy of Cystic Fibrosis Further Reading

  1. Anson DS, Smith GJ, Parsons DW (2006) Gene therapy for cystic fibrosis airway disease: is clinical success imminent? Curr Gene Ther 6:161–179PubMedGoogle Scholar
  2. Flotte TR, Ng P, Dylla DE et al (2007) Viral vector-mediated and cell-based therapies for treatment of cystic fibrosis. Mol Ther 15:229–241PubMedGoogle Scholar
  3. Griesenbach U, Alton EW (2009) Gene transfer to the lung: lessons learned from more than 2 decades of CF gene therapy. Adv Drug Deliv Rev 61:128–139PubMedGoogle Scholar
  4. Griesenbach U, Geddes DM, Alton EW (2006) Gene therapy progress and prospects: cystic fibrosis. Gene Ther 13:1061–1067PubMedGoogle Scholar
  5. O’Sullivan BP, Freedman SD (2009) Cystic fibrosis. Lancet 373:1891–1904PubMedGoogle Scholar
  6. Riordan JR (2008) CFTR function and prospects for therapy. Annu Rev Biochem 77:701–726PubMedGoogle Scholar

Selected Bibliography

  1. Crystal RG, McElvaney NG, Rosenfeld MA et al (1994) Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet 8:42–51PubMedGoogle Scholar
  2. Kinsey BM, Densmore CL, Orson FM (2005) Non-viral gene delivery to the lungs. Curr Gene Ther 5:181–194PubMedGoogle Scholar
  3. Kremer KL, Dunning KR, Parsons DW, Anson DS (2007) Gene delivery to airway epithelial cells in vivo: a direct comparison of apical and basolateral transduction strategies using pseudotyped lentivirus vectors. J Gene Med 9:362–368PubMedGoogle Scholar
  4. Li W, Zhang L, Johnson JS et al (2009) Generation of novel AAV variants by directed evolution for improved CFTR delivery to human ciliated airway epithelium. Mol Ther 17:2067–2077PubMedGoogle Scholar
  5. Tagalakis AD, McAnulty RJ, Devaney J et al (2008) A receptor-targeted nanocomplex vector system optimized for respiratory gene transfer. Mol Ther 16:907–915PubMedGoogle Scholar

Gene Therapy of Muscular Dystrophies Further Reading

  1. Athanasopoulos T, Graham IR, Foster H, Dickson G (2004) Recombinant adeno-associated viral (rAAV) vectors as therapeutic tools for Duchenne muscular dystrophy (DMD). Gene Ther 11[Suppl 1]:S109–121Google Scholar
  2. Chakkalakal JV, Thompson J, Parks RJ, Jasmin BJ (2005) Molecular, cellular, and pharmacological therapies for Duchenne/Becker muscular dystrophies. FASEB J 19:880–891PubMedGoogle Scholar
  3. Foster K, Foster H, Dickson JG (2006) Gene therapy progress and prospects: Duchenne muscular dystrophy. Gene Ther 13:1677–1685PubMedGoogle Scholar

Selected Bibliography

  1. Alter J, Lou F, Rabinowitz A et al (2006) Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med 12:175–177PubMedGoogle Scholar
  2. Cerletti M, Negri T, Cozzi F et al (2003) Dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer. Gene Ther 10:750–757PubMedGoogle Scholar
  3. Duan D (2006) Challenges and opportunities in dystrophin-deficient cardiomyopathy gene therapy. Hum Mol Genet 15[Spec No 2]:R253–261PubMedGoogle Scholar
  4. Goyenvalle A, Vulin A, Fougerousse F et al (2004) Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science 306:1796–1799PubMedGoogle Scholar
  5. Gregorevic P, Blankinship MJ, Allen JM et al (2004) Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med 10:828–834PubMedGoogle Scholar
  6. Heemskerk H, de Winter CL, van Ommen GJ et al (2009) Development of antisense-mediated exon skipping as a treatment for duchenne muscular dystrophy. Ann N Y Acad Sci 1175:71–79PubMedGoogle Scholar
  7. Lu QL, Rabinowitz A, Chen YC et al (2005) Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc Natl Acad Sci U S A 102:198–203PubMedGoogle Scholar
  8. Mendell JR, Rodino-Klapac LR, Rosales-Quintero X et al (2009) Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol 66:290–297PubMedGoogle Scholar
  9. Nelson R (2004) Utrophin therapy for Duchenne muscular dystrophy? Lancet Neurol 3:637PubMedGoogle Scholar
  10. Romero NB, Braun S, Benveniste O et al (2004) Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy. Hum Gene Ther 15:1065–1076PubMedGoogle Scholar
  11. Scott JM, Li S, Harper SQ et al (2002) Viral vectors for gene transfer of micro-, mini-, or fulllength dystrophin. Neuromuscul Disord 12[Suppl 1]:S23–29Google Scholar
  12. van Deutekom JC, Janson AA, Ginjaar IB et al (2007) Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 357:2677–2686PubMedGoogle Scholar
  13. Wang Z, Zhu T, Qiao C et al (2005) Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat Biotechnol 23:321–328PubMedGoogle Scholar

Gene Therapy of Hemophilia Further Reading

  1. Bolton-Maggs PH, Pasi KJ (2003) Haemophilias A and B. Lancet 361:1801–1809PubMedGoogle Scholar
  2. Foster K, Foster H, Dickson JG (2006) Gene therapy progress and prospects: Duchenne muscular dystrophy. Gene Ther 13:1677–1685PubMedGoogle Scholar
  3. Graw J, Brackmann HH, Oldenburg J et al (2005) Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet 6:488–501PubMedGoogle Scholar
  4. Hasbrouck NC, High KA (2008) AAV-mediated gene transfer for the treatment of hemophilia B: problems and prospects. Gene Ther 15:870–875PubMedGoogle Scholar
  5. Mingozzi F, High KA (2007) Immune responses to AAV in clinical trials. Curr Gene Ther 7:316–324PubMedGoogle Scholar
  6. Murphy SL, High KA (2008) Gene therapy for haemophilia. Br J Haematol 140:479–487PubMedGoogle Scholar

Selected Bibliography

  1. Jiang H, Pierce GF, Ozelo MC et al (2006) Evidence of multiyear factor IX expression by AAVmediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Mol Ther 14:452–455PubMedGoogle Scholar
  2. Kay MA, Manno CS, Ragni MV et al (2000) Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 24:257–261PubMedGoogle Scholar
  3. Manno CS, Pierce GF, Arruda VR et al (2006) Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 12:342–347PubMedGoogle Scholar
  4. Margaritis P, Roy E, Aljamali MN et al (2009) Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood 113:3682–3689PubMedGoogle Scholar
  5. Wang L, Nichols TC, Read MS et al (2000) Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver. Mol Ther 1:154–158PubMedGoogle Scholar

Gene Therapy of Cancer Further Reading

  1. Aghi M, Hochberg F, Breakefield XO (2000) Prodrug activation enzymes in cancer gene therapy. J Gene Med 2:148–164PubMedGoogle Scholar
  2. Anderson RJ, Schneider J (2007) Plasmid DNA and viral vector-based vaccines for the treatment of cancer. Vaccine 25[Suppl 2]:B24–34PubMedGoogle Scholar
  3. Cattaneo R, Miest T, Shashkova EV, Barry MA (2008) Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded. Nat Rev Micro 6:529–540Google Scholar
  4. Heath WR, Belz GT, Behrens GMN et al (2004) Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol Rev 199:9–26PubMedGoogle Scholar
  5. Hermiston TW, Kirn DH (2005) Genetically based therapeutics for cancer: similarities and contrasts with traditional drug discovery and development. Mol Ther 11:496–507PubMedGoogle Scholar
  6. June CH (2007) Adoptive T cell therapy for cancer in the clinic. J Clin Invest 117:1466–1476PubMedGoogle Scholar
  7. June CH (2007) Principles of adoptive T cell cancer therapy. J Clin Invest 117:1204–1212PubMedGoogle Scholar
  8. Larin SS, Georgiev GP, Kiselev SL (2004) Gene transfer approaches in cancer immunotherapy. Gene Ther 11[Suppl 1]:S18–25Google Scholar
  9. Liu TC, Kirn D (2008) Gene therapy progress and prospects cancer: oncolytic viruses. Gene Ther 15:877–884PubMedGoogle Scholar
  10. McNeish IA, Bell SJ, Lemoine NR (2004) Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes. Gene Ther 11:497–503PubMedGoogle Scholar
  11. Offringa R (2006) Cancer. Cancer immunotherapy is more than a numbers game. Science 314:68–69PubMedGoogle Scholar
  12. Palmer DH, Young LS, Mautner V (2006) Cancer gene-therapy: clinical trials. Trends Biotechnol 24:76–82PubMedGoogle Scholar
  13. Rice J, Ottensmeier CH, Stevenson FK (2008) DNA vaccines: precision tools for activating effective immunity against cancer. Nat Rev Cancer 8:108–120PubMedGoogle Scholar
  14. Rossig C, Brenner MK (2004) Genetic modification of T lymphocytes for adoptive immunotherapy. Mol Ther 10:5–18PubMedGoogle Scholar

Selected Bibliography

  1. Bonini C, Ferrari G, Verzeletti S et al (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276:1719–1724PubMedGoogle Scholar
  2. Breckpot K, Aerts JL, Thielemans K (2007) Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics. Gene Ther 14:847–862PubMedGoogle Scholar
  3. Cesco-Gaspere M, Zentilin L, Giacca M, Burrone OR (2008) Boosting anti-idiotype immune response with recombinant AAV enhances tumour protection induced by gene gun vaccination. Scand J Immunol 68:58–66PubMedGoogle Scholar
  4. Finke LH, Wentworth K, Blumenstein B et al (2007) Lessons from randomized phase III studies with active cancer immunotherapies: outcomes from the 2006 meeting of the Cancer Vaccine Consortium (CVC). Vaccine 25[Suppl 2]:B97–B109PubMedGoogle Scholar
  5. Folkman J, Watson K, Ingber D, Hanahan D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61PubMedGoogle Scholar
  6. Johnson LA, Morgan RA, Dudley ME et al (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114:535–546PubMedGoogle Scholar
  7. McNeish IA, Bell SJ, Lemoine NR (2004) Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes. Gene Ther 11:497–503PubMedGoogle Scholar
  8. Morgan RA, Dudley ME, Wunderlich JR et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129PubMedGoogle Scholar
  9. Nestle FO, Farkas A, Conrad C (2005) Dendritic-cell-based therapeutic vaccination against cancer. Curr Opin Immunol 17:163–169PubMedGoogle Scholar
  10. Parmigiani RB, Bettoni F, Vibranovski MD et al (2006) Characterization of a cancer/testis (CT) antigen gene family capable of eliciting humoral response in cancer patients. Proc Natl Acad Sci U S A 103:18066–18071PubMedGoogle Scholar
  11. Pulkkanen KJ, Yla-Herttuala S (2005) Gene therapy for malignant glioma: current clinical status. Mol Ther 12:585–598PubMedGoogle Scholar
  12. Rapoport AP, Stadtmauer EA, Aqui N et al (2005) Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 11:1230–1237PubMedGoogle Scholar
  13. Ringdén O, Karlsson H, Olsson R et al (2009) The allogeneic graft-versus-cancer effect. Br J Haematol 147:614–633PubMedGoogle Scholar
  14. Rosenberg SA, Aebersold P, Cornetta K et al (1990) Gene transfer into humans: immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 323:570–578PubMedGoogle Scholar
  15. Rosenthal R, Viehl CT, Guller U et al (2008) Active specific immunotherapy phase III trials for malignant melanoma: systematic analysis and critical appraisal. J Am Coll Surg 207:95–105PubMedGoogle Scholar
  16. Tasciotti E, Zoppe M, Giacca M (2003) Transcellular transfer of active HSV-1 thymidine kinase mediated by an 11-amino-acid peptide from HIV-1 Tat. Cancer Gene Ther 10:64–74PubMedGoogle Scholar
  17. Terando AM, Faries MB, Morton DL (2007) Vaccine therapy for melanoma: current status and future directions. Vaccine 25[Suppl 2]:B4–16PubMedGoogle Scholar

Gene Therapy of Neurodegenerative Disorders Further Reading

  1. Azzouz M (2006) Gene therapy for ALS: progress and prospects. Biochim Biophys Acta 1762:1122–1127PubMedGoogle Scholar
  2. Baker D, Hankey DJ (2003) Gene therapy in autoimmune, demyelinating disease of the central nervous system. Gene Ther 10:844–853PubMedGoogle Scholar
  3. Bradbury J (2005) Hope for AD with NGF gene-therapy trial. Lancet Neurol 4:335PubMedGoogle Scholar
  4. Burton EA, Glorioso JC, Fink DJ (2003) Gene therapy progress and prospects: Parkinson’s disease. Gene Ther 10:1721–1727PubMedGoogle Scholar
  5. Choudry RB, Cudkowicz ME (2005) Clinical trials in amyotrophic lateral sclerosis: the tenuous past and the promising future. J Clin Pharmacol 45:1334–1344PubMedGoogle Scholar
  6. Federici T, Boulis N (2007) Gene therapy for peripheral nervous system diseases. Curr Gene Ther 7:239–248PubMedGoogle Scholar
  7. Fiandaca M, Forsayeth J, Bankiewicz K (2008) Current status of gene therapy trials for Parkinson’s disease. Exp Neurol 209:51–57PubMedGoogle Scholar
  8. Kaspar BK, Llado J, Sherkat N et al (2003) Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301:839–842PubMedGoogle Scholar
  9. Mitchell JD, Borasio GD (2007) Amyotrophic lateral sclerosis. Lancet 369:2031–2041PubMedGoogle Scholar
  10. Palfi S (2008) Towards gene therapy for Parkinson’s disease. Lancet Neurol 7:375–376PubMedGoogle Scholar
  11. Sheridan C (2007) Positive clinical data in Parkinson’s and ischemia buoy gene therapy. Nat Biotechnol 25:823–824PubMedGoogle Scholar
  12. Sumner CJ (2006) Therapeutics development for spinal muscular atrophy. NeuroRx 3:235–245PubMedGoogle Scholar
  13. Tuszynski MH (2002) Growth-factor gene therapy for neurodegenerative disorders. Lancet Neurol 1:51–57PubMedGoogle Scholar
  14. Zacchigna S, Giacca M (2009) Chapter 20: Gene therapy perspectives for nerve repair. Int Rev Neurobiol 87:381–392PubMedGoogle Scholar

Selected Bibliography

  1. Azzouz M, Le T, Ralph GS et al (2004) Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J Clin Invest 114:1726–1731PubMedGoogle Scholar
  2. Azzouz M, Ralph GS, Storkebaum E et al (2004) VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429:413–417PubMedGoogle Scholar
  3. Bloch J, Bachoud-Levi AC, Deglon N et al (2004) Neuroprotective gene therapy for Huntington’s disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study. Hum Gene Ther 15:968–975PubMedGoogle Scholar
  4. Christine CW, Starr PA, Larson PS et al (2009) Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73:1662–1669PubMedGoogle Scholar
  5. Eberling JL, Jagust WJ, Christine CW et al (2008) Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 70:1980–1983PubMedGoogle Scholar
  6. Hua Y, Vickers TA, Okunola HL et al (2008) Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet 82:834–848PubMedGoogle Scholar
  7. Kaplitt MG, Feigin A, Tang C et al (2007) Safety and tolerability of gene therapy with an adenoassociated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet 369:2097–2105PubMedGoogle Scholar
  8. Kennington E (2009) Gene therapy delivers an alternative approach to Alzheimer’s disease. Nat Rev Drug Discov 8:275PubMedGoogle Scholar
  9. Lewis TB, Standaert DG (2008) Design of clinical trials of gene therapy in Parkinson disease. Exp Neurol 209:41–47PubMedGoogle Scholar
  10. Mandel RJ, Burger C (2004) Clinical trials in neurological disorders using AAV vectors: promises and challenges. Curr Opin Mol Ther 6:482–490PubMedGoogle Scholar
  11. Mandel RJ, Burger C, Snyder RO (2008) Viral vectors for in vivo gene transfer in Parkinson’s disease: properties and clinical grade production. Exp Neurol 209:58–71PubMedGoogle Scholar
  12. Nagahara AH, Merrill DA, Coppola G et al (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15:331–337PubMedGoogle Scholar
  13. Ralph GS, Radcliffe PA, Day DM et al (2005) Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med 11:429–433PubMedGoogle Scholar
  14. Storkebaum E, Lambrechts D, Carmeliet P (2004) VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 26:943–954PubMedGoogle Scholar
  15. Towne C, Schneider BL, Kieran D et al (2009) Efficient transduction of non-human primate motor neurons after intramuscular delivery of recombinant AAV serotype 6. Gene Ther 17:141–146PubMedGoogle Scholar
  16. Tuszynski MH, Thal L, Pay M et al (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 11:551–555PubMedGoogle Scholar

Gene Therapy of Eye Diseases Further Reading

  1. Bainbridge JW, Ali RR (2008) Success in sight: the eyes have it! Ocular gene therapy trials for LCA look promising. Gene Ther 15:1191–1192PubMedGoogle Scholar
  2. Bainbridge JW, Tan MH, Ali RR (2006) Gene therapy progress and prospects: the eye. Gene Ther 13:1191–1197PubMedGoogle Scholar
  3. Bennett J, Maguire AM (2000) Gene therapy for ocular disease. Mol Ther 1:501–505PubMedGoogle Scholar
  4. Buch PK, Bainbridge JW, Ali RR (2008) AAV-mediated gene therapy for retinal disorders: from mouse to man. Gene Ther 15:849–857PubMedGoogle Scholar
  5. Jager RD, Mieler WF, Miller JW (2008) Age-related macular degeneration. N Engl J Med 358:2606–2617PubMedGoogle Scholar
  6. Kaiser J (2008) Gene therapy. Two teams report progress in reversing loss of sight. Science 320:606–607PubMedGoogle Scholar
  7. Smith AJ, Bainbridge JW, Ali RR (2009) Prospects for retinal gene replacement therapy. Trends Genet 25:156–165PubMedGoogle Scholar

Selected Bibliography

  1. Acland GM, Aguirre GD, Ray J et al (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–95PubMedGoogle Scholar
  2. Bainbridge JW, Smith AJ, Barker SS et al (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 358:2231–2239PubMedGoogle Scholar
  3. Dinculescu A, Glushakova L, Min SH, Hauswirth WW (2005) Adeno-associated virus-vectored gene therapy for retinal disease. Hum Gene Ther 16:649–663PubMedGoogle Scholar
  4. Gehrs KM, Anderson DH, Johnson LV, Hageman GS (2006) Age-related macular degeneration: emerging pathogenetic and therapeutic concepts. Ann Med 38:450–471PubMedGoogle Scholar
  5. Le Meur G, Stieger K, Smith AJ et al (2007) Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther 14:292–303PubMedGoogle Scholar
  6. Maguire AM, Simonelli F, Pierce EA et al (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358:2240–2248PubMedGoogle Scholar

Gene Therapy of Cardiovascular Disorders Further Reading

  1. Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478PubMedGoogle Scholar
  2. Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165–177PubMedGoogle Scholar
  3. Bhargava B, Karthikeyan G, Abizaid AS, Mehran R (2003) New approaches to preventing restenosis. BMJ 327:274–279PubMedGoogle Scholar
  4. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936PubMedGoogle Scholar
  5. Crook MF, Akyurek LM (2003) Gene transfer strategies to inhibit neointima formation. Trends Cardiovasc Med 13:102–106PubMedGoogle Scholar
  6. Giacca M (2007) Virus-mediated gene transfer to induce therapeutic angiogenesis: where do we stand? Int J Nanomed 2:527–540Google Scholar
  7. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling: in control of vascular function. Nat Rev Mol Cell Biol 7:359–371PubMedGoogle Scholar
  8. Rissanen TT, Yla-Herttuala S (2007) Current status of cardiovascular gene therapy. Mol Ther 15:1233–1247PubMedGoogle Scholar
  9. Stewart S, MacIntyre K, Hole DJ et al (2001) More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail 3:315–322PubMedGoogle Scholar
  10. Vincent KA, Jiang C, Boltje I, Kelly RA (2007) Gene therapy progress and prospects: therapeutic angiogenesis for ischemic cardiovascular disease. Gene Ther 14:781–789PubMedGoogle Scholar
  11. Vinge LE, Raake PW, Koch WJ (2008) Gene therapy in heart failure. Circ Res 102:1458–1470PubMedGoogle Scholar
  12. Yancopoulos GD, Davis S, Gale NW et al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248PubMedGoogle Scholar
  13. Yla-Herttuala S, Alitalo K (2003) Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 9:694–701PubMedGoogle Scholar
  14. Yla-Herttuala S, Markkanen JE, Rissanen TT (2004) Gene therapy for ischemic cardiovascular diseases: some lessons learned from the first clinical trials. Trends Cardiovasc Med 14:295–300PubMedGoogle Scholar
  15. Yla-Herttuala S, Martin JF (2000) Cardiovascular gene therapy. Lancet 355:213–222PubMedGoogle Scholar

Slected Bibliography

  1. Arsic N, Zacchigna S, Zentilin L et al (2004) Vascular endothelial growth factor stimulates skeletal muscle regeneration in vivo. Mol Ther 10:844–854PubMedGoogle Scholar
  2. Arsic N, Zentilin L, Zacchigna S et al (2003) The biology of VEGF and its receptors. Nat Med 9:669–676Google Scholar
  3. Baumgartner I, Pieczek A, Manor O et al (1998) Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 97:1114–1123PubMedGoogle Scholar
  4. del Monte F, Harding SE, Schmidt U et al (1999) Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 100:2308–2311Google Scholar
  5. Ferrarini M, Arsic N, Recchia FA et al (2006) Adeno-associated virus-mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs. Circ Res 98:954–961PubMedGoogle Scholar
  6. Grines CL, Watkins MW, Helmer G et al (2002) Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105:1291–1297PubMedGoogle Scholar
  7. Inagaki K, Fuess S, Storm TA et al (2006) Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 14:45–53PubMedGoogle Scholar
  8. Lafont A, Guerot C, Lemarchand P (1995) Which gene for which restenosis? Lancet 346:1442–1443PubMedGoogle Scholar
  9. Melo LG, Pachori AS, Kong D et al (2004) Gene and cell-based therapies for heart disease. FASEB J 18:648–663PubMedGoogle Scholar
  10. Simons M, Bonow RO, Chronos NA et al (2000) Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation 102:E73–E86PubMedGoogle Scholar
  11. Sinagra G, Giacca M (2003) Induction of functional neovascularization by combined VEGF and angiopoietin-1 gene transfer using AAV vectors. Mol Ther 7:450–459PubMedGoogle Scholar
  12. Tafuro S, Ayuso E, Zacchigna S et al (2009) Inducible adeno-associated virus vectors promote functional angiogenesis in adult organisms via regulated vascular endothelial growth factor expression. Cardiovasc Res 83:663–671PubMedGoogle Scholar
  13. Vale PR, Losordo DW, Milliken CE et al (2000) Left ventricular electromechanical mapping to assess efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 102:965–974PubMedGoogle Scholar
  14. Zacchigna S, Tasciotti E, Kusmic C et al (2007) In vivo imaging shows abnormal function of vascular endothelial growth factor-induced vasculature. Hum Gene Ther 18:515–524PubMedGoogle Scholar

Gene Therapy of HIV Infection Further Reading

  1. Baltimore D (1988) Gene therapy. Intracellular immunization. Nature 335:395–396PubMedGoogle Scholar
  2. Dropulic B, June CH (2006) Gene-based immunotherapy for human immunodeficiency virus infection and acquired immunodeficiency syndrome. Hum Gene Ther 17:577–588PubMedGoogle Scholar
  3. Fillat C, Carrio M, Cascante A, Sangro B (2003) Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application. Curr Gene Ther 3:13–26PubMedGoogle Scholar
  4. Giacca M (2008) Gene therapy to induce cellular resistance to HIV-1 infection: lessons from clinical trials. Adv Pharmacol 56:297–325PubMedGoogle Scholar
  5. Haasnoot J, Westerhout EM, Berkhout B (2007) RNA interference against viruses: strike and counterstrike. Nat Biotechnol 25:1435–1443PubMedGoogle Scholar
  6. Manilla P, Rebello T, Afable C et al (2005) Regulatory considerations for novel gene therapy products: a review of the process leading to the first clinical lentiviral vector. Hum Gene Ther 16:17–25PubMedGoogle Scholar
  7. Morris K.V, Rossi JJ (2006) Lentiviral-mediated delivery of siRNAs for antiviral therapy. Gene Ther 13:553–558PubMedGoogle Scholar
  8. Rossi JJ (2006) RNAi as a treatment for HIV-1 infection. Biotechniques [Suppl]:25–29Google Scholar
  9. Rossi JJ, June CH, Kohn DB (2007) Genetic therapies against HIV. Nat Biotechnol 25:1444–1454PubMedGoogle Scholar
  10. Strayer DS, Akkina R, Bunnell BA et al (2005) Current status of gene therapy strategies to treat HIV/AIDS. Mol Ther 11:823–842PubMedGoogle Scholar
  11. Wolkowicz R, Nolan GP (2005) Gene therapy progress and prospects: novel gene therapy approaches for AIDS. Gene Ther 12:467–476PubMedGoogle Scholar

Selected Bibliography

  1. Buchbinder SP, Mehrotra DV, Duerr A et al (2008) Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of concept trial. Lancet 372:1881–1893PubMedGoogle Scholar
  2. Das AT, Brummelkamp TR, Westerhout EM et al (2004) Human immunodeficiency virus type 1 escapes from RNA interference-mediated inhibition. J Virol 78:2601–2605PubMedGoogle Scholar
  3. Levine, BL, Humeau, LM, Boyer J et al (2006) Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci U S A 103:17372–17377PubMedGoogle Scholar
  4. Li MJ, Kim J, Li S et al (2005) Long-term inhibition of HIV-1 infection in primary hematopoietic cells by lentiviral vector delivery of a triple combination of anti-HIV shRNA, anti-CCR5 ribozyme, and a nucleolar-localizing TAR decoy. Mol Ther 12:900–909PubMedGoogle Scholar
  5. Mitsuyasu RT, Merigan TC, Carr A et al (2009) Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat Med 15:285–292PubMedGoogle Scholar
  6. Morgan RA, Walker R (1996) Gene therapy for AIDS using retroviral mediated gene transfer to deliver HIV-1 antisense TAR and transdominant Rev protein genes to syngeneic lymphocytes in HIV-1 infected identical twins. Hum Gene Ther 7:1281–1306PubMedGoogle Scholar
  7. Nisole S, Stoye JP, Saib A (2005) TRIM family proteins: retroviral restriction and antiviral defence. Nat Rev Microbiol 3:799–808PubMedGoogle Scholar
  8. Novina CD, Murray MF, Dykxhoorn DM et al (2002) siRNA-directed inhibition of HIV-1 infection. Nat Med 8:681–686PubMedGoogle Scholar
  9. Poeschla E, Corbeau P, Flossie W-S (1996) Development of HIV vectors for anti-HIV gene therapy. Proc Natl Acad Sci U S A 93:11395–11399PubMedGoogle Scholar
  10. Rondon IJ, Marasco WA (1997) Intracellular antibodies (intrabodies) for gene therapy of infectious diseases. Annu Rev Microbiol 51:257–283PubMedGoogle Scholar
  11. Sarver N, Cantin EM, Chang PS et al (1990) Ribozymes as potential anti-HIV-1 therapeutic agents. Science 247:1222–1225PubMedGoogle Scholar
  12. Schambach A, Schiedlmeier B, Kuhlcke K et al (2006) Towards hematopoietic stem cell-mediated protection against infection with human immunodeficiency virus. Gene Ther 13:1037–1047PubMedGoogle Scholar
  13. ter Brake O, Konstantinova P, Ceylan M, Berkhout B (2006) Silencing of HIV-1 with RNA interference: a multiple shRNA approach. Mol Ther 14:883–892PubMedGoogle Scholar
  14. Westerhout EM, Ooms M, Vink M et al (2005) HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome. Nucleic Acids Res 33:796–804PubMedGoogle Scholar

Gene Therapy of Liver Diseases Further Reading

  1. Broedl UC, Rader DJ (2005) Gene therapy for lipoprotein disorders. Exp Opin Biol Ther 5:1029–1038Google Scholar
  2. Nguyen TH, Ferry N (2004) Liver gene therapy: advances and hurdles. Gene Ther 11[Suppl 1]:S76–84Google Scholar
  3. Nguyen TH, Mainot S, Lainas P et al (2009) Ex vivo liver-directed gene therapy for the treatment of metabolic diseases: advances in hepatocyte transplantation and retroviral vectors. Curr Gene Ther 9:136–149PubMedGoogle Scholar
  4. Stecenko AA, Brigham KL (2003) Gene therapy progress and prospects: alpha-1 antitrypsin. Gene Ther 10:95–99PubMedGoogle Scholar
  5. Wood AM, Stockley RA (2007) Alpha one antitrypsin deficiency: from gene to treatment. Respiration 74:481–492PubMedGoogle Scholar

Selected Bibliography

  1. Grossman M, Rader DJ, Muller DW et al (1995) A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med 1:1148–1154PubMedGoogle Scholar
  2. Grossman M, Raper SE, Kozarsky K et al (1994) Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet 6:335–341PubMedGoogle Scholar
  3. Kozarsky KF, Jooss K, Donahee M et al (1996) Effective treatment of familial hypercholester — olaemia in the mouse model using adenovirus-mediated transfer of the VLDL receptor gene. Nat Genet 13:54–62PubMedGoogle Scholar
  4. Miranda PS, Bosma PJ (2009) Towards liver-directed gene therapy for Crigler-Najjar syndrome. Curr Gene Ther 9:72–82PubMedGoogle Scholar
  5. Stoller JK, Aboussouan LS (2005) Alpha1-antitrypsin deficiency. Lancet 365:2225–2236PubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2010

Authors and Affiliations

  • Mauro Giacca
    • 1
  1. 1.International Centre for Genetic Engineering and Biotechnology (ICGEB)TriesteItaly

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