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Gene therapy

Gene therapy using an adenovirus vector. A new gene is inserted into a cell using an adenovirus. If the treatment is successful, the new gene will make functional protein to treat a disease.

Gene therapy is the use of nucleic acid polymers as a drug to treat disease by therapeutic delivery into a patient's cells, where they are either expressed as proteins, interfere with the expression of proteins, or possibly even correct genetic mutations. The most common form of gene therapy involves using DNA that encodes a functional, therapeutic gene to replace a mutated gene. In gene therapy, the nucleic acid molecule is packaged within a "vector", which is used to get the molecule inside cells within the body.

Gene therapy was first conceptualized in 1972, with the authors urging caution before commencing gene therapy studies in humans. The first FDA-approved gene therapy experiment in the United States occurred in 1990, when Ashanti DeSilva was treated for ADA-SCID.[1] By January 2014, about 2,000 clinical trials had been conducted or had been approved using a number of techniques for gene therapy.[2]

Although early clinical failures led many to dismiss gene therapy as over-hyped, clinical successes since 2006 have bolstered new optimism in the promise of gene therapy. These include successful treatment of patients with the retinal disease Leber's congenital amaurosis,[3][4][5][6] X-linked SCID,[7] ADA-SCID,[8][9] adrenoleukodystrophy,[10] chronic lymphocytic leukemia (CLL),[11] acute lymphocytic leukemia (ALL),[12] multiple myeloma,[13] haemophilia[9] and Parkinson's disease.[14] These clinical successes have led to a renewed interest in gene therapy, with several articles in scientific and popular publications calling for continued investment in the field[15][16] and between 2013 and April 2014, US companies invested over $600 million in gene therapy.[17]

In 2012, Glybera became the first gene therapy treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[18][19]


  • Approach 1
  • Types of gene therapy 2
    • Somatic gene therapy 2.1
    • Germline gene therapy 2.2
  • Vectors in gene therapy 3
    • Viruses 3.1
    • Non-viral methods 3.2
  • Technological hurdles 4
    • Deaths 4.1
  • Development of gene therapy technology 5
    • 1970s and earlier 5.1
    • 1990s 5.2
    • 2000s 5.3
      • 2003 5.3.1
      • 2006 5.3.2
      • 2007 5.3.3
      • 2008 5.3.4
      • 2009 5.3.5
    • 2010s 5.4
      • 2010 5.4.1
      • 2011 5.4.2
      • 2012 5.4.3
      • 2013 5.4.4
      • 2014 5.4.5
  • Speculative uses for gene therapy 6
    • Gene doping 6.1
    • Human genetic engineering 6.2
  • Evidence regarding clinical use of Gene Therapy 7
  • Regulations 8
    • United States 8.1
  • Popular culture 9
  • See also 10
  • References 11
  • Further reading 12
  • External links 13


Following early advances in genetic engineering of bacteria, cells, and small animals, scientists have started considering how this technique could be applied to medicine; could human chromosomes be modified to treat disease. Two main approaches have been considered - adding a gene to replace a gene that wasn't working properly, or disrupting genes that were not working properly.[20] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. As of 2014, gene therapy was still generally an experimental technique, although in 2012 Glybera became the first gene therapy treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission, as a treatment for a disease caused by a defect in a single gene, lipoprotein lipase.[18][19]

In gene therapy, DNA must be administered to the patient, get to the cells that need repair, enter the cell, and express a protein in a medically useful way.[21] Generally the DNA is incorporated into an engineered virus that serves as a vector, to get the DNA through the bloodstream, into cells, and incorporated into a chromosome.[22][23] However, so-called naked DNA approaches have also been explored, especially in the context of vaccine development.[24]

Generally, efforts have focused on administering a gene that causes a protein to be expressed, that the patient directly needs. However, with development of our understanding of the function of nucleases such as zinc finger nucleases in humans, efforts have begun to incorporate genes encoding nucleases into chromosomes; the expressed nucleases then "edit" the chromosome, disrupting genes causing disease. As of 2014 these approaches have been limited to taking cells from patients, delivering the nuclease gene to the cells, and then administering the transformed cells to patients.[25]

There are other technologies in which nucleic acids are being developed as drugs, such as antisense, small interfering RNA, and others. To the extent that these technologies do not seek to alter the chromosome, but instead are intended to directly interact with other biomolecules such as RNA, they are generally not considered "gene therapy" per se.

Types of gene therapy

Gene therapy may be classified into the two following types, only one of which has been used in humans:

Somatic gene therapy

As the name suggests, in somatic gene therapy, the therapeutic genes are transferred into the somatic cells (non sex-cells), or body, of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient's offspring or later generations. Somatic gene therapy represents the mainstream line of current basic and clinical research, where the therapeutic DNA transgene (either integrated in the genome or as an external episome or plasmid) is used to treat a disease in an individual.

Several somatic cell gene transfer experiments are currently in clinical trials with varied success. Over 600 clinical trials utilizing somatic cell therapy are underway in the United States. Most of these trials focus on treating severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. These disorders are good candidates for somatic cell therapy because they are caused by single gene defects. While somatic cell therapy is promising for treatment, a complete correction of a genetic disorder or the replacement of multiple genes in somatic cells is not yet possible. Only a few of the many clinical trials are in the advanced stages.[26]

Germline gene therapy

In germline gene therapy,

  • Gene Therapy: Molecular Bandage? University of Utah's Genetic Science Learning Center
  • The American Society of Gene & Cell Therapy
  • The European Society of Gene & Cell Therapy
  • Research Group at Cambridge, UK working on overcoming current hurdles to successful gene therapy
  • Council for Responsible Genetics
  • Molecular Medicine and Gene Therapy at Lund University
  • Gene Therapy Frees β-Thalassemia Patient From Transfusions
  • Clinical Trial at Sloan Kettering
  • Stem Cell Therapy Trial Offers Hope

External links

  • Tinkov S, Bekeredjian R, Winter G, Coester C (16–20 November). "Polyplex-conjugated microbubbles for enhanced ultrasound targeted gene therapy".  
  • Gardlík R, Pálffy R, Hodosy J, Lukács J, Turna J, Celec P (Apr 2005). "Vectors and delivery systems in gene therapy". Med Sci Monit. 11 (4): RA110–21.  
  • Staff (18 November 2005). "Gene Therapy" (FAQ). Human Genome Project Information.  
  • Salmons B, Günzburg WH (Apr 1993). "Targeting of retroviral vectors for gene therapy". Hum Gene Ther. 4 (2): 129–41.  
  • Baum C, Düllmann J, Li Z, Fehse B, Meyer J, Williams DA, von Kalle C (Mar 2003). "Side effects of retroviral gene transfer into hematopoietic stem cells". Blood 101 (6): 2099–114.  
  • Horn PA, Morris JC, Neff T, Kiem HP (Sep 2004). "Stem cell gene transfer—efficacy and safety in large animal studies". Mol. Ther. 10 (3): 417–31.  
  • Wang H, Shayakhmetov DM, Leege T, Harkey M, Li Q, Papayannopoulou T, Stamatoyannopolous G, Lieber A (September 2005). "A Capsid-Modified Helper-Dependent Adenovirus Vector Containing the β-Globin Locus Control Region Displays a Nonrandom Integration Pattern and Allows Stable, Erythroid-Specific Gene Expression". Journal of Virology 79 (17): 10999–1013.  

Further reading

  1. ^ a b Sheridan C (2011). "Gene therapy finds its niche". Nature Biotechnology 29 (2): 121–128.  
  2. ^ a b (January 2014) Gene Therapy Clinical Trials Worldwide Database The Journal of Gene Medicine,, Retrieved 28 April 2014
  3. ^ a b Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J (2008). "Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis". New England Journal of Medicine 358 (21): 2240–2248.  
  4. ^ a b Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A (2009). "Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration". Molecular Therapy 18 (3): 643–650.  
  5. ^ a b Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EA, Conlon TJ, Sumaroka A, Roman AJ, Byrne BJ, Jacobson SG (2009). "Vision 1 Year after Gene Therapy for Leber's Congenital Amaurosis". New England Journal of Medicine 361 (7): 725–727.  
  6. ^ a b Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR (2008). "Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis". New England Journal of Medicine 358 (21): 2231–2239.  
  7. ^ Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M (2010). "20 years of gene therapy for SCID". Nature Immunology 11 (6): 457–460.  
  8. ^ Ferrua F, Brigida I, Aiuti A (2010). "Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency". Current Opinion in Allergy and Clinical Immunology 10 (6): 551–556.  
  9. ^ a b c d Geddes, Linda (30 October 2013) 'Bubble kid' success puts gene therapy back on track' The New Scientist, Retrieved 2 November 2013
  10. ^ Cartier N, Aubourg P (2009). "Hematopoietic Stem Cell Transplantation and Hematopoietic Stem Cell Gene Therapy in X-Linked Adrenoleukodystrophy". Brain Pathology 20 (4): 857–862.  
  11. ^ a b Ledford, H. (2011). "Cell therapy fights leukaemia". Nature.  
  12. ^ a b Coghlan, Andy (26 March 2013) Gene therapy cures leukaemia in eight days The New Scientist, Retrieved 15 April 2013
  13. ^ a b Coghlan, Andy (11 December 2013) Souped-up immune cells force leukaemia into remission New Scientist, Retrieved 15 April 2013
  14. ^ LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During MJ, Kaplitt MG, Feigin A (2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: A double-blind, sham-surgery controlled, randomised trial". The Lancet Neurology 10 (4): 309–319.  
  15. ^ "Gene therapy deserves a fresh chance". Nature 461 (7268): 1173–2009. 2009.  
  16. ^ Kolata, G. (6 November 2009). After Setbacks, Small Successes for Gene Therapy. New York Times.
  17. ^ Herper, Matthew (26 March 2014) Gene Therapy's Big Comeback Forbes magazine, Retrieved 28 April 2014
  18. ^ a b c Gallagher, James. (2 November 2012) BBC News – Gene therapy: Glybera approved by European Commission. Retrieved on 15 December 2012.
  19. ^ a b c Richards, Sabrina. "Gene Therapy Arrives in Europe". The Scientist. Retrieved 16 November 2012. 
  20. ^ U.S. National Library of Medicine, Genomics Home Reference. What is gene therapy?
  21. ^ U.S. National Library of Medicine, Genomics Home Reference. How does gene therapy work?
  22. ^ Pezzoli D, Chiesa R, De Nardo L, Candiani G (2012). "We still have a long way to go to effectively deliver genes!". J Appl Biomater Funct Mater 10 (2): 82–91.  
  23. ^ Vannucci L, Lai M, Chiuppesi F, Ceccherini-Nelli L, Pistello M (2013). "Viral vectors: a look back and ahead on gene transfer technology". New Microbiol. 36 (1): 1–22.  
  24. ^ Gothelf A, Gehl J (2012). "What you always needed to know about electroporation based DNA vaccines". Hum Vaccin Immunother 8 (11): 1694–702.  
  25. ^ Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD (2010). "Genome editing with engineered zinc finger nucleases". Nature Reviews Genetics 11 (9): 636–646.  
  26. ^ Mavilio F, Ferrari G (2008). "Genetic modification of somatic stem cells. The progress, problems and prospects of a new therapeutic technology". EMBO Rep. 9 Suppl 1: S64–9.  
  27. ^ a b c "International Law". The Genetics and Public Policy Center, Johns Hopkins University Berman Institute of Bioethics. 2010. 
  28. ^ Strachnan, T. and Read, A. P. (2004) Human Molecular Genetics, 3rd Edition, Garland Publishing, p. 616, ISBN 0815341849.
  29. ^ Hanna, K., 2006, Germline Gene Transfer, National Human Genome Research Institute, [1]
  30. ^ 2013, Human Cloning and Genetic Modification, Association of Reproductive Health Officials, [2]
  31. ^ 2013, Gene Therapy, American Medical Association
  32. ^ Korthof G. "The implications of Steele's soma-to-germline feedback for human gene therapy". 
  33. ^ Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM (2006). "Gene therapy: Therapeutic gene causing lymphoma". Nature 440 (7088): 1123.  
  34. ^ Thrasher AJ, Gaspar HB, Baum C, Modlich U, Schambach A, Candotti F, Otsu M, Sorrentino B, Scobie L, Cameron E, Blyth K, Neil J, Abina SH, Cavazzana-Calvo M, Fischer A (2006). "Gene therapy: X-SCID transgene leukaemogenicity". Nature 443 (7109): E5–E6; discussion E6–7.  
  35. ^ Young, Susan (11 February 2014) Genome Surgery MIT Technology Review, Retrieved 17 February 2014
  36. ^ (31 October 2013) Gene therapy needs a hero to live up to the hype The New Scientist, Retrieved 2 November 2012
  37. ^ Crasto, Anthony Melvin (2013) Glybera – The Most Expensive Drug in the world & First Approved Gene Therapy in the West All About Drug, Retrieved 2 November 2013
  38. ^ Retrieved on 15 December 2012.
  39. ^ Frank KM, Hogarth DK, Miller JL, Mandal S, Mease PJ, Samulski RJ, Weisgerber GA, Hart J (2009). "Investigation of the Cause of Death in a Gene-Therapy Trial". New England Journal of Medicine 361 (2): 161–169.  
  40. ^ Friedmann T, Roblin R (1972). "Gene Therapy for Human Genetic Disease?". Science 175 (4025): 949–955.  
  41. ^ Rogers S, New Scientist 1970, p. 194
  42. ^ "The first gene therapy". Life Sciences Foundation. 2011-06-21. Retrieved 2014-01-07. 
  43. ^ Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, Shearer G, Chang L, Chiang Y, Tolstoshev P, Greenblatt JJ, Rosenberg SA, Klein H, Berger M, Mullen CA, Ramsey WJ, Muul L, Morgan RA, Anderson WF (1995). "T lymphocyte-directed gene therapy for ADA- SCID: Initial trial results after 4 years". Science 270 (5235): 475–480.  
  44. ^ Penman, Danny (11 October 2002). "Subtle gene therapy tackles blood disorder". New Scientist. Retrieved 17 August 2010. 
  45. ^ "DNA nanoballs boost gene therapy". New Scientist. 12 May 2012. Retrieved 17 August 2010. 
  46. ^ Wilson, Jennifer Fisher (18 March 2002). "Murine Gene Therapy Corrects Symptoms of Sickle Cell Disease". The Scientist – Magazine of the Life Sciences. Retrieved 17 August 2010. 
  47. ^ St. Jude Children's Research Hospital (4 December 2008). "Gene Therapy Corrects Sickle Cell Disease In Laboratory Study". ScienceDaily. Retrieved 29 December 2012. 
  48. ^ Abbott A (1992). "Gene therapy. Italians first to use stem cells". Nature 356 (6369): 465–199.  
  49. ^ Cavazzana-Calvo M, Thrasher A, Mavilio F (Feb 2004). "The future of gene therapy". Nature 427 (6977): 779–81.  
  50. ^ Stein, Rob (11 October 2010). "First patient treated in stem cell study". Washington Post. Retrieved 10 November 2010. 
  51. ^ "Death Prompts FDA to Suspend Arthritis Gene Therapy Trial". Medpage Today. 2007-07-27. Retrieved 10 November 2010. 
  52. ^ Stolberg, Sheryl Gay (2000-01-22). "Gene Therapy Ordered Halted At University". New York Times. Retrieved 10 November 2010. 
  53. ^ Ananthaswamy, Anil (20 March 2003). "Undercover genes slip into the brain". New Scientist. Retrieved 17 August 2010. 
  54. ^ Holmes, Bob (13 March 2003). "Gene therapy may switch off Huntington's". New Scientist. Retrieved 17 August 2010. 
  55. ^ Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kühlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Lüthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M (2006). "Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1". Nature Medicine 12 (4): 401–409.  
  56. ^ Brown BD, Venneri MA, Zingale A, Sergi Sergi L, Naldini L (2006). "Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer". Nature Medicine 12 (5): 585–591.  
  57. ^ Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006). "Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes". Science 314 (5796): 126–129.  
  58. ^ Levine BL, Humeau LM, Boyer J, MacGregor RR, Rebello T, Lu X, Binder GK, Slepushkin V, Lemiale F, Mascola JR, Bushman FD, Dropulic B, June CH (2006). "Gene transfer in humans using a conditionally replicating lentiviral vector". Proceedings of the National Academy of Sciences 103 (46): 17372–17377.  
  59. ^ "Penn Medicine presents HIV gene therapy trial data at CROI 2009". EurekAlert!. 10 February 2009. Retrieved 19 November 2009. 
  60. ^ "Gene therapy first for poor sight". BBC News. 1 May 2007. Retrieved 3 May 2010. 
  61. ^ A. M. Maguire, F. Simonelli, and F. Simonelli, "Safety and efficacy of gene transfer for Leber's congenital amaurosis," New England Journal of Medicine, vol. 358, no. 21, pp. 2240–2248, 2008.
  62. ^ Dolgin, E. (2009). "Colour blindness corrected by gene therapy". Nature.  
  63. ^ Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P (2009). "Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy". Science 326 (5954): 818–23.  
  64. ^ Komáromy AM, Alexander JJ, Rowlan JS, Garcia MM, Chiodo VA, Kaya A, Tanaka JC, Acland GM, Hauswirth WW, Aguirre GD (2010). "Gene therapy rescues cone function in congenital achromatopsia". Human Molecular Genetics 19 (13): 2581–2593.  
  65. ^ Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, Down J, Denaro M, Brady T, Westerman K, Cavallesco R, Gillet-Legrand B, Caccavelli L, Sgarra R, Maouche-Chrétien L, Bernaudin F, Girot R, Dorazio R, Mulder GJ, Polack A, Bank A, Soulier J, Larghero J, Kabbara N, Dalle B, Gourmel B, Socie G, Chrétien S, Cartier N, Aubourg P, Fischer A, Cornetta K, Galacteros F, Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-Abina S, Leboulch P (2010). "Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia". Nature 467 (7313): 318–22.  
  66. ^ Galanello R, Origa R (2010). "Beta-thalassemia". Orphanet Journal of Rare Diseases 5: 11.  
  67. ^ a b c Leboulch P (20 March 2013). "Five year outcome of lentiviral gene therapy for human beta-thalassemia, lessons and prospects". Proceedings of the 3rd Pan-European Conference on Haemoglobinopathies and Rare Anaemias 3 (1s). 
  68. ^ a b Beals, Jacquelyn K. (16 September 2010). Gene Therapy Frees Beta-Thalassemia Patient From Transfusions for 2+ Years. (16 September 2010). Retrieved on 2012-12-15.
  69. ^ (11 July 2012) ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin Gene, Clinical trial NCT01639690 at the Memorial Sloan-Kettering Cancer Center, Retrieved 12 February 2014
  70. ^ Rosenberg, Tina (29 May 2011) The Man Who Had HIV and Now Does Not, New York Magazine.
  71. ^ "Gene Therapy Turns Several Leukemia Patients Cancer Free. Will It Work for Other Cancers, Too?". Singularity Hub. Retrieved 2014-01-07. 
  72. ^ Yang ZJ, Zhang YR, Chen B, Zhang SL, Jia EZ, Wang LS, Zhu TB, Li CJ, Wang H, Huang J, Cao KJ, Ma WZ, Wu B, Wang LS, Wu CT (2008). "Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease". Molecular Biology Reports 36 (6): 1323–1329.  
  73. ^ Hahn W, Pyun WB, Kim DS, Yoo WS, Lee SD, Won JH, Shin GJ, Kim JM, Kim S (2011). "Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model". The Journal of Gene Medicine 13 (10): 549–555.  
  74. ^ On Cancer: Launch of Stem Cell Therapy Trial Offers Hope for Patients with Inherited Blood Disorder | Memorial Sloan-Kettering Cancer Center. (16 July 2012). Retrieved on 15 December 2012.
  75. ^ ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin Gene. Retrieved on 15 December 2012.
  76. ^ Pollack, Andrew (20 July 2012) European Agency Backs Approval of a Gene Therapy, New York Times.
  77. ^ First Gene Therapy Approved by European Commission. UniQure (2 November 2012). Retrieved on 15 December 2012.
  78. ^ "Chiesi and uniQure delay Glybera launch to add data". Biotechnology.  
  79. ^ Bosely, Sarah (30 April 2013) Pioneering gene therapy trials offer hope for heart patients The Guardian, Retrieved 28 April 2014
  80. ^ (8 September 2013) First gene therapy trial for heart failure begins in UK The Physicians Clinic, Retrieved 28 April 2014
  81. ^ (10 April 2014) Celladon Receives Breakthrough Therapy Designation From FDA for MYDICAR(R), Novel, First-in-Class Therapy in Development to Treat Heart Failure New York Times, Retrieved 28 April 2014
  82. ^ Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L (2013). "Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy". Science 341 (6148): 1233158.  
  83. ^ Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L (2013). "Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome". Science 341 (6148): 1233151.  
  84. ^ MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC (2014). "Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial". Lancet 383 (9923): 1129–37.  
  85. ^ Beali, Abigail(25 January 2014) Gene therapy restores sight in people with eye disease The New Scientist, Retrieved 25 January 2014
  86. ^ Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH (2014). "Gene Editing ofCCR5in Autologous CD4 T Cells of Persons Infected with HIV". New England Journal of Medicine 370 (10): 901–10.  
  87. ^ Dvorsky, George (6 March 2014) Scientists Create Genetically Modified Cells That Protect Against HIV io9, Biotechnology, Retrieved 6 March 2014
  88. ^ "WADA Gene Doping". WADA. Retrieved September 27, 2013. 
  89. ^ Kayser, B.; Mauron, A.; Miah, A. (2007). "Current anti-doping policy: A critical appraisal". BMC Medical Ethics 8: 2.  
  90. ^ Powell R, Buchanan A (2011). "Breaking evolution's chains: the prospect of deliberate genetic modification in humans". J Med Philos 36 (1): 6–27.  
  91. ^ Baylis F, Robert JS (2004). "The inevitability of genetic enhancement technologies". Bioethics 18 (1): 1–26.  
  92. ^ Evans, John (2002). Playing God?: Human Genetic Engineering and the Rationalization of Public Bioethical Debate. University of Chicago Press. 
  93. ^ Gene Therapy and Genetic Engineering. The Center for Health Ethics, University of Missouri School of Medicine. 25 Apr. 2013.
  94. ^ Roco MC, Bainbridge WS (2002). Journal of Nanoparticle Research 4 (4): 281–295.  
  95. ^ Lee, Tim WR (26 Nov 2013). "Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease". Cochrane Database Syst Rev. 11 (11): CD005599.  
  96. ^ Olowoyeye, A (October 2015). "Gene therapy for sickle cell disease". Cochrane Database of Systematic Reviews 11 (10): CD007652.  
  97. ^ [World Medical Association. 59th General Assembly. World Medical Association Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects). October 2008.]
  98. ^ Human Genome Organization. HUGO Ethics Committee. Statement on Gene Therapy Research. April 2001. [3]
  99. ^ Isasi, Nguyen, Knoppers. National Regulatory Frameworks Regarding Human Genetic Modification Technologies (Somatic and Germline Modification). Genetics & Public Policy Center. October 2006 >
  100. ^ National Institutes of Health. NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. Revised March 2013. [4]
  101. ^ U.S. Department of Health & Human Services. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. 18 April 1979. [5]
  102. ^ U.S. Food and Drug Administration. Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products. Federal Register. Vol. 58. No. 197. 14 October 1993. [6]
  103. ^ U.S. Department of Health and Human Services. Food and Drug Administration. Center for Biologics Evaluation and Research. Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy. March 1998.
  104. ^ "A Real-life 'I Am Legend?' Researcher Champions Development Of 'Reovirus' As Potential Treatment For Cancer". 9 May 2008. Retrieved 17 August 2010. 


See also

  • Gene therapy is the basis for the plotline of the film I Am Legend.[104]

Popular culture

The United States Food and Drug Administration (FDA) regulates the quality and safety of gene therapy products and supervises how these products are implicated clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[102][103]

The National Institutes of Health (NIH) mainly serves as the gene therapy regulator for federally funded research institutions and projects. Privately funded human genetic research can only be recommended to voluntarily follow their regulations. NIH provides funding for lab research that develops or enhances devices utilized in human genetic engineering and to evaluate the ethics and quality of science present in current research labs. The NIH maintains a mandatory registry of human genetic engineering research protocols from all federally funded projects. An advisory committee to the NIH published a set of guidelines on the manipulation of genes.[100] The document for the NIH guidelines discusses safety considerations for the lab as well as for any human patient test subject. A wide range of various experimental types which involve any type of gene transfer or alteration are discussed. Several sections specifically pertain to human genetic engineering including Section III-C-1. This section states the review process researches must undergo and the aspects that are considered when attempting to be approved to begin clinical research involving human genetic transfer into a patient. This document is an important tool required for scientists to follow in order to further scientific progress in the field of somatic cell therapy.[101]

No federal legislation specifically lays out protocol and restrictions about either germline or somatic human genetic engineering. Instead, this subject is governed by overlapping regulations from local and federal agencies. Included agencies, from the Department of Health and Human Services, are the Food and Drug Administration and the Recombinant DNA Advisory Committee of the National Institutes of Health. Additionally, researchers who wish to receive federal funds when conducting research about an investigational new drug application, which is commonly the case for somatic human genetic engineering, are required to obey international and federal guidelines dealing with the protection of human test subjects.[99]

United States

[98] One key regulation comes from the

Policies on genetic modification tend to fall in the realm of general guidelines about human-involved biomedical research. Universal restrictions and documents have been made by international organizations to set a general standard on the issue of involving humans directly in research.


No trials of gene therapy for sickle cell disease was found in a systematic review conducted on October 2014. [96]

Data from trials on Topical cystic fibrosis transmembrane conductance regulator gene therapy do not support its clinical use and outcomes studied in these trials are not of clinical relevance.[95]

Evidence regarding clinical use of Gene Therapy

It has been speculated that genetic engineering could be used to change physical appearance, metabolism, and even improve physical capabilities and mental faculties like memory and intelligence, although for now these uses are limited to science fiction. These speculations have in turn led to ethical concerns and claims, including the belief that every fetus has an inherent right to remain genetically unmodified, the belief that parents hold the rights to modify their unborn offspring, and the belief that every child has the right to be born free from preventable diseases.[90][91][92] On the other hand, others have made claims that many people try to improve themselves already through diet, exercise, education, cosmetics, and plastic surgery and that accomplishing these goals through genetics could be more efficient and worthwhile.[93][94] This view sees the prevention of genetic diseases as a duty to humankind in preventing harm to future generations.

Human genetic engineering

There is a risk that athletes might abuse gene therapy technologies to improve their athletic performance.[88] This idea is known as gene doping and is as yet not known to be in use but a number of gene therapies have potential applications to athletic enhancement. In some cases, scholars have argued that genetic technology can make doping safer and thus more ethically acceptable. For example, Kayser et al. argue that if anything, gene doping will level the playing field if all athletes receive equal access: this will ensure that all athletes compete solely on how well they are performing relative to their maximum potential. In other cases, scientists and medics consider that any application of a therapeutic intervention for non-therapeutic or enhancing purposes compromises the ethical foundation of medicine and the spirit of sport.[89]

Gene doping

Several uses for gene therapy have been speculated.

Speculative uses for gene therapy

In March 2014 researchers at the University of Pennsylvania reported that 12 patients with HIV had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation known to protect against HIV (CCR5 deficiency). Results were promising.[86][87]

In January 2014, researchers at the University of Oxford reported that six people suffering from choroideremia had been treated with a genetically engineered adeno-associated virus with a copy of a gene REP1. Over a six month to two year period all had improved their sight. Choroideremia is an inherited genetic eye disease for which in the past there has been no treatment and patients eventually go blind.[84][85]


In October 2013, Amit Nathswani of the Royal Free London NHS Foundation Trust in London reported that they had treated six people with haemophilia in early 2011 using genetically engineered adeno-associated virus. Over two years later all six were still producing blood plasma clotting factor.[9]

In October 2013, the Great Ormond Street Hospital, London reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and their immune systems were showing signs of full recovery. Another three children treated since then were also making good progress. ADA-SCID children have no functioning immune system and are sometimes known as "bubble children."[9]

In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months the results were promising. Three of the children had metachromatic leukodystrophy which causes children to lose cognitive and motor skills.[82] The other children had Wiskott-Aldrich syndrome which leaves them to open to infection, autoimmune diseases and cancer due to a faulty immune system.[83]

Following encouraging Phase 1 trials, in April 2013, researchers in the UK and the US announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[79] at several hospitals in the US and Europe to use gene therapy to combat heart disease. These trials were designed to increase the levels of SERCA2a protein in the heart muscles and improve the function of these muscles.[80] The FDA granted this a Breakthrough Therapy Designation which would speed up the trial and approval process in the USA.[81]

In March 2013, Researchers at the Memorial Sloan-Kettering Cancer Center in New York, reported that three of five subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients immune systems would make normal T-cells and B-cells after a couple of months however they were given bone marrow to make sure. One patient had relapsed and died and one had died of a blood clot unrelated to the disease.[12]


In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1 which exist only on cancerous myeloma cells. This procedure had been developed by a company called Adaptimmune.[13]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment, called Alipogene tiparvovec (Glybera), compensates for lipoprotein lipase deficiency, which can cause severe pancreatitis.[76] The recommendation was endorsed by the European Commission in November 2012[18][19] and commercial rollout is expected in late 2014.[77][78]

The FDA approves clinical trials of the use of gene therapy on thalassemia major patients in the US. Researchers at Memorial Sloan Kettering Cancer Center in New York begin to recruit 10 participants for the study in July 2012.[74] The study is expected to end in 2014.[75]


Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[72][73]

In August 2011, two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The study carried out by the researchers at the University of Pennsylvania used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[11] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[71]

In 2007 and 2008, a man being treated by Gero Hütter was cured of HIV by repeated Hematopoietic stem cell transplantation (see also Allogeneic stem cell transplantation, Allogeneic bone marrow transplantation, Allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor; this cure was not completely accepted by the medical community until 2011.[70] This cure required complete ablation of existing bone marrow which is very debilitating.


In September 2010, it was announced that an 18 year old male patient in France with beta-thalassemia major had been successfully treated with gene therapy.[65] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[66] A team directed by Dr. Phillipe Leboulch (of the University of Paris, Bluebird Bio and Harvard Medical School[67]) used a lentiviral vector to transduce the human ß-globin gene into purified blood and marrow cells obtained from the patient in June 2007.[68] The patient's haemoglobin levels were stable at 9 to 10 g/dL, about a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions had not been needed.[67][68] Further clinical trials were planned.[69] Bone marrow transplants are the only cure for thalassemia but 75% of patients are unable to find a matching bone marrow donor.[67]

A paper by Komáromy et al. published in April 2010, deals with gene therapy for a form of achromatopsia in dogs. Achromatopsia, or complete color blindness, is presented as an ideal model to develop gene therapy directed to cone photoreceptors. Cone function and day vision have been restored for at least 33 months in two young dogs with achromatopsia. However, the therapy was less efficient for older dogs.[64]



In September 2009, the journal Nature reported that researchers at the University of Washington and University of Florida were able to give trichromatic vision to squirrel monkeys using gene therapy, a hopeful precursor to a treatment for color blindness in humans.[62] In November 2009, the journal Science reported that researchers succeeded at halting a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[63]


In all three clinical trials, patients recovered functional vision without apparent side-effects.[3][4][5][6] These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.

In May 2008, two more groups, one at the University of Florida and another at the University of Pennsylvania, reported positive results in independent clinical trials using gene therapy to treat Leber's congenital amaurosis.


On 1 May 2007 Moorfields Eye Hospital and University College London's Institute of Ophthalmology announced the world's first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23 year-old British male, Robert Johnson, in early 2007.[60] Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in New England Journal of Medicine in April 2008.[61] They researched the safety of the subretinal delivery of recombinant adeno-associated virus (AAV) carrying RPE65 gene, and found it yielded positive results, with patients having modest increase in vision, and, perhaps more importantly, no apparent side-effects.


In November 2006 Preston Nix from the University of Pennsylvania School of Medicine reported on VRX496, a gene-based immunotherapy for the treatment of human immunodeficiency virus (HIV) that uses a lentiviral vector for delivery of an antisense gene against the HIV envelope. In the Phase I trial enrolling five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens, a single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was safe and well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. In addition, all five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in U.S. Food and Drug Administration-approved human clinical trials for any disease.[58] Data from an ongoing Phase I/II clinical trial were presented at CROI 2009.[59]

In August 2006, scientists at the National Institutes of Health (Bethesda, Maryland) successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells. This study constitutes one of the first demonstrations that gene therapy can be effective in treating cancer.[57]

In May 2006 a team of scientists led by Dr. Luigi Naldini and Dr. Brian Brown from the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) in immune system recognizes the new gene as foreign and rejects the cells carrying it. To overcome this problem, the HSR-TIGET group utilized a newly uncovered network of genes regulated by molecules known as microRNAs. Dr. Naldini's group reasoned that they could use this natural function of microRNA to selectively turn off the identity of their therapeutic gene in cells of the immune system and prevent the gene from being found and destroyed. The researchers injected mice with the gene containing an immune-cell microRNA target sequence, and the mice did not reject the gene, as previously occurred when vectors without the microRNA target sequence were used. This work will have important implications for the treatment of hemophilia and other genetic diseases by gene therapy.

In March 2006 an international group of scientists announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and which gives a defective immune system. The study, published in Nature Medicine, is believed to be the first to show that gene therapy can cure diseases of the myeloid system.[55]


RNA interference or gene silencing may be a new way to treat Huntington's disease. Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[54]

In 2003 a University of California, Los Angeles research team inserted genes into the brain using liposomes coated in a polymer called polyethylene glycol. The transfer of genes into the brain is a significant achievement because viral vectors are too big to get across the blood–brain barrier. This method has potential for treating Parkinson's disease.[53]



The 1999 death of Jesse Gelsinger in a gene therapy clinical trial resulted in a significant setback to gene therapy research in the United States.[50][51] As a result, the U.S. FDA suspended several clinical trials pending the re-evaluation of ethical and procedural practices in the field.[52]

In 1993 Andrew Gobea was born with severe combined immunodeficiency (SCID). Genetic screening before birth showed that he had SCID. Blood was removed from Andrew's placenta and umbilical cord immediately after birth, containing stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and was inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses entered and inserted the gene into the stem cells' chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood system via a vein. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.

In 1992 Doctor Claudio Bordignon working at the Vita-Salute San Raffaele University, Milan, Italy performed the first procedure of gene therapy using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[48] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase-deficiency (SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) held from 2000 and 2002 was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the United States, the United Kingdom, France, Italy, and Germany.[49]

Sickle-cell disease is successfully treated in mice.[46] The mice – which have essentially the same defect that causes sickle cell disease in humans – through the use a viral vector, were made to express the production of fetal hemoglobin (HbF), which normally ceases to be produced by an individual shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF has long been shown to temporarily alleviate the symptoms of sickle cell disease. The researchers demonstrated this method of gene therapy to be a more permanent means to increase the production of the therapeutic HbF.[47]

New gene therapy approach repairs errors in messenger RNA derived from defective genes. This technique has the potential to treat the blood disorder thalassaemia, cystic fibrosis, and some cancers.[44] Researchers at Case Western Reserve University and Copernicus Therapeutics are able to create tiny liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[45]

The first approved gene therapy case in the United States took place on 14 September 1990, at the National Institute of Health, under the direction of Professor William French Anderson.[42] It was performed on a four year old girl named Ashanti DeSilva. It was a treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The effects were only temporary, but successful.[43]


In 1972 Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?"[40] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[41]

1970s and earlier

Development of gene therapy technology

Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999,[38] which represented a major setback in the field. One X-SCID patient died of leukemia following gene therapy treatment in 2003.[1] In 2007, a rheumatoid arthritis patient died from an infection in a gene therapy trial; a subsequent investigation concluded that the death was not related to her gene therapy treatment.[39]


  • Short-lived nature of gene therapy – Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.
  • Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system's enhanced response to invaders that it has seen before makes it difficult for gene therapy to be repeated in patients.
  • Problems with viral vectors – Viruses, the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient: toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
  • Multigene disorders – Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy.
  • For countries in which germ-line gene therapy is illegal, indications[32] that the Weismann barrier (between soma and germ-line) can be breached are relevant; spread to the testes, therefore could impact the germline against the intentions of the therapy.
  • Chance of inducing a tumor (insertional mutagenesis) – If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.[33][34] One possible solution for this is to add a functional tumor suppressor gene onto the DNA to be integrated; however, this poses its own problems, since the longer the DNA is, the harder it is to integrate it efficiently into cell genomes. The development of CRISPR technology in 2012 allowed researchers to make much more precise changes at exact locations in the genome.[35]
  • The cost - only a small number of patients can be treated with gene therapy because of the extremely high cost (Alipogene tiparvovec or Glybera, for example, at a cost of $1.6 million per patient was reported in 2013 to be the most expensive drug in the world).[36][37]

Some of the unsolved problems with the technology underlying gene therapy include:

Technological hurdles

There are several methods for non-viral gene therapy, including the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, and the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Non-viral methods can present certain advantages over viral methods, such as large scale production and low host immunogenicity. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques that approach the transfection efficiencies of viruses.

Non-viral methods

A number of viruses have been used for human gene therapy, including retrovirus, adenovirus, lentivirus, herpes simplex virus, vaccinia, pox virus, and adeno-associated virus.[2]

All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. Therefore this has been recognized as a plausible strategy for gene therapy, by removing the viral DNA and using the virus as a vehicle to deliver the therapeutic DNA.


Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by a number of methods. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).

Vectors in gene therapy

[31][30][29][27] The USA has no federal legislation specifically addressing human germ-line or somatic genetic modification (beyond the FDA testing regulations for therapies in general).[28] and higher risk than somatic gene therapy (e.g. using non-integrative vectors).[27] prohibit this for application in human beings, at least for the present, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[27]

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