Gene Therapy: A New Approach in Modern Medicine

Document Type: Narrative Review

Authors

1 Department of Biology, Faculty of Basic Science, Shahed University, Tehran, Iran

2 Green Gene Company, Tehran, Iran

3 Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

Abstract

In general, gene therapy is the transfer of a genetic material to treat a disease, or at least to improve the clinical status of a patient. One way gene therapy works is to turn viruses into genetic vectors that carry the gene of interest to the target cells. Based on the genome’s nature, these vectors are divided into RNA-based or DNA-based viral vectors. Most RNA-based vectors are derived from simple retroviruses, such as the murine leukemia virus. One major drawback of these viruses is that they are not transferred to non-dividing cells (post-mitotic cells). This problem can be solved by using new retroviral vectors derived from lentiviruses, such as the human immunodeficiency virus (HIV). DNA-based vectors originate from adeno-viruses and adeno-associated viruses (AAVs). An example of gene deletion due to gene therapy is the deletion of the human CCR5 gene in T cells (which control HIV infection). Although available vector systems have the ability to transfer genes to living cells (in the human body), an ideal vector for gene delivery has not yet been found. Therefore, the current viral vectors should be used with great caution in human cases. Moreover, the development of new vectors is necessary.

Keywords


  1. Patil PM, Chaudhari PD, Sahu M, Duragkar NJ. Review article on gene therapy. Int J Genet. 2012;4(1):74-79. doi:10.9735/0975-2862.4.1.74-79.
  2. Kumar SR, Markusic DM, Biswas M, High KA, Herzog RW. Clinical development of gene therapy: results and lessons from recent successes. Mol Ther Methods Clin Dev. 2016;3:16034. doi:10.1038/mtm.2016.34.
  3. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342(6165):1432-1433. doi:10.1126/science.342.6165.1432.
  4. Wang X, Shin SC, Chiang AF, et al. Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets corrects murine hemophilia A. Mol Ther. 2015;23(4):617-626. doi:10.1038/mt.2015.20.
  5. Brown BD. A shot in the bone corrects a genetic disease. Mol Ther. 2015;23(4):614-615. doi:10.1038/mt.2015.38.
  6. Yla-Herttuala S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. Mol Ther. 2012;20(10):1831-1832. doi:10.1038/mt.2012.194.
  7. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14(9):642- 662. doi:10.1038/nrd4663.
  8. Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. Genome editing with engineered zinc finger nucleases. Nat Rev Genet. 2010;11(9):636-646. doi:10.1038/nrg2842.
  9. Durai S, Mani M, Kandavelou K, Wu J, Porteus MH, Chandrasegaran S. Zinc finger nucleases: custom-designed molecular scissors for genome engineering of plant and mammalian cells. Nucleic Acids Res. 2005;33(18):5978-5990. doi:10.1093/nar/gki912.
  10. Friedmann T, Roblin R. Gene therapy for human genetic disease? Science. 1972;175(4025):949-955. doi:10.1126/science.175.4025.949.
  11. Harwood AJ. Protocols for gene analysis. 1st ed. Totowa, New Jersey: Humana Press; 1994. Volume 31. doi:10.1385/0896032582.
  12. Ramamoorth M, Narvekar A. Non viral vectors in gene therapy-an overview. J Clin Diagn Res. 2015;9(1):Ge01-06. doi:10.7860/JCDR/2015/10443.5394.
  13. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341-345. doi:10.1038/nbt.1807.
  14. Wrobel I, Collins D. Fusion of cationic liposomes with mammalian cells occurs after endocytosis. Biochim Biophys Acta. 1995;1235(2):296-304. doi:10.1016/0005-2736(95)80017-A.
  15. Al-Dosari MS, Gao X. Nonviral gene delivery: principle, limitations, and recent progress. AAPS J. 2009;11(4):671-681. doi:10.1208/s12248-009-9143-y.
  16. Dobson J. Gene therapy progress and prospects: magnetic nanoparticle-based gene delivery. Gene Ther. 2006;13(4):283-287. doi:10.1038/sj.gt.3302720.
  17. Jones CH, Chen CK, Ravikrishnan A, Rane S, Pfeifer BA. Overcoming nonviral gene delivery barriers: perspective and future. Mol Pharm. 2013;10(11):4082-4098. doi:10.1021/mp400467x.
  18. Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM. Gene therapy: therapeutic gene causing lymphoma. Nature. 2006;440(7088):1123. doi:10.1038/4401123a.
  19. Gao X, Huang L. Potentiation of cationic liposome-mediated gene delivery by polycations. Biochemistry. 1996;35(3):1027-1036. doi:10.1021/bi952436a.
  20. Horn PA, Morris JC, Neff T, Kiem HP. Stem cell gene transfer--efficacy and safety in large animal studies. Mol Ther. 2004;10(3):417-431. doi:10.1016/j.ymthe.2004.05.017.
  21. Farhood H, Serbina N, Huang L. The role of dioleoyl phosphatidylethanolamine in cationic liposome mediated gene transfer. Biochim Biophys Acta. 1995;1235(2):289-295. doi:10.1016/0005-2736(95)80016-9.
  22. Taymans JM, Nkiliza A, Chartier-Harlin MC. Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson’s disease pathogenesis. Trends Mol Med. 2015;21(8):466- 472. doi:10.1016/j.molmed.2015.05.004.
  23. van der Brug MP, Singleton A, Gasser T, Lewis PA. Parkinson’s disease: From human genetics to clinical trials. Sci Transl Med. 2015;7(305):205ps220. doi:10.1126/scitranslmed.aaa8280.
  24. Fuji RN, Flagella M, Baca M, et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Transl Med. 2015;7(273):273ra215. doi:10.1126/scitranslmed.aaa3634.
  25. Combs B, Kneynsberg A, Kanaan NM. Gene Therapy Models of Alzheimer’s Disease and Other Dementias. Methods Mol Biol. 2016;1382:339-366. doi:10.1007/978-1-4939-3271-9_25.
  26. Tuszynski MH, Yang JH, Barba D, et al. Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurol. 2015;72(10):1139-1147. doi:10.1001/jamaneurol.2015.1807.
  27. Oakland M, Sinn PL, McCray PB, Jr. Advances in cell and gene-based therapies for cystic fibrosis lung disease. Mol Ther. 2012;20(6):1108- 1115. doi:10.1038/mt.2012.32.
  28. Cooney AL, Abou Alaiwa MH, Shah VS, et al. Lentiviral-mediated phenotypic correction of cystic fibrosis pigs. JCI Insight. 2016;1(14). doi:10.1172/jci.insight.88730.
  29. Amer MH. Gene therapy for cancer: present status and future perspective. Mol Cell Ther. 2014;2:27. doi: 10.1186/2052-8426-2-27.
  30. Liu SX, Xia ZS, Zhong YQ. Gene therapy in pancreatic cancer. World J Gastroenterol. 2014;20(37):13343-13368. doi:10.3748/wjg.v20.i37.13343.
  31. Stoff-Khalili MA, Dall P, Curiel DT. Gene therapy for carcinoma of the breast. Cancer Gene Ther. 2006;13(7):633-647. doi:10.1038/sj.cgt.7700929.
  32. Husain SR, Han J, Au P, Shannon K, Puri RK. Gene therapy for cancer: regulatory considerations for approval. Cancer Gene Ther. 2015;22(12):554-563. doi:10.1038/cgt.2015.58.
  33. Ginn SL, Amaya AK, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2017: An update. J Gene Med. 2018;20(5):e3015. doi:10.1002/jgm.3015.
  34. Aiuti A, Biasco L, Scaramuzza S, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151. doi:10.1126/science.1233151.
  35. Hacein-Bey Abina S, Gaspar HB, Blondeau J, et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015;313(15):1550-1563. doi:10.1001/jama.2015.3253.
  36. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467(7313):318-322. doi:10.1038/nature09328.
  37. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326(5954):818-823. doi:10.1126/science.1171242.
  38. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy. Methods Enzymol. 2012;507:187-198. doi:10.1016/B978-0-12-386509-0.00010-7.
  39. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158. doi:10.1126/science.1233158.
  40. Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371(21):1994-2004. doi:10.1056/NEJMoa1407309.
  41. Baxalta reports continued progress on phase 1/2 clinical trial of BAX335, investigational gene therapy treatment for hemophilia B. Baxter website. http://www.baxter.com/news-media/newsroom/press-releases/2015/06_24_15_bax335.page. Published 2015.
  42. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540-549. doi:10.1200/JCO.2014.56.2025.
  43. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra138. doi:10.1126/scitranslmed.3005930.
  44. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517. doi:10.1056/NEJMoa1407222.
  45. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517-528. doi:10.1016/S0140-6736(14)61403-3.
  46. Leone P, Shera D, McPhee SW, et al. Long-term follow-up after gene therapy for canavan disease. Sci Transl Med. 2012;4(165):165ra163. doi:10.1126/scitranslmed.3003454.
  47. Tardieu M, Zerah M, Husson B, et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum Gene Ther. 2014;25(6):506-516. doi:10.1089/hum.2013.238.
  48. Li B, Ma W, Ling C, et al. Site-Directed Mutagenesis of Surface- Exposed Lysine Residues Leads to Improved Transduction by AAV2, But Not AAV8, Vectors in Murine Hepatocytes In Vivo. Hum Gene Ther Methods. 2015;26(6):211-220. doi:10.1089/hgtb.2015.115.
  49. Ferreira V, Twisk J, Kwikkers K, et al. Immune responses to intramuscular administration of alipogene tiparvovec (AAV1- LPL(S447X)) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy. Hum Gene Ther. 2014;25(3):180-188. doi:10.1089/hum.2013.169.
  50. Testa F, Maguire AM, Rossi S, et al. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology. 2013;120(6):1283-1291. doi:10.1016/j.ophtha.2012.11.048.
  51. Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010;18(3):643-650. doi:10.1038/mt.2009.277.
  52. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374(9701):1597-1605. doi:10.1016/S0140-6736(09)61836-5.
  53. Kaufmann KB, Buning H, Galy A, Schambach A, Grez M. Gene therapy on the move. EMBO Mol Med. 2013;5(11):1642-1661. doi:10.1002/emmm.201202287.
  54. Naldini L. Gene therapy returns to centre stage. Nature. 2015;526(7573):351-360. doi:10.1038/nature15818.