Gene therapy and gene correction: targets, progress, and challenges for treating human diseases

Abstract

The field of gene therapy has made significant strides over the last several decades toward the treatment of previously untreatable genetic disease. Gene therapy techniques have been aimed at mitigating disease features of recessive and dominant disorders, as well as several cancers and other diseases. While there have been numerous disease targets of gene therapy trials, only four therapies have reached FDA and/or EMA approval for clinical use. Gene correction using CRISPR-Cas9 is an extension of gene therapy that has received considerable attention in recent years and boasts many possible uses beyond classical gene therapy approaches. While there is significant therapeutic potential using gene therapy and gene correction strategies, a number of hurdles remain to be overcome before they become more common in clinical use, particularly with regards to safety and efficacy. As research progresses in this exciting field, it is likely that these therapies will become first-line treatments and will have tremendous positive impacts on the lives of patients with genetic disorders.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The use of CRISPR-Cas9 for genome editing.
Fig. 2: Regulation of gene expression using Cas9.

References

  1. 1.

    Szybalska E, Szybalski W. Genetics of human cess line. IV. DNA-mediated heritable transformation of a biochemical trait. PNAS. 1962;48:2026–34.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Rogers S, Pfuderer P. Use of viruses as carriers added genetic information. Nature. 1968;219:749–51.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Rogers S, Lowenthal A, Terheggen H, Columbo J. Induction of arginase activity with the Shope papilloma virus in tissue culture cells from an argininemic patient. J Exp Med. 1973;137:1091–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Terheggen H. Unsuccessful trial of gene replacement in arginase deficiency. Z Kinderheilkd. 1975;119:1–3.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Blaese R, Culver K, Miller D, Carter C, Fleisher T, Clerici M. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science. 1995;270:475.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Wirth T, Parker N, Yla-Herttuala S. History of gene therapy. Gene. 2013;525:162–9.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Ribeil J, Hacein-Bey-Abina S, Payen E, Magnani A, Semerano M, Magrin E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;37:848–55.

    Article  Google Scholar 

  8. 8.

    Nathwani A, Reiss U, Tuddenham E, Rosales C, Chowary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia b. N Engl J Med. 2014;371:1994–2004.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    Griesenbach U, Pytel K, Alton E. Cystic fibrosis gene therapy in the UK and elsewhere. Hum Gene Ther. 2015;26:266–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Gaucer S, Lwin S, Titeux M, Abdul-Wahab A, Pironon N, Izmiryan A, et al. GENEGRAFT ex vivo phase I/II gene therapy trial for recessive dystrophic epidermolysis bullosa British. J Dermatol. 2019;182:788–818.

    Google Scholar 

  11. 11.

    den Hollander A, Black A, Bennett J, Cremers F. Lighting a candle in the dark: adavances in genetics and gene therapy of recessive retinal dystrophies. JCI. 2011;120:3042–51.

    Article  CAS  Google Scholar 

  12. 12.

    Rodrigues G, Shalaev E, Karami T, Cunningham J, Slater N, Rivers H. Pharmaceutical development of AAV-based gene therapy products for the eye. Pharm Res. 2019;36:29.

    Article  CAS  Google Scholar 

  13. 13.

    Shibata S, Ranum P, Moteki H, Pan B, Goodwin A, Goodman S, et al. RNA interference prevents autosomal-dominant hearing loss. AJHG. 2016;98:1101–13.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Stoica L, Sena-Esteves M. Adeno associated viral vector delivered RNAi for gene therapy of SOD1 amyotrophic lateral sclerosis. Front Mol Neurosci. 2016;9:56.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Wallace L, Giesige C, Griffin D, Rodino-Klapaca L, Harper S. RNAi therapy for dominant limb girdle muscular dystrophy type 1A. Mol Ther. 2016;24:S248.

    Article  Google Scholar 

  16. 16.

    Maheshwari R, Tekade M, Sharma P, Tekade R. Nanocarriers assisted siRNA gene therapy for the management of cardiovascular disorders. Curr Pharm Des. 2015;21:4427–40.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Somasuntharam I, Boopathy A, Khan R, Martinez M, Brown M, Murthy N, et al. Delivery of Nox2-NADPH oxidase siRNA with polyketal nanoparticles for improving cardiac function following myocardial infarction. Biomaterials. 2013;34:7790–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Kwekkeboom R, Lei Z, Doevendans P, Musters R, Sluijter P. Targeted delivery of miRNA therapeutics for cardiovascular diseases: opportunities and challenges. Clin Sci. 2014;127:351–65.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet. 2002;30:365–6.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    de Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nat Genet. 2003;33:192–6.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Shovlin C, Hughes J, Scott J, Seidman C, Seidman J. Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet. 1997;61:68–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Pingault V, Bondurand N, Kuhlbrodt K, Goerich D, Prehu M, Puliti A, et al. SOX10 mutations in patients with Waardenburg-Hirschprung disease. Nat Genet. 1998;18:171–3.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Kuehn H, Caminha I, Niemela J, Rao K, Davis J, Fleisher T, et al. FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome. J Immunol. 2011;186:6035–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Kortum F, Das S, Flindt M, Morris-Rosendahl D, Stefanova I, Goldstein A, et al. The coreFOXG1syndrome phenotype consists ofpostnatal microcephaly, severe mental retardation,absent language, dyskinesia, and corpuscallosum hypogenesis. J Med Genet. 2011;48:396–406.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Huang V, Qin Y, Wang J, Wang X, Place R, Lin G, et al. RNAa is conserved in mammalian cells. PLoS ONE. 2010;5:e8848.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Zhang Z, Wang Z, Liu X, Wang J, Feng L, Li C, et al. Up-regulation of p21WAF1/CIP1 by small activating RNA inhibits the in vitro and in vivo growth of pancreatic cancer cells. Tumori. 2012;98:804–11.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Place R, Wang J, Noonan E, Meyers R, Manoharan M, Charisse K, et al. Forumulation of small activating RNA into lipidoid nanoparticles inhibits xenograft prostate tumor growth by inducing p21 expression. Molecular Therapy. Nucleic Acids. 2012;1:e15.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Wright D, Li T, Yang B, Spalding M. TALEN-mediated genoe editing: prospects and perspectives. Biochem J. 2014;462:15–24.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Le Provost F, Lillico S, Passet B, Young R, Whitelaw B, VIlotte J. Zinc finger nuclease technology heralds a new era in mammalian transgenesis. Trends Biotechnol. 2010;28:134–41.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Horvath P, Barrangou R. CRISPR/Cas, the immune system of bacteria and archaea. Science. 2010;327:167–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Cong L, Ran F, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Ran F, Hsu P, Wright J, Agarwala V, Scott D, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8:2281–308.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Srivastava M, Raghavan S. DNA double-strand break repair inhibitors as cancer therapeutics. Chem Biol. 2014;22:17–29.

    Article  CAS  Google Scholar 

  34. 34.

    Hoeijmakers J. Genomic maintenance mechanisms for preventing cancer. Nature. 2001;411:366–74.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Vilenchik M, Knudson A. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. PNAS. 2003;100:12871–6.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Jacobson N, Andrews M, Shepard A, Nishimura D, Searby C, Fingert J, et al. Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor. Hum Mol Genet. 2001;10:117–25.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Joe M, Sohn S, Hur W, Moon Y, Choi Y, Kee C. Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells. Biochem Biophys Res Commun. 2003;312:592–600.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Yam G, Gaplovska-Kysela K, Zuber C, Roth J. Aggregated myocilin induces Russell bodies and causes apoptosis: implications for the pathogenesis of myocilin-caused primary open-angle glaucoma. Am J Pathol. 2007;170:100–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Alvarado J, Murphy C, Juster R. Trabecular meshwork cellularity in primary open-angle glaucoma and nonglaucomatous normals. Ophthalmology. 1984;91:564–79.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Jain A, Zode G, Kasetti R, Ran F, Yan W, Sharma T, et al. CRISPR-Cas9–based treatment of myocilin-associated glaucoma. PNAS. 2017;114:11199–204.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Jackow J, Guo Z, Hansen C, Abaci H, Doucet Y, Shin J, et al. CRISPR/Cas9-based targeted genome editing for correction of recessive dystrophic epidermolysis bullosa using iPS cells. PNAS. 2019;116:26846–52.

    CAS  Article  Google Scholar 

  42. 42.

    Burnight E, Gupta M, Wiley L, Anfinson K, Tran A, Triboulet R, et al. Using CRISPR-Cas9 to generate gene-corrected autologous iPSCs for the treatment of inherited retinal degeneration. Mol Ther. 2017;25:1999–2013.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Chavez A, Scheiman J, Vora S, Pruitt B, Tuttle M, Iyer E, et al. Highly-efficient Cas9-mediated transcriptional programming. Nat Methods. 2015;12:326–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Saayman S, Lazar D, Scott T, Hart J, Takahashi M, Burnett J, et al. Potent and targeted activation of latent HIV-1 using the CRISPR/dCas9 activator complex. Mol Ther. 2016;24:488–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Hsu M, Liao H, Truong V, Huang K, Yu F, Chen H, et al. CRISPR-based activation of endogenous neurotrophic genes in adipose stem cell sheets to stimulate peripheral nerve regeneration. Theranostics. 2019;9:6099–111.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Vojta A, Dobrinic P, Tadic V, Bockor L, Korac P, Julg B, et al. Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acid Res. 2016;44:5615–28.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Chira S, Jackson C, Oprea I, Ozturk F, Pepper M, Diaconu I, et al. Progresses towards safe and efficient gene therapy vectors. Oncotarget. 2015;6:30675–703.

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Dong J, Fan P, Frizzell R. Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum Gene Ther. 1996;7:2101–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Lundstrom K. Viral vectors in gene therapy. Diseases. 2018;6:42.

    PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Sakamoto M, Yuasa K, Yoshimura M, Yokota T, Ikemoto T, Suzuki M, et al. Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene. Biochem Biophys Res Commun. 2002;293:1265–72.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Simonelli F, Maguire A, Testa F, Pierce E, Mingozzi F, Bennicelli J, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010;18:643–50.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Cideciyan A, Hauswirth W, Aleman T, Kaushal S, Schwartz S, Boye S, et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther. 2009;20:999–1004.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    McTaggart S, Al-Rubeai M. Retroviral vectors for human gene delivery. Biotechnol Adv. 2002;20:1–31.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Zhang W, Li L, Li D, Liu J, Li X, Li W, et al. The first approved gene therapy product for cancer Ad-p53 (Gendicine): 12 years in the clinic. Hum Gene Ther. 2018;29:160–79.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Milone M, O’Doherty U. Clinical use of lentiviral vectors. Leukemia. 2018;32:1529–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Yin H, Kanasty R, Eltoukhy A, Vegas A, Dorkin J, Anderson D. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;15:541–55.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Niidome T, Huang L. Gene therapy progress and prospects: nonviral vectors. Gene Ther. 2002;9:1647–52.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Jayakumar R, Chennazhi K, Muzzarelli R, Tamura H, Nair S, Selvamurugan N. Chitosan conjugated DNA nanoparticles in gene therapy. Carbohydr Polym. 2010;79:1–8.

    CAS  Article  Google Scholar 

  59. 59.

    de la Fuente M, Seijo B, Alonso M. Novel hyaluronic acid-chitosan nanoparticles for ocular gene therapy. IOVS. 2008;49:2016–24.

    Google Scholar 

  60. 60.

    Zheng F, Shi X, Yang G, Gong L, Yuan H, Cui Y, et al. Chitosan nanoparticle as gene therapy vector via gastrointestinal mucosa administration: Results of an in vitro and in vivo study. Life Sci. 2007;80:388–96.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Cheong S, Lee C, Kim S, Jeong H, Kim E, Park E, et al. Superparamagnetic iron oxide nanoparticles-loaded chitosan-linoleic acid nanoparticles as an effective hepatocyte-targeted gene delivery system. Int J Pharm. 2009;372:169–76.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Kim T, Jin H, Kim H, Cho M, Cho C. Mannosylated chitosan nanoparticle-based cytokinegene therapy suppressed cancer growth in BALB/c mice bearing CT-26 carcinoma cells. Mol Cancer Ther. 2006;5:1723–32.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Xue Y, Wang N, Zeng Z, Huang J, Xiang Z, Guan Y. Neuroprotective effect of chitosan nanoparticle gene delivery system grafted with acteoside (ACT) in Parkinson’s disease models. J Mater Sci Technol. 2020;43:197–207.

    Article  Google Scholar 

  64. 64.

    Tan A, Rajadas J, Seifalaian A. Exosomes as nano-theranostic delivery platforms for gene therapy. Adv Drug Deliv Rev. 2013;65:357–67.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Toh W, Lai R, Hui J, Lim S. MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment. Semin Cell Dev Biol. 2017;67:56–64.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Akao Y, Itoh T, Noguchi S, Itoh Y, Ohtsuki Y, Naoe T. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther. 2011;19:395–9.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Xitong D, Xiaorong Z. Targeted therapeutic delivery using engineered exosomes and its applications in cardiovascular diseases. Gene. 2016;575:377–84.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Liu Y, Li D, Liu Z, Zhou Y, Chu D, Li X, et al. Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Sci Rep. 2015;5:17543.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Gyorgy B, Sage C, AA I, Scheffer D, Brisson A, Tan S, et al. Rescue of hearing by gene delivery to inner-ear hair cells using exosome-associated AAV. Mol Ther. 2017;25:379–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Stolberg S. The biotech death of Jesse Gelsinger. N Y Times Mag. 1999;136-140:149–50.

    Google Scholar 

  71. 71.

    Braun C, Boztug K, Paruynski A, Witzel M, Schwartzer A, Rothe M, et al. Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy and genotoxicity. Sci Transl Med. 2014;6:227ra33.

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack M, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415–9.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Xiong W, Wu D, Xue U, Wang S, Chung M, Ji X, et al. AAV cis-regulatory sequences are correlated with ocular toxicity. PNAS. 2019;116:5785–94.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Yuasa K, Yoshimura M, Urasawa N, Ohshima S, Howell J, Nakamura A, et al. Injection of a recombinant AAV serotype 2 into canine skeletal muscles evokes strong immune responses against transgene products. Gene Ther. 2007;14:1249–60.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Wilson J, Flotte T. Moving forward after two deaths in a gene therapy trial of myotubular myopathy. Hum Gene Ther. 2020;31:695–6.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Hinderer C, Katz N, Buza E, Dyer C, Goode T, Bell P, et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus expressing human SMN. Hum Gene Ther. 2018;29:285–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Therapeutics A. 2020. https://myotubulartrust.org/wp-content/uploads/23JUNE2020-Letter-to-Patient-Community_Sent.pdf.

  78. 78.

    Yang Y, Chi Y, Tang X, Ertl H, Zhou D. Rapid, efficient, and modular generation of Adenoviral vectors via isothermal assembly. Curr Protoc Mol Biol. 2016;16:S113.

    Google Scholar 

  79. 79.

    Sumida S, Truitt D, Lemckert A, Vogels R, Custers J, Addo M, et al. Neutralizing antibodies to Adenovirus serotype 5 vaccine vectors are directed primarily against the Adenovirus hexon protein. J Immunol. 2005;174:7179–85.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Yu B, Wang Z, Dong J, Wang C, Gu L, Sun C, et al. A serological survey of human adenovirus serotype 2 and 5 circulating pediatric populations in Changchun, China, 2011. Virol J. 2012;9:287.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Halbert C, Miller A, McNamara S, Emerson J, Gibson R, Ramsey B, et al. Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: implications for gene therapy using AAV vectors. Hum Gene Ther. 2006;17:440–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Manno C, Pierce G, Arruda V, Glader B, Ragni M, Rasko J, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342–7.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Wang Z, Allen J, Riddell Sg P, Storb R, Tapscott S, Chamberlain J, et al. Immunity to adeno-associated virus-mediated gene transfer in a random-bred canine model of Duchenne muscular dystrophy. Hum Gene Ther. 2007;18:18–26.

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Luo Y. Refining CRISPR-based genome and epigenome editing off-targets. Cell Biol Toxicol. 2019;35:281–3.

    PubMed  Article  Google Scholar 

  85. 85.

    Kang S, Lee W, JAn, Lee J, Kim Y, Kim H. et al. Prediction-based highly sensitive CRISPR off-target validation using target-specific DNA enrichment. Nat Commun. 2020;11:3596.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Wang D, Mou H, Li S, Li Y, Hough S, Tran K, et al. Adenovirus-mediated somatic genome editing of Pten by CRISPR/Cas9 in mouse liver in spite of Cas9-specific immune responses. Hum Gene Ther. 2015;26:432–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Cutting G. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015;16:45–56.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Ashley-Koch A, Yang Q, Olney R. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000;151:839–45.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Russell S, Bennett J, Wellman J, Chung D, Yu Z, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hPRE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390:849–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Sheffield V, Zhang Q, Heon E, Drack A, Stone E, Carmi R. The Bardet–Biedl syndrome. In: Erickson R, Wynshaw-Boris A, editors. Epstein’s Inborn Errors of Development, 3rd ed. New York, NY: Oxford University Press; 2016.

  91. 91.

    Reuter J, Spacek D, Snyder M. High-throughput sequencing technologies. Mol Cell. 2016;58:586–97.

    Article  CAS  Google Scholar 

  92. 92.

    Sertkaya A, Birkenbach A, Berlind A, Eyraud J. Examination of clinical trial costs and barriers for drug development. Asian J Pharmaceutical and Clinical Research. 2014;10:53–6.

    Google Scholar 

  93. 93.

    Darrow J. Luxturna: FDA documents reveal the value of a costly gene therapy. Drug Discov Today. 2019;24:949–54.

    PubMed  Article  Google Scholar 

  94. 94.

    Aartsma-Rus A, Krieg A. FDA approves eteplirsen for Duchenne muscular dystrophy: the next chapter in the eteplirsen saga. Nucleic Acid Ther. 2017;27:1–3.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Seo S, Mullins R, Dumitrescu A, Bhattarai S, Gratie D, Wang K, et al. Subretinal gene therapy of mice with Bardet-Biedl syndrome type 1. Investig Ophthalmol Vis Sci. 2013;11:6118–32.

    Article  CAS  Google Scholar 

  96. 96.

    Singh G, Dash D. Electrostatic mis-interactions cause overexpression toxicity of proteins in E. coli. PLoS ONE. 2013;8:e64893.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Ferrua F, Cicalese M, Galimberti S, Giannelli S, Dionisio F, Barzaghi F, et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 2019;6:e239–53.

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Pendaries V, Gasc G, Titeux M, Tonasso L, Majia J, Hovnanian A. siRNA-mediated allele-specific inhibition of mutant type VII collagen in dominant dystrophic epidermolysis bullosa. J Investig Dermatol. 2012;132:1741–3.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Leachman S, Hickerson R, Schwartz S, Bullough E, Hutcherson S, Boucher K, et al. First-in-human mutation-targeting siRNA phase Ib trial of an inherited skin disorder. Mol Ther. 2010;18:442–6.

    CAS  PubMed  Article  Google Scholar 

Download references

Funding

This work was funded by the National Institutes of Health, grant numbers R01 EY011298 (VCS), R01 EY017168 (VCS) and an institutional grant to the Department of Ophthalmology and Visual Sciences at the University of Iowa (P30EY025580), as well as the Roy J. Carver Charitable Trust (VCS).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Val C. Sheffield.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cring, M.R., Sheffield, V.C. Gene therapy and gene correction: targets, progress, and challenges for treating human diseases. Gene Ther (2020). https://doi.org/10.1038/s41434-020-00197-8

Download citation

Further reading

Search