Invited Review Article| Volume 103, ISSUE 1, P2-9, July 2021

Advances in gene therapy and their application to skin diseases: A review

  • Satoru Shinkuma
    Correspondence to: Department of Dermatology, Nara Medical University School of Medicine, 840, Shijo-cho, Kashihara, 634-8522, Japan.
    Department of Dermatology, Nara Medical University School of Medicine, Kashihara, Japan
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      • Gene therapy represents a viable treatment option for various diseases.
      • Clinical trials have been conducted on gene therapy addressing genodermatoses.
      • This review summarizes the current use of gene therapy in the dermatological field.
      • Superficial gene-therapy sites can be evaluated for presence of neoplasms.
      • Therefore, dermatologists have an important role in gene therapy application.


      With recent advances in genetic engineering technology, gene therapy is now being considered as a treatment not only for congenital diseases but also acquired diseases, such as cancer. Gene therapeutic agents for hereditary immune disorders, haemophilia, retinal diseases, neurodegenerative diseases, and lymphoma have been approved in the United States and Europe. In the field of dermatology, clinical trials of gene therapy have been conducted, because the skin is an easily accessible organ that represents an attractive tissue for gene therapy. In recent years, gene therapy has been attempted for a variety of skin diseases, such as genodermatoses (including epidermolysis bullosa and Netherton syndrome), cutaneous lymphoma, and malignant melanoma. As a result, it is difficult to grasp the current status of gene therapy in dermatology. This review focuses on each of the gene-transfer techniques currently in use and describes the current status of gene therapy for skin diseases using each technology.


      αGLA (α-galactosidase A), AAV (adeno-associated virus), ASO (antisense oligonucleotide), COL7A1 (collagen type VII α-1 chain), CBCL (cutaneous B-cell lymphoma), CR (complete response), CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9), CTCL (cutaneous T cell lymphoma), DEB (dystrophic epidermolysis bullosa), DSB (double-strand break), EB (epidermolysis bullosa), EBGraft (gene-corrected autologous skin-equivalent grafts (EB patients)), gRNA (guide RNA), HIV (human immunodeficiency virus), HR (homologous recombination), HSV (herpes simplex virus), IL2RG (interleukin 2 receptor subunit γ), JEB (junctional epidermolysis bullosa), LAMB3 (laminin subunit β3), LTR (long terminal repeat), MLV (Moloney murine leukaemia virus), NHEJ (non-homologous end joining), NS (Netherton syndrome), PR (partial response), RDEB (autosomal recessive dystrophic epidermolysis bullosa), SCID (severe combined immunodeficiency), SIN (self-inactivating), SPINK5 (serine peptidase inhibitor Kazal-type 5), T-VEC (talimogene laherparepvec), TALEN (transcription activator-like effector nuclease), ZFN (zinc finger nuclease)


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        • Anderson W.F.
        Human gene therapy.
        Science. 1992; 256: 808-813
        • Cavazzana-Calvo M.
        • Hacein-Bey S.
        • de Saint Basile G.
        • et al.
        Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.
        Science. 2000; 288: 669-672
        • Baum C.
        • Düllmann J.
        • Li Z.
        • et al.
        Side effects of retroviral gene transfer into hematopoietic stem cells.
        Blood. 2003; 101: 2099-2114
        • Raper S.E.
        • Yudkoff M.
        • Chirmule N.
        • et al.
        A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency.
        Hum. Gene Ther. 2002; 13: 163-175
        • Brenner S.
        • Malech H.L.
        Current developments in the design of onco-retrovirus and lentivirus vector systems for hematopoietic cell gene therapy.
        Biochim. Biophys. Acta. 2003; 1640: 1-24
        • Elsner C.
        • Bohne J.
        The retroviral vector family: something for everyone.
        Virus Genes. 2017; 53: 714-722
        • Kurian K.M.
        • Watson C.J.
        • Wyllie A.H.
        Retroviral vectors.
        Mol. Pathol. 2000; 53: 173-176
        • Shinkuma S.
        • McMillan J.R.
        • Shimizu H.
        Ultrastructure and molecular pathogenesis of epidermolysis bullosa.
        Clin. Dermatol. 2011; 29: 412-419
        • Mavilio F.
        • Pellegrini G.
        • Ferrari S.
        • et al.
        Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells.
        Nat. Med. 2006; 12: 1397-1402
        • De Rosa L.
        • Carulli S.
        • Cocchiarella F.
        • et al.
        Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa.
        Stem Cell Rep. 2014; 2: 1-8
        • Bauer J.W.
        • Koller J.
        • Murauer E.M.
        • et al.
        Closure of a large chronic wound through transplantation of gene-corrected epidermal stem cells.
        J. Invest. Dermatol. 2017; 137: 778-781
        • Hirsch T.
        • Rothoeft T.
        • Teig N.
        • et al.
        Regeneration of the entire human epidermis using transgenic stem cells.
        Nature. 2017; 551: 327-332
        • Eichstadt S.
        • Barriga M.
        • Ponakala A.
        • et al.
        Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa.
        JCI Insight. 2019; 4e130554
        • Siprashvili Z.
        • Nguyen N.T.
        • Gorell E.S.
        • et al.
        Safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with recessive dystrophic epidermolysis bullosa.
        JAMA. 2016; 316: 1808-1817
        • Demeulemeester J.
        • De Rijck J.
        • Gijsbers R.
        • Debyser Z.
        Retroviral integration: site matters: mechanisms and consequences of retroviral integration site selection.
        BioEssays. 2015; 37: 1202-1214
        • Finkelshtein D.
        • Werman A.
        • Novick D.
        • Barak S.
        • Rubinstein M.
        LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus.
        Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 7306-7311
        • Malim M.H.
        • Hauber J.
        • Le S.Y.
        • Maizel J.V.
        • Cullen B.R.
        The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA.
        Nature. 1989; 338: 254-257
        • Wu C.
        • Dunbar C.E.
        Stem cell gene therapy: The risks of insertional mutagenesis and approaches to minimize genotoxicity.
        Front. Med. 2011; 5: 356-371
        • Jacków J.
        • Titeux M.
        • Portier S.
        • et al.
        Gene-corrected fibroblast therapy for recessive dystrophic epidermolysis bullosa using a self-inactivating COL7A1 retroviral vector.
        J. Invest. Dermatol. 2016; 136: 1346-1354
        • Di W.L.
        • Lwin S.M.
        • Petrova A.
        • et al.
        Generation and clinical application of gene-modified autologous epidermal sheets in netherton syndrome: lessons learned from a Phase 1 trial.
        Hum. Gene Ther. 2019; 30: 1067-1078
        • Kishibe M.
        Physiological and pathological roles of kallikrein-related peptidases in the epidermis.
        J. Dermatol. Sci. 2019; 95: 50-55
        • Gaucher S.
        • Lwin S.M.
        • Titeux M.
        • et al.
        EBGene trial: patient preselection outcomes for the European GENEGRAFT ex vivo phase I/II gene therapy trial for recessive dystrophic epidermolysis bullosa.
        Br. J. Dermatol. 2020; 182: 794-797
        • Has C.
        • South A.
        • Uitto J.
        Molecular Therapeutics in development for epidermolysis bullosa: Update.
        Mol. Diagn. Ther. 2020; 2020: 299-309
        • Lwin S.M.
        • Syed F.
        • Di W.L.
        • et al.
        Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa.
        JCI Insight. 2019; 4e126243
        • Zhang C.
        • Zhou D.
        Adenoviral vector-based strategies against infectious disease and cancer.
        Hum. Vaccin. Immunother. 2016; 12: 2064-2074
        • Hammer S.M.
        • Sobieszczyk M.E.
        • Janes H.
        • et al.
        Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine.
        N. Engl. J. Med. 2013; 369: 2083-2092
        • Ledgerwood J.E.
        • DeZure A.D.
        • Stanley D.A.
        • et al.
        Chimpanzee adenovirus vector Ebola vaccine.
        N. Engl. J. Med. 2017; 376: 928-938
        • Dummer R.
        • Rochlitz C.
        • Velu T.
        • et al.
        Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma.
        Mol. Ther. 2008; 16: 985-994
        • Stewart A.K.
        • Lassam N.J.
        • Quirt I.C.
        • et al.
        Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: Results of a phase 1 clinical trial.
        Gene Ther. 1999; 6: 350-363
        • Dummer R.
        • Bergh J.
        • Karlsson Y.
        • et al.
        Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumours.
        Cancer Gene Ther. 2000; 7: 1069-1076
        • Dummer R.
        • Hassel J.C.
        • Fellenberg F.
        • et al.
        Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumour regressions in cutaneous lymphomas.
        Blood. 2004; 104: 1631-1638
        • Dummer R.
        • Eichmüller S.
        • Gellrich S.
        • et al.
        Phase II clinical trial of intratumoral application of TG1042 (adenovirus-interferon-gamma) in patients with advanced cutaneous T-cell lymphomas and multilesional cutaneous B-cell lymphomas.
        Mol. Ther. 2010; 18: 1244-1247
        • Naso M.F.
        • Tomkowicz B.
        • Perry 3rd, W.L.
        • Strohl W.R.
        Adeno-associated virus (AAV) as a vector for gene therapy.
        BioDrugs. 2017; 31: 317-334
        • Gao G.
        • Vandenberghe L.H.
        • Wilson J.M.
        New recombinant serotypes of AAV vectors.
        Curr. Gene Ther. 2005; 5: 285-297
        • Kok K.
        • Zwiers K.C.
        • Boot R.G.
        • Overkleeft H.S.
        • Aerts J.M.F.G.
        • Artola M.
        Fabry disease: Molecular basis, pathophysiology, diagnostics and potential therapeutic directions.
        Biomolecules. 2021; 11: 271
        • Artusi S.
        • Miyagawa Y.
        • Goins W.F.
        • Cohen J.B.
        • Glorioso J.C.
        Herpes simplex virus vectors for gene transfer to the central nervous system.
        Diseases. 2018; 6: 74
        • Rehman H.
        • Silk A.W.
        • Kane M.P.
        • Kaufman H.L.
        Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy.
        J. Immunother. Cancer. 2016; 4: 53
        • Raman S.S.
        • Hecht J.R.
        • Chan E.
        Talimogene laherparepvec: Review of its mechanism of action and clinical efficacy and safety.
        Immunotherapy. 2019; 11: 705-723
        • Bedikian A.Y.
        • Millward M.
        • Pehamberger H.
        • et al.
        Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the oblimersen Melanoma Study Group.
        J. Clin. Oncol. 2006; 24: 4738-4745
        • Bornert O.
        • Hogervorst M.
        • Nauroy P.
        • et al.
        QR-313, an antisense oligonucleotide, shows therapeutic efficacy for treatment of dominant and recessive dystrophic epidermolysis bullosa: a preclinical study.
        J. Invest. Dermatol. 2021; 141883-893.e6
        • Urnov F.D.
        • Miller J.C.
        • Lee Y.L.
        • et al.
        Highly efficient endogenous human gene correction using designed zinc-finger nucleases.
        Nature. 2005; 435: 646-651
        • Urnov F.D.
        • Rebar E.J.
        • Holmes M.C.
        • Zhang H.S.
        • Gregory P.D.
        Genome editing with engineered zinc finger nucleases.
        Nat. Rev. Genet. 2010; 11: 636-646
        • Cermak T.
        • Doyle E.L.
        • Christian M.
        • et al.
        Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting.
        Nucleic Acids Res. 2011; 39: e82
        • Jinek M.
        • Chylinski K.
        • Fonfara I.
        • Hauer M.
        • Doudna J.A.
        • Charpentier E.
        A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.
        Science. 2012; 337: 816-821
        • March O.P.
        • Kocher T.
        • Koller U.
        Context-dependent strategies for enhanced genome editing of genodermatoses.
        Cells. 2020; 9: 112
        • Shinkuma S.
        • Guo Z.
        • Christiano A.M.
        Site-specific genome editing for correction of induced pluripotent stem cells derived from dominant dystrophic epidermolysis bullosa.
        Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 5676-5681
        • Takashima S.
        • Shinkuma S.
        • Fujita Y.
        • et al.
        Efficient gene reframing therapy for recessive dystrophic epidermolysis bullosa with CRISPR/Cas9.
        J. Invest. Dermatol. 2019; 139 (e4): 1711-1721
        • Min Y.L.
        • Bassel-Duby R.
        • Olson E.N.
        CRISPR correction of Duchenne muscular dystrophy.
        Annu. Rev. Med. 2019; 70: 239-255
        • Itoh M.
        • Kawagoe S.
        • Tamai K.
        • Nakagawa H.
        • Asahina A.
        • Okano H.J.
        Footprint-free gene mutation correction in induced pluripotent stem cell (iPSC) derived from recessive dystrophic epidermolysis bullosa (RDEB) using the CRISPR/Cas9 and piggyBac transposon system.
        J. Dermatol. Sci. 2020; 98: 163-172
        • Jacków J.
        • Guo Z.
        • Hansen C.
        • et al.
        CRISPR/Cas9-based targeted genome editing for correction of recessive dystrophic epidermolysis bullosa using iPS cells.
        Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 26846-26852


      Satoru Shinkuma (M.D., Ph.D.) received his M.D. in 2004 from Nara Medical University School of Medicine, Kashihara, Japan and Ph.D. in 2011 from Hokkaido University, Sapporo, Japan. Dr. Shinkuma then worked as a postdoctoral fellow at Columbia University, New York, USA (2013–2014). After returning to Japan, he worked as an assistant professor at Hokkaido University and then as associate professor at Niigata University and is now an associate professor at Nara Medical University. His research interest is in the field of gene therapy and regenerative therapy for genetic skin disorders, particularly epidermolysis bullosa and congenital hair disorders.