Klin Monbl Augenheilkd 2003; 220(11): 731-737
DOI: 10.1055/s-2003-44610
Übersicht
© Georg Thieme Verlag Stuttgart · New York

Gentherapie bei Hornhauterkrankungen

Gene Therapy in Corneal DiseasesFriedrich  Hoffmann1 , Claas  Junghans2
  • 1Augenklinik, Universitätsklinikum Benjamin Franklin (UKBF), Freie Universität Berlin
  • 2Mologen, Berlin
Further Information

Publication History

Eingegangen: 14. Juli 2003

Angenommen: 21. August 2003

Publication Date:
21 November 2003 (online)

Zusammenfassung

In der Vergangenheit wurden euphorische Erwartungen in die Gentherapie geweckt, die aber bisher nicht nur nicht erfüllt, sondern im Gegenteil wegen eines Ausbleibens konkreter klinischer Erfolge sowie des Eintretens tragischer Zwischenfälle enttäuscht wurden. Trotz des großen Zukunftspotenzials der Gentherapie werden wohl für längere Zeit zahlreiche gentherapeutische Pilotstudien abgebrochen werden. Aber trotz aller Misserfolge werden Krankheiten für experimentelle Protokolle, die beispielsweise nur eine vorübergehenden Genexpression vorsehen oder solche, die sich auf einzelne Organe beschränken und daher nur eine niedrige Dosis des Vehikels (Vektors) benötigen, weiterhin Ziel experimenteller Gentransferversuche bleiben. Wegen seiner guten und selektiven Erreichbarkeit, des geringen Volumens und des dadurch bedingten geringen Bedarfs an Genfähren sowie seines besonderen immunologischen Status ist gerade das Auge als potenzielles Zielorgan hervorragend geeignet. Die Hornhauttransplantation ist eine Indikation mit verbesserbarer Prognose, die vom Methodenkatalog der Gentransferprotokolle profitieren kann. Die Hornhaut steht zudem vor einer Transplantation einem Gentransfer ex vivo zur Verfügung. Die Augenheilkunde könnte daher beim klinischen Gentransfer eine Pionierstellung einnehmen. Eine Literatursynopse beschreibt den gegenwärtigen Stand der experimentellen Verbesserung der Hornhauttransplantation, der Beeinflussung der Narbenbildung, der Neovaskularisation und der Herpesinfektion der Kornea. Das wesentliche Problem der Gentherapie ist die nicht zufrieden stellende Technik des Gentransfers. Die Schwierigkeiten und die aktuellen Verbesserungen werden erörtert.

Abstract

Gene therapy raised euphoric expectations in the past that have yet to be met and have even been lowered due to the absence of concrete clinical successes and the occurrence of some tragic incidents. In spite of the great future potential of gene therapy, numerous pilot studies in this field will probably be discontinued for a long time. However, despite these failures, diseases will continue to be the aim of gene transfer studies with experimental protocols using only temporary gene expression or those restricted to individual organs and thus requiring only a low dose of the vehicle (vector). The eye is exceptionally well suited as a potential target organ because of its good and selective accessibility, low volume and the resultant low number of gene ferries required as well as its special immunological status. The prognosis of corneal grafting can be improved and profit from the methods catalogue of gene transfer protocols. Moreover, the cornea can be used for ex vivo gene transfer before grafting. Ophthalmology could thus occupy a pioneer position in clinical gene transfer. A survey of the literature describes the current state of experimental improvement in corneal grafting, the effect on scarring, neovascularization, and herpetic corneal infection. The essential problem of gene therapy is the unsatisfactory gene transfer technique. Difficulties and current improvements are discussed.

Literatur

  • 1 Arancibia-Carcamo C V, Oral H B, Haskard D O, Larkin D F, George A J. Lipoadenofection-mediated gene delivery to the corneal endothelium: prospects for modulating graft rejection.  Transplantation. 1998;  65 62-67
  • 2 Bainbridge J W, Stephens C, Parsley K, Demaison C, Halfyard A, Thrasher A J, Ali R R. In vivo gene transfer to the mouse eye using an HIV-based lentiviral vector; efficient long-term transduction of corneal endothelium and retinal pigment epithelium.  Gene Ther. 2001;  8 1665-1668
  • 3 Behrens A, Gordon E M, Li L, Liu P X, Chen Z, Peng H, Bree L la, Anderson W F, Hall F L, McDonnell P J. Retroviral gene therapy vectors for prevention of excimer laser-induced corneal haze.  Invest Ophthalmol Vis Sci. 2002;  43 968-977
  • 4 Bradshaw J J, Obritsch W F, Cho B J, Gregerson D S, Holland E J. Ex vivo transduction of corneal epithelial progenitor cells using a retroviral vector.  Invest Ophthalmol Vis Sci. 1999;  40 230-235
  • 5 Chaum E, Hatton M P. Gene therapy for genetic and acquired retinal diseases.  Surv Ophthalmol. 2002;  47 449-469
  • 6 Comer R M, King W J, Ardjomand N, Theoharis S, George A J, Larkin D F. Effect of administration of CTLA4-Ig as protein or cDNA on corneal allograft survival.  Invest Ophthalmol Vis Sci. 2002;  43 1095-1103
  • 7 Cordeiro M F, Mead A, Ali R R, Alexander R A, Murray S, Chen C, York-Defalco C, Dean N M, Schultz G S, Khaw P T. Novel antisense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome.  Gene Ther. 2003;  10 59-71
  • 8 Cui B, Carr D J. A plasmid construct encoding murine interferon beta antagonizes the replication of herpes simplex virus type I in vitro and in vivo.  J Neuroimmunol. 2000;  108 92-102
  • 9 Garcia-Sanchez F, Pizzorno G, Fu S Q, Nanakorn T, Krause D S, Liang J, Adams E, Leffert J J, Yin L H, Cooperberg M R, Hanania E, Wang W L, Won J H, Peng X Y, Cote R, Brown R, Burtness B, Giles R, Crystal R, Deisseroth A B. Cytosine deaminase adenoviral vector and 5-fluorocytosine selectively reduce breast cancer cells 1 million-fold when they contaminate hematopoietic cells: a potential purging method for autologous transplantation.  Blood. 1998;  92 672-682
  • 10 Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M. Gene therapy of X-linked severe combined immunodeficiency.  Int J Hematol. 2002;  76 295-298
  • 11 Hacein-Bey-Abina S, Kalle C von, Schmidt M, LeDeist F, Wulffraat N, McIntyre E, Radford I, Villeval J L, Fraser C C, Cavazzana-Calvo M, Fischer A. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency.  N Engl J Med. 2003;  348 255-256
  • 12 Hart S L, Arancibia-Carcamo C V, Wolfert M A, Mailhos C, O'Reilly N J, Ali R R, Coutelle C, George A J, Harbottle R P, Knight A M, Larkin D F, Levinsky R J, Seymour L W, Thrasher A J, Kinnon C. Lipid-mediated enhancement of transfection by a nonviral integrin-targeting vector.  Hum Gene Ther. 1998;  9 575-585
  • 13 Hoffmann F, Zhang E P, Mueller A, Schulte F, Foss H D, Franke J, Coupland S E. Contribution of lymphatic drainage system in corneal allograft rejection in mice.  Graefes Arch Clin Exp Ophthalmol. 2001;  239 850-858
  • 14 Igarashi T, Miyake K, Suzuki N, Kato K, Takahashi H, Ohara K, Shimada T. New strategy for in vivo transgene expression in corneal epithelial progenitor cells.  Curr Eye Res. 2002;  24 46-50
  • 15 Inoue T, Inoue Y, Hayashi K, Yoshida A, Nishida K, Shimomura Y, Fujisawa Y, Aono A, Tano Y. Topical administration of HSV gD-IL-2 DNA is highly protective against murine herpetic stromal keratitis.  Cornea. 2002;  21 106-110
  • 16 Kagaya F, Hori J, Kamiya K, Kaji Y, Oshika T, Amano S, Yamagami S, Tsuru T, Tanaka S, Matsuda H, Yagita H, Okumura K. Inhibition of murine corneal allograft rejection by treatment with antibodies to CD80 and CD86.  Exp Eye Res. 2002;  74 131-139
  • 17 Kamata Y, Okuyama T, Kosuga M, O'Hira A, Kanaji A, Sasaki K, Yamada M, Azuma N. Adenovirus-mediated gene therapy for corneal clouding in mice with mucopolysaccharidosis type VII.  Mol Ther. 2001;  4 307-312
  • 18 Klebe S, Sykes P J, Coster D J, Bloom D C, Williams K A. Gene transfer to ovine corneal endothelium.  Clin Experiment Ophthalmol. 2001;  29 316-322
  • 19 Klebe S, Sykes P J, Coster D J, Krishnan R, Williams K A. Prolongation of sheep corneal allograft survival by ex vivo transfer of the gene encoding interleukin-10.  Transplantation. 2001;  71 1214-1220
  • 20 König Merediz S A, Zhang E P, Wittig B, Hoffmann F. Ballistic transfer of minimalistic immunologically defined expression constructs for IL4 and CTLA4 into the corneal epithelium in mice after orthotopic corneal allograft transplantation.  Graefes Arch Clin Exp Ophthalmol. 2000;  238 701-707
  • 21 Krauzewicz N, Cox C, Soeda E, Clark B, Rayner S, Griffin B E. Sustained ex vivo and in vivo transfer of a reporter gene using polyoma virus pseudocapsids.  Gene Ther. 2000;  7 1094-1102
  • 22 Kubo H, Gardner T A, Wada Y, Koeneman K S, Gotoh A, Yang L, Kao C, Lim S D, Amin M B, Yang H, Black M E, Matsubara S, Nakagawa M, Gillenwater J Y, Zhau H E, Chung L W. Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer.  Hum Gene Ther. 2003;  14 227-241
  • 23 Kuffova L, Lumsden L, Vesela V, Taylor J A, Filipec M, Holan V, Dick A D, Forrester J V. Kinetics of leukocyte and myeloid cell traffic in the murine corneal allograft response.  Transplantation. 2001;  72 1292-1298
  • 24 Lai C M, Spilsbury K, Brankov M, Zaknich T, Rakoczy P E. Inhibition of corneal neovascularization by recombinant adenovirus mediated antisense VEGF RNA.  Exp Eye Res. 2002;  75 625-634
  • 25 Lai Y K, Shen W Y, Brankov M, Lai C M, Constable I J, Rakoczy P E. Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy.  Gene Ther. 2002;  9 804-813
  • 26 Larkin D F, Oral H B, Ring C J, Lemoine N R, George A J. Adenovirus-mediated gene delivery to the corneal endothelium.  Transplantation. 1996;  61 363-370
  • 27 Liu H, Wu X, Xiao H, Kappes J C. Targeting human immunodeficiency virus (HIV) type 2 integrase protein into HIV type 1.  J Virol. 1999;  73 8831-8836
  • 28 Lopez J V, Culver M, Stephens J C, Johnson W E, O'Brien S J. Rates of nuclear and cytoplasmic mitochondrial DNA sequence divergence in mammals.  Mol Biol Evol. 1997;  14 277-286
  • 29 Lui V W, Falo L D, Huang L. Systemic production of IL-12 by naked DNA mediated gene transfer: toxicity and attenuation of transgene expression in vivo.  J Gene Med. 2001;  3 384-393
  • 30 Masuda I, Matsuo T, Yasuda T, Matsuo N. Gene transfer with liposomes to the intraocular tissues by different routes of administration.  Invest Ophthalmol Vis Sci. 1996;  37 1914-1920
  • 31 Mohan R R, Schultz G S, Hong J W, Wilson S E. Gene transfer into rabbit keratocytes using AAV and lipid-mediated plasmid DNA vectors with a lamellar flap for stromal access.  Exp Eye Res. 2003;  76 373-383
  • 32 Moore J E, McMullen T C, Campbell I L, Rohan R, Kaji Y, Afshari N A, Usui T, Archer D B, Adamis A P. The inflammatory milieu associated with conjunctivalized cornea and its alteration with IL-1 RA gene therapy.  Invest Ophthalmol Vis Sci. 2002;  43 2905-2915
  • 33 Müller A, Zhang E P, Schroff M, Wittig B, Hoffmann F. Influence of ballistic gene transfer on antigen-presenting cells in murine corneas.  Graefes Arch Clin Exp Ophthalmol. 2002;  240 851-859
  • 34 Nam N H, Parang K. Current targets for anticancer drug discovery.  Curr Drug Targets. 2003;  4 159-179
  • 35 Noisakran S, Campbell I L, Carr D J. Ectopic expression of DNA encoding IFN-α 1 in the cornea protects mice from herpes simplex virus type 1-induced encephalitis.  J Immunol. 1999;  162 4184-4190
  • 36 Noisakran S, Carr D J. Topical application of the cornea post-infection with plasmid DNA encoding interferon-α1 but not recombinant interferon-αA reduces herpes simplex virus type 1-induced mortality in mice.  J Neuroimmunol. 2001;  121 49-58
  • 37 Noisakran S J, Carr D J. Therapeutic efficacy of DNA encoding IFN-α1 against corneal HSV-1 infection.  Curr Eye Res. 2000;  20 405-412
  • 38 Oral H B, Larkin D F, Fehervari Z, Byrnes A P, Rankin A M, Haskard D O, Wood M J, Dallman M J, George A J. Ex vivo adenovirus-mediated gene transfer and immunomodulatory protein production in human cornea.  Gene Ther. 1997;  4 639-647
  • 39 Oshima Y, Sakamoto T, Hisatomi T, Tsutsumi C, Sassa Y, Ishibashi T, Inomata H. Targeted gene transfer to corneal stroma in vivo by electric pulses.  Exp Eye Res. 2002;  74 191-198
  • 40 Oshima Y, Sakamoto T, Yamanaka I, Nishi T, Ishibashi T, Inomata H. Targeted gene transfer to corneal endothelium in vivo by electric pulse.  Gene Ther. 1998;  5 1347-1354
  • 41 Plank C, Oberhauser B, Mechtler K, Koch C, Wagner E. The influence of endosome-disruptive peptides on gene transfer using synthetic virus-like gene transfer systems.  J Biol Chem. 1994;  269 12918-12924
  • 42 Pleyer U, Bertelmann E, Rieck P, Hartmann C, Volk H D, Ritter T. Survival of corneal allografts following adenovirus-mediated gene transfer of interleukin-4.  Graefes Arch Clin Exp Ophthalmol. 2000;  238 531-536
  • 43 Pleyer U, Groth D, Hinz B, Keil O, Bertelmann E, Rieck P, Reszka R. Efficiency and toxicity of liposome-mediated gene transfer to corneal endothelial cells.  Exp Eye Res. 2001;  73 1-7
  • 44 Plskova J, Duncan L, Holan V, Filipec M, Kraal G, Forrester J V. The immune response to corneal allograft requires a site-specific draining lymph node.  Transplantation. 2002;  73 210-215
  • 45 Rayner S A, Larkin D F, George A J. TNF receptor secretion after ex vivo adenoviral gene transfer to cornea and effect on in vivo graft survival.  Invest Ophthalmol Vis Sci. 2001;  42 1568-1573
  • 46 Rubanyi G M. The future of human gene therapy.  Mol Aspects Med. 2001;  22 113-142
  • 47 Sakamoto T, Oshima Y, Nakagawa K, Ishibashi T, Inomata H, Sueishi K. Target gene transfer of tissue plasminogen activator to cornea by electric pulse inhibits intracameral fibrin formation and corneal cloudiness.  Hum Gene Ther. 1999;  10 2551-2557
  • 48 Satoh T, Timme T L, Saika T, Ebara S, Yang G, Wang J, Ren C, Kusaka N, Mouraviev V, Thompson T C. Adenoviral Vector-Mediated mRTVP-1 Gene Therapy for Prostate Cancer.  Hum Gene Ther. 2003;  14 91-101
  • 49 Schakowski F, Gorschluter M, Junghans C, Schroff M, Buttgereit P, Ziske C, Schottker B, König Merediz S A, Sauerbruch T, Wittig B, Schmidt-Wolf I G. A novel minimal-size vector (MIDGE) improves transgene expression in colon carcinoma cells and avoids transfection of undesired DNA.  Mol Ther. 2001;  3 793-800
  • 50 Shewring L, Collins L, Lightman S L, Hart S, Gustafsson K, Fabre J W. A nonviral vector system for efficient gene transfer to corneal endothelial cells via membrane integrins.  Transplantation. 1997;  64 763-769
  • 51 Stechschulte S U, Joussen A M, Recum H A von, Poulaki V, Moromizato Y, Yuan J, D'Amato R J, Kuo C, Adamis A P. Rapid ocular angiogenic control via naked DNA delivery to cornea.  Invest Ophthalmol Vis Sci. 2001;  42 1975-1979
  • 52 Tan P H, King W J, Chen D, Awad H M, Mackett M, Lechler R I, Larkin D F, George A J. Transferrin receptor-mediated gene transfer to the corneal endothelium.  Transplantation. 2001;  71 552-560
  • 53 Tanelian D L, Barry M A, Johnston S A, Le T, Smith G. Controlled gene gun delivery and expression of DNA within the cornea.  Biotechniques. 1997;  23 484-488
  • 54 Tsai M L, Chen S L, Chou P I, Wen L Y, Tsai R J, Tsao Y P. Inducible adeno-associated virus vector-delivered transgene expression in corneal endothelium.  Invest Ophthalmol Vis Sci. 2002;  43 751-757
  • 55 Tsubota K, Inoue H, Ando K, Ono M, Yoshino K, Saito I. Adenovirus-mediated gene transfer to the ocular surface epithelium.  Exp Eye Res. 1998;  67 531-538
  • 56 Wang X, Appukuttan B, Ott S, Patel R, Irvine J, Song J, Park J H, Smith R, Stout J T. Efficient and sustained transgene expression in human corneal cells mediated by a lentiviral vector.  Gene Ther. 2000;  7 196-200
  • 57 Wu G Y, Wu C H. Receptor-mediated in vitro gene transformation by a soluble DNA carrier system.  J Biol Chem. 1987;  262 4429-4432
  • 58 Yamagami S, Dana M R, Tsuru T. Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk corneal transplantation.  Cornea. 2002;  21 405-409
  • 59 Zhang E P, Muller A, Schulte F, Konig M S, Sack F, Junghans C, Wittig B, Hoffmann F. Minimizing side effects of ballistic gene transfer into the murine corneal epithelium.  Graefes Arch Clin Exp Ophthalmol. 2002;  240 114-119

Prof. Dr. Friedrich Hoffmann

Freie Universität Berlin · Universitätsklinikum Benjamin Franklin · Augenklinik und Poliklinik

Hindenburgdamm 30

12200 Berlin

Email: fhoffman@zedat.fu-berlin.de

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