Gene Therapy Successfully Delays Degeneration in a Mouse Model of PDE6A-Linked Retinitis Pigmentosa (RP43)

被引:18
作者
Schoen, Christian [1 ]
Sothilingam, Vithiyanjali [2 ]
Muehlfriedel, Regine [2 ]
Garrido, Marina Garcia [2 ]
Beck, Susanne C. [2 ]
Tanimoto, Naoyuki [2 ]
Wissinger, Bernd [3 ]
Paquet-Durand, Francois [4 ]
Biel, Martin [1 ]
Michalakis, Stylianos [1 ]
Seeliger, Mathias W. [2 ]
机构
[1] Ludwig Maximilians Univ Munchen, Ctr Integrated Prot Sci Munich CiPSM, Dept Pharm, Ctr Drug Res, Munich, Germany
[2] Eberhard Karls Univ, Div Ocular Neurodegenerat, Tubingen, Germany
[3] Eberhard Karls Univ, Div Mol Genet Lab, Tubingen, Germany
[4] Eberhard Karls Univ, Inst Ophthalm Res, Ctr Ophthalmol, Tubingen, Germany
关键词
retinitis pigmentosa; phosphodiesterase; 6; gene therapy; AAV; ANTIGEN-PRESENTING CELLS; GAMMA ELISPOT ASSAYS; HUMAN T-CELLS; DENDRITIC CELLS; RETROVIRAL VECTORS; ANTITUMOR-ACTIVITY; E5; ONCOPROTEIN; HLA-A; RECEPTOR; EXPRESSION;
D O I
10.1089/hum.2017.156
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Retinitis pigmentosa type 43 (RP43) is a blinding disease caused by mutations in the gene for rod phosphodiesterase 6 alpha (PDE6A). The disease process begins with a dysfunction of rod photoreceptors, subsequently followed by a currently untreatable progressive degeneration of the entire outer retina. Aiming at a curative approach via PDE6A gene supplementation, a novel adeno-associated viral (AAV) vector was developed for expression of the human PDE6A cDNA under control of the human rhodopsin promotor (rAAV8. PDE6A). This study assessed the therapeutic efficacy of rAAV8. PDE6A in the Pde6a nmf363/nmf363-mutant mouse model of RP43. All mice included in this study were treated with subretinal injections of the vector at 2 weeks after birth. The therapeutic effect was monitored at 1 month and 6 months post injection. Biological function of the transgene was assessed in vivo by means of electroretinography. The degree of morphological rescue was investigated both in vivo using optical coherence tomography and ex vivo by immunohistological staining. It was found that the novel rAAV8. PDE6A vector resulted in a stable and efficient expression of PDE6A protein in rod photoreceptors of Pde6a nmf363/nmf363 mice following treatment at both the short-and long-term time points. The treatment led to a substantial morphological preservation of outer nuclear layer thickness, rod outer segment structure, and prolonged survival of cone photoreceptors for at least 6 months. Additionally, the ERG analysis confirmed a restoration of retinal function in a group of treated mice. Taken together, this study provides successful proofof- concept for the cross-species efficacy of the rAAV8. PDE6A vector developed for use in human patients. Importantly, the data show stable expression and rescue effects for a prolonged period of time, raising hope for future translational studies based on this approach.
引用
收藏
页码:1180 / 1188
页数:9
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共 50 条
[1]  
Alamyar E., 2012, Immunome Res, V8, DOI DOI 10.3390/nu50x000x
[2]   Impaired tumor antigen processing by immunoproteasome-expressing CD40-activated B cells and dendritic cells [J].
Anderson, Karen S. ;
Zeng, Wanyong ;
Sasada, Tetsuro ;
Choi, Jaewon ;
Riemer, Angelika B. ;
Su, Mei ;
Drakoulakos, Donna ;
Kang, Yoon-Joong ;
Brusic, Vladimir ;
Wu, Catherine ;
Reinherz, Ellis L. .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 2011, 60 (06) :857-867
[3]   The use of clonal mRNA as an antigenic format for the detection of antigen-specific T lymphocytes in IFN-γ ELISPOT assays [J].
Britten, CM ;
Meyer, RG ;
Frankenberg, N ;
Huber, C ;
Wölfel, T .
JOURNAL OF IMMUNOLOGICAL METHODS, 2004, 287 (1-2) :125-136
[4]   The use of HLA-A*0201-transfected K562 as standard antigen-presenting cells for CD8+ T lymphocytes in IFN-γ ELISPOT assays [J].
Britten, CM ;
Meyer, RG ;
Kreer, TA ;
Drexler, I ;
Wölfel, T ;
Herr, W .
JOURNAL OF IMMUNOLOGICAL METHODS, 2002, 259 (1-2) :95-110
[5]   Three-day dendritic cells for vaccine development: Antigen uptake, processing and presentation [J].
Buerdek, Maja ;
Spranger, Stefani ;
Wilde, Susanne ;
Frankenberger, Bernhard ;
Schendel, Dolores J. ;
Geiger, Christiane .
JOURNAL OF TRANSLATIONAL MEDICINE, 2010, 8
[6]   Identification of a Titin-Derived HLA-A1-Presented Peptide as a Cross-Reactive Target for Engineered MAGE A3-Directed T Cells [J].
Cameron, Brian J. ;
Gerry, Andrew B. ;
Dukes, Joseph ;
Harper, Jane V. ;
Kannan, Vivekanandan ;
Bianchi, Frayne C. ;
Grand, Francis ;
Brewer, Joanna E. ;
Gupta, Minnal ;
Plesa, Gabriela ;
Bossi, Giovanna ;
Vuidepot, Annelise ;
Powlesland, Alex S. ;
Legg, Alison ;
Adams, Katherine J. ;
Bennett, Alan D. ;
Pumphrey, Nicholas J. ;
Williams, Daniel D. ;
Binder-Scholl, Gwendolyn ;
Kulikovskaya, Irina ;
Levine, Bruce L. ;
Riley, James L. ;
Varela-Rohena, Angel ;
Stadtmauer, Edward A. ;
Rapoport, Aaron P. ;
Linette, Gerald P. ;
June, Carl H. ;
Hassan, Namir J. ;
Kalos, Michael ;
Jakobsen, Bent K. .
SCIENCE TRANSLATIONAL MEDICINE, 2013, 5 (197)
[7]   Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations [J].
Cao, K ;
Hollenbach, J ;
Shi, XJ ;
Shi, WX ;
Chopek, M ;
Fernández-Viña, MA .
HUMAN IMMUNOLOGY, 2001, 62 (09) :1009-1030
[8]   The expression of HPV-16 E5 protein in squamous neoplastic changes in the uterine cervix [J].
Chang, JL ;
Tsao, YP ;
Liu, DW ;
Huang, SJ ;
Lee, WH ;
Chen, SL .
JOURNAL OF BIOMEDICAL SCIENCE, 2001, 8 (02) :206-213
[9]   Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability [J].
Cohen, Cyrille J. ;
Zhao, Yangbing ;
Zheng, Zhili ;
Rosenberg, Steven A. ;
Morgan, Richard A. .
CANCER RESEARCH, 2006, 66 (17) :8878-8886
[10]   Development of Human Anti-Murine T-Cell Receptor Antibodies in Both Responding and Nonresponding Patients Enrolled in TCR Gene Therapy Trials [J].
Davis, Jeremy L. ;
Theoret, Marc R. ;
Zheng, Zhili ;
Lamers, Cor H. J. ;
Rosenberg, Steven A. ;
Morgan, Richard A. .
CLINICAL CANCER RESEARCH, 2010, 16 (23) :5852-5861