Abstract
Leber congenital amaurosis (LCA) is a retinitis pigmentosa with early onset, leading to blindness in infants. There is currently no efficient therapy to treat LCA. At the present time, mutations in seven different genes have been associated with the disease (Hanein et al. 2004). In 10 to 15% of the cases LCA originates from a mutation in RPE65 (Gu et al. 1997), a gene specifically expressed in the cells of the retinal pigment epithelium layer (RPE cells). This gene encodes a 65kD protein the function of which has been dissected in a recently published study demonstrating its crucial role as a regulator of the visual cycle and a chaperone for the chromophore of the visual pigment (Xue et al. 2004). The patients affected by a mutation in this gene could benefit from a substitutive gene therapy consisting in the transfer of a fully functional allele of the RPE65 gene in RPE cells. Furthermore, animal models of RPE65 mutations have been identified (Aguirre et al. 1998; Veske et al. 1999) or genetically produced (Redmond et al. 1998) and thus provide the necessary tools to set up the conditions of such a strategy before a clinical trial can be started. The proof of feasibility of this approach has indeed already been established in dogs bearing a spontaneous mutation in the RPE65 gene (Acland et al. 2001; NarfstrÖm et al. 2003), as well as in knock-out mice (Dejneka et al. 2004; Lai et al. 2004). These studies have shown that an adeno-associated virus (AAV)-derived vector is able to deliver the RPE65 gene to RPE cells and thus to restore vision at least partially. Nevertheless, before a clinical trial can take place, a great effort must be provided to assess the bio-safety of the procedure. In particular, trans-gene expression has to be tightly controlled to achieve the following criteria: (i) expression should occur only in RPE cells; (ii) expression should reach the therapeutic level without disturbing the homeostasis of the target cells.
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References
Acland, G. M., Aguirre, G. D., Ray, J., Zhang, Q., Aleman, T. S., et al., 2001, Gene therapy restores vision in a canine model of childhood blindness, Nat Genet 28:92.
Aguirre, G. D., Baldwin, V., Pearce-Kelling, S., Narfström, K., Ray, K., and Acland, G. M., 1998, Congenital stationary night blindness in the dog: Common mutation in the RPE65 gene indicates founder effect, Mol Vis 4:23.
Ali, R. R., Reichel, M. B., Thrasher, A. J., Levinsky, R. J., Kinnon, C., Kanuga, N., Hunt, D. M., and Bhattacharya, S. S., 1996, Gene transfer into the mouse retina mediated by an adeno-associated viral vector, Hum Mol Genet 5:591.
Bainbridge, J. W., Stephens, C., Parsley, K., Demaison, C., Halfyard, A., Thrasher, A. J., and Ali, R. R., 2001, 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 8:1665.
Bennett, J., 2004, Gene therapy for leber congenital amaurosis, Novartis Found Symp 255:195.
Bennett, J., Duan, D., Engelhardt, J. F., and Maguire, A. M., 1997, Real-time, noninvasive in vivo assessment of adeno-associated virus-mediated retinal transduction, Invest Ophthalmol Vis Sci 38:2857.
Bennett, J., Maguire, A. M., Cideciyan, A. V., Schnell, M., Glover, E., et al., 1999, Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina, Proc Natl Acad Sci U S A 96:9920.
Bennett, J., Wilson, J., Sun, D., Forbes, B., and Maguire, A., 1994, Adenovirus vector-mediated in vivo gene transfer into adult murine retina, Invest Ophthalmol Vis Sci 35:2535.
Dejneka, N. S., Surace, E. M., Aleman, T. S., Cideciyan, A. V., Lyubarsky, A., et al., 2004, In utero gene therapy rescues vision in a murine model of congenital blindness, Mol Ther 9:182.
Flannery, J. G., Zolotukhin, S., Vaquero, M. I., LaVail, M. M., Muzyczka, N., and Hauswirth, W. W., 1997, Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus, Proc Natl Acad Sci U S A 94:6916.
Gu, S. M., Thompson, D. A., Srikumari, C. R., Lorenz, B., Finckh, U., et al., 1997, Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy, Nat Genet 17:194.
Hanein, S., Perrault, I., Gerber, S., Tanguy, G., Barbet, F., et al., 2004, Leber congenital amaurosis: Comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis, Hum Mutat 23:306.
Hinterhuber, G., Cauza, K., Brugger, K., Dingelmaier-Hovorka, R., Horvat, R., Wolff, K., and Foedinger, D., 2004, RPE65 of retinal pigment epithelium, a putative receptor molecule for plasma retinol-binding protein, is expressed in human keratinocytes, J Invest Dermatol 122:406.
Hoffman, L. M., Maguire, A. M., and Bennett, J., 1997, Cell-mediated immune response and stability of intraocular transgene expression after adenovirus-mediated delivery, Invest Ophthalmol Vis Sci 38:2224.
Kostic, C., Chiodini, F., Salmon, P., Wiznerowicz, M., Deglon, N., et al., 2003, Activity analysis of housekeeping promoters using self-inactivating lentiviral vector delivery into the mouse retina, Gene Ther 10:818.
Kumar-Singh, R., and Farber, D. B., 1998, Encapsidated adenovirus mini-chromosome-mediated delivery of genes to the retina: Application to the rescue of photoreceptor degeneration, Hum Mol Genet 7:1893.
Lai, C. M., Yu, M. J., Brankov, M., Barnett, N. L., Zhou, X., Redmond, T. M., Narfström, K., and Rakoczy, P. E., 2004, Recombinant adeno-associated virus type 2-mediated gene delivery into the RPE65-/-knockout mouse eye results in limited rescue, Genet Vaccines Ther 2:3.
Li, T., Adamian, M., Roof, D. J., Berson, E. L., Dryja, T. P., Roessler, B. J., and Davidson, B. L., 1994, In vivo transfer of a reporter gene to the retina mediated by an adenoviral vector, Invest Ophthalmol Vis Sci 35:2543.
Miyoshi, H., Takahashi, M., Gage, F. H., and Verma, I. M., 1997, Stable and efficient gene transfer into the retina using an hiv-based lentiviral vector, Proc Natl Acad Sci U S A 94:10319.
Naldini, L., Blömer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., Verma, I. M., and Trono, D., 1996, In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector, Science 272:263.
Narfström, K., Katz, M. L., Bragadottir, R., Seeliger, M., Boulanger, A., Redmond, T. M., Caro, L., Lai, C. M., and Rakoczy, P. E., 2003, Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog, Invest Ophthalmol Vis Sci 44:1663.
Redmond, T. M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, P., Ma, J. X., Crouch, R. K., and Pfeifer, K., 1998, RPE65 is necessary for production of 11-cis-vitamin a in the retinal visual cycle, Nat Genet 20:344.
Reichel, M. B., Ali, R. R., Thrasher, A. J., Hunt, D. M., Bhattacharya, S. S., and Baker, D., 1998, Immune responses limit adenovirally mediated gene expression in the adult mouse eye, Gene Ther 5:1038.
Salmon, P., Oberholzer, J., Occhiodoro, T., Morel, P., Lou, J., and Trono, D., 2000, Reversible immortalization of human primary cells by lentivector-mediated transfer of specific genes, Mol Ther 2:404.
Seeliger, M. W., Grimm, C., Stahlberg, F., Friedburg, C., Jaissle, G., et al., 2001, New views on RPE65 deficiency: The rod system is the source of vision in a mouse model of leber congenital amaurosis, Nat Genet 29:70.
Veske, A., Nilsson, S. E., Narfström, K., and Gal, A., 1999, Retinal dystrophy of swedish briard/briard-beagle dogs is due to a 4-bp deletion in RPE65, Genomics 57:57.
Xue, L., Gollapalli, D. R., Maiti, P., Jahng, W. J., and Rando, R. R., 2004, A palmitoylation switch mechanism in the regulation of the visual cycle, Cell 117:761.
Znoiko, S. L., Crouch, R. K., Moiseyev, G., and Ma, J. X., 2002, Identification of the RPE65 protein in mammalian cone photoreceptors, Invest Ophthalmol Vis Sci 43:1604.
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Bemelmans, AP. et al. (2006). Lentiviral Vectors Containing a Retinal Pigment Epithelium Specific Promoter for Leber Congenital Amaurosis Gene Therapy. In: Hollyfield, J.G., Anderson, R.E., LaVail, M.M. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 572. Springer, Boston, MA. https://doi.org/10.1007/0-387-32442-9_35
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DOI: https://doi.org/10.1007/0-387-32442-9_35
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