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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. [ABSTRACT FROM AUTHOR]