Mol Ther 2018 Feb 7 26(2):524-541
European Research Council
Retinal gene transfer with adeno-associated viral (AAV) vectors holds great promise for the treatment of inherited retinal degenerations (IRDs). One limit of AAV is its transfer capacity of about 5 kb, which can be expanded to about 9 kb, using dual AAV vectors. This strategy would still not suffice for treatment of IRDs such as Usher syndrome type 1D or Alström syndrome type I (ALMS) due to mutations in CDH23 or ALMS1, respectively. To overcome this limitation, we generated triple AAV vectors, with a maximal transfer capacity of about 14 kb. Transcriptomic analysis following triple AAV transduction showed the expected full-length products along a number of aberrant transcripts. However, only the full-length transcripts are efficiently translated in vivo. We additionally showed that approximately 4% of mouse photoreceptors are transduced by triple AAV vectors and showed correct localization of recombinant ALMS1. The low-photoreceptor transduction levels might justify the modest and transient improvement we observe in the retina of a mouse model of ALMS. However, the levels of transduction mediated by triple AAV vectors in pig retina reached 40% of those observed with single vectors, and this bodes well for further improving the efficiency of triple AAV vectors in the retina. Mol Ther 2018 Feb 7 26(2):524-541.
Maddalena, Andrea; Tornabene, Patrizia; Tiberi, Paola; Minopoli, Renato; Manfredi, Anna; Mutarelli, Margherita; Rossi, Settimio; Simonelli, Francesca; Naggert, Juergen K.; Cacchiarelli, Davide; and Auricchio, Alberto, "Triple Vectors Expand AAV Transfer Capacity in the Retina." (2018). Faculty Research 2018. 50.