Recombinant adeno-associated virus (rAAV) vectors are the carriers of choice for retinal gene therapy
Inherited retinal dystrophies in humans are typically progressive diseases that steadily worsen over decades. Therefore, effective clinical applications require a therapy that alters disease course over the long-term. Administration of therapeutic genes using rAAV vectors meets this requirement; stable transduction of retinal cells by rAAV vectors provides efficient and sustained gene therapy.
A lack of pathogenicity and low immunogenicity are key characteristics of rAAVs, and support their use over other potential vectors for human gene therapy. The safety and efficacy of rAAV vector-mediated retinal gene transfer has been demonstrated in several species, including humans.
rAAV vectors are currently among the most commonly used viral vectors for gene therapy. The generation of rAAV vectors is inspired by the properties of their wild-type AAV counterparts. These are non-enveloped, non-pathogenic, and replication-defective viruses of the parvovirus family, and have not been associated with any known human diseases.
rAAV vectors are composed of a capsid surrounding an expression cassette, and are devoid of viral coding sequences. The therapeutic gene, packaged into the viral capsid, is delivered into the target cells.
In an rAAV vector, the capsid serotype (1–9) confers some targeting specificity. The promoter has a direct impact on the regulation of protein expression.
A technology adapted to ophthalmic applications
rAAV vectors are injected subretinally (between the photoreceptors and the retinal pigment epithelium), allowing optimal vector access to the diseased cells and enabling functional recovery though expression of the healthy gene.