AAV PHP.S-CAG-tdTOMATO

Gene therapy aims to transfer therapeutic genes into the patient's cells in order to treat the disease at the genetic level. In most cases, the natural ability of viruses to enter cells and deliver genetic material is used to transfer therapeutic genes to target cells. Depending on the target cell, two different approaches are mainly used: Stem cells or dividing precursor cells are treated in vitro with viral vectors (e.g. retroviral or lentiviral vectors) that are able to stably insert the therapeutic gene into the target cell genome. As a result, the therapeutic gene remains in the progenitor cells. A major issue associated with integrating vectors is the potential for insertional mutagenesis. Therefore, post-mitotic, non-dividing cells are often targeted in vivo with non-integrating vectors derived from, for example, adeno-associated viruses (AAV), adenoviruses, or herpes simplex viruses. The genetic information encoded in these vectors is retained for a long time in the form of free DNA.

With three approvals and more than two hundred ongoing clinical trials, AAV vectors have become one of the main gene delivery vehicles for gene therapy. In 2012, Alipogene tiparvovec (Glybera) became the first AAV therapy approved in Europe for the treatment of lipoprotein lipase deficiency. Since then, Voretigene neparvovec (Luxturna) for the treatment of Leber congenital amaurosis and Onasemnogene abeparvovec (Zolgensma) for the treatment of spinal muscular atrophy have been approved by the U.S. Food and Drug Administration (FDA) in 2017 and 2019, respectively. A major factor in the success of AAV as a therapeutic gene delivery vector is its low immunogenicity and lack of pathogenicity. Current clinical research focuses on the treatment of monogenic diseases through gene replacement, gene silencing or gene editing, as well as gene addition using AAV-based vectors. AAV also has potential for cancer treatment, development of novel vaccines, and vector-based immunoprophylaxis.