AAV Biology

Adeno-associated virus (AAV) is a non-pathogenic parvovirus. First reported in 1965 as a contaminant of adenovirus, it has since been characterized as naturally replication deficient, requiring helper viruses such as adenovirus for propagation. The viral genome is a small (~4.7 kb) single-stranded DNA that contains two large open-reading frames (ORFs) flanked by inverted terminal repeats (ITRs). One ORF encodes the non-structural proteins, Rep78, Rep68, Rep52 and Rep40, and another encodes the structural proteins, VP1, VP2 and VP3. The viral DNA is packaged in an icosahedrally symmetric and non-enveloped capsid formed by 60 proteins consisting of VP1, VP2 and VP3 at a ratio about 1:1:10.

AAV vectors

AAV vectors have been widely used as gene delivery vehicles for both basic scientific research, and human gene therapy. They have been successfully used in clinical trials, and are approved as drugs for human use. 

AAV is often the preferred method for delivering genes to target cells due to its high titer, mild immune response, ability to infect a broad range of cells, and overall safety. 

  • Non-pathogenic. AAV has increasingly become an important gene therapy vector, which is largely due to the fact that wild-type AAV (wtAAV) is not related to any known human diseases.

  • Low immunogenicity. AAV safely transduces postmitotic tissues with relatively low immunogenicity compared with other vectors like adenovirus and HSV.

  • Broad  tropism range. AAV vectors have a broad host and cell type tropism range and transduce both dividing and nondividing cells in vitro and in vivo. Furthermore, the recent discovery of novel AAV serotypes will expand even more the universe of potential target organs, tissues and cells.

  • Long term and high expression. AAV vectors maintain (over several years) high levels of gene expression in vivo, in the absence of a significant immune response to the transgene product .

AAV gene therapy

AAV vectors have been widely used as gene delivery vehicles for both basic scientific research, and human gene therapy. They have been successfully used in clinical trials, and are approved as drugs for human use.  
  • Glybera (Alipogene tiparvovec) is a gene therapy treatment designed to reverse lipoprotein lipase deficiency (LPLD), a rare inherited disorder which can cause severe pancreatitis. Glybera is composed of an adeno-associated virus serotype 1 (AAV1) viral vector with an intact copy of the human lipoprotein lipase (LPL) gene for delivery to muscle cells.

  • LUXTURNA is the first FDA-approved gene therapy for a genetic disease, the first and only pharmacologic treatment for an inherited retinal disease (IRD) and the first adeno-associated virus (AAV) vector gene therapy. 

  • Zolgensma (Novartis, AveXis), an AAV-delivered gene therapy used to treat spinal muscular atrophy (SMA) also known as AVXS-101.