AAV therapeutics - Fighting genetic diseases at their source

The beginnings of gene therapy: 30 years of hope

For a long time, most genetic diseases were considered untreatable. Many of them are caused by faulty genes that are present in almost every cell in the body, making them nearly impossible to cure via traditional medicines. For patients suffering from genetic disorders, this meant that treatment was limited to alleviating the symptoms that came with their condition.

For decades, scientists have been working on finding a way to address the sources of these illnesses. In 1972, American scientists Friedmann and Roblin proposed that “gene therapy may ameliorate some human genetic diseases in the future”. Yet it took more than thirty years until gene therapy was first approved for clinical use in humans.

Viruses as shuttles: solving the challenge to introduce healthy genes into the body

Gene therapy aims to treat a disease by delivering a healthy copy of a gene into a patient's cells. This way, cells which have been lacking correct instructions to work properly receive the tools that will allow them to restore their function. In practice, however, one major obstacle in the development of gene therapies has always been the delivery mechanism: genes cannot simply be inserted directly into the body. In order for genes to reach the cells they are supposed to repair, a carrier - also called a vector - is needed.

The most promising carriers for genes used in gene therapy, and this might sound surprising, are viruses. But then, transporting genetic material into cells is what viruses do best. However, not all viruses are created equal: adeno-associated viruses (AAVs) are uniquely suited to deliver healthy genes to the cells that need them. In contrast to other viruses, AAVs are not known to cause disease in humans and they do not replicate on their own, making them the perfect one-time shuttles to deliver gene content.  For use in gene therapy, the viral DNA is removed and only the protein shell, or capsid, of these non-pathogenic viruses is used.

Depending on what cells need to be addressed, different types of AAV (serotypes) can be used, which are either naturally occurring or re-engineered. Some serotypes, for example, target liver cells, while others enter retina cells or muscle cells. This allows for a targeted therapy.

AAV capsids are then filled with the functioning gene and a promoter. A promoter is a short DNA sequence that acts as a “switch”, telling the gene when and where to start the process leading to synthesizing a protein, and how much of a protein is needed for the cell to function properly. Promoters can be artificially designed to regulate the activity of a gene with a high level of selectivity: these are called synthetic promoters. The role of synthetic promoters is to control gene activation with precision, so that specific genetic pathways can be targeted in specific cells in the body, addressing specific diseases.

Once these AAV capsids are filled with the genes, they can be injected into a patient’s body. From there, they make their way to the intended cells and begin producing the missing proteins.

Treating the “untreatable”

The effect on a patient’s situation may be enormous. Once the genes are in the cells, they often remain there for years. And since the cells are then functioning as they should, the illness may practically non-existent during this time.

AAV therapeutics have shown promise to restore blood clotting in people with hemophilia, vision in patients with Leber’s congenital amaurosis (a rare form of inherited blindness) and to stop the progression of spinal muscular atrophy in babies, delivering true breakthrough innovation to patients.

And the development of AAV technology is only beginning. In 2019, the US FDA released a report predicting that by 2025, 10 to 20 new cell and gene products will be approved yearly, giving hope to patients who are currently still suffering from “untreatable” diseases.