Gene therapy using ancient viruses

Comic from Pedromics
Adeno-associated viruses (AAVs) are small viruses with a single-stranded DNA genome, and can insert their genomic material into a specific site on human chromosome 19. This property makes them extremely useful in gene therapy applications, mainly to treat muscle and eye diseases, but also neurodegenerative diseases, arthritis, cystic fibrosis, and hemophilia. AAV vectors have been used for some time to deliver genes directly to the brain, where they infect non-dividing cells that are able to express AAV genomes.
AAVs are useful because they are non-pathogenic to people, in contrast to adenoviruses. However, approximately 30-90% of people have already been exposed to AAVs and have developed immunity to them, resulting in their ineligibility for AAV-based gene therapies. The immune system normally protects the body from pathogens, but in some cases, we would prefer to have the immune system to be non-reactive. This applies when receiving an organ transplant, for example. When a patient is receiving an organ from a donor, it is imperative that the two immune systems are matched so that the recipient does not reject the transplant. The patient will usually be put on immunosuppressive drugs to tone down the immune response.
In order to efficiently deliver genes via an AAV vector, the immune system cannot recognize the virus as a pathogen. Recently, a team of scientists from the Schepens Eye Research Institute and the Massachusetts Eye and Ear Infirmary teamed together to develop AAVs that do not elicit an immune response1. They accomplished this by looking at the evolutionary history of AAVs that are circulating today, and then making the ancestral viruses and testing them as gene therapy vectors in mammalian tissues. The team of scientists tested one of these viruses, called Anc80L65, in mouse retina, liver, and skeletal muscle, and found that gene expression was on par with that of AAV8, a commonly used gene therapy vector. Some animals already had pre-existing immunity to AAV8, and were still able to express the gene delivered by Anc80L65. The scientists created an additional 8 viruses, representing different branching points on the AAV evolutionary tree, and hope that in addition to being useful as gene therapy tools, these viruses will aid in the understanding of basic viral biology.

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In the past, scientists have used different approaches to modify AAV vectors to help them evade the host immune response. These methods include rearranging the capsid proteins so that the host’s antibodies can’t recognize the surface of the virus and neutralize it. When the proteins on the capsid are complementary to cell surface receptors on the host, they can bind to these receptors to facilitate receptor-mediated endocytosis. This enables the virus to enter the cell and inject its DNA into the cell nucleus, where the viral DNA is integrated into the host cell’s genome and expressed along with the other host genes.
There are some disadvantages to using AAV vectors to deliver genes. One of these is that the genome of AAV is very small and limits the amount of genetic material that the virus can carry. Other viruses, such as adenoviruses and retroviruses, can carry almost double the amount of genetic material as AAVs. The biggest disadvantage is that there can be a host immune response mounted against these small viruses. This prevents the administration of the vector in a number of patients. Most of the immune response is from the humoral and cell-mediated immune system, and consists of neutralizing antibodies and killing of infected cells by cytotoxic T cells2. In a recent study, it was found that 96% of the subjects had antibodies to AAV, and 32% of those had neutralizing activity3. It is therefore very important to be able to mitigate the immune response in order to effectively use AAV as gene therapy vectors. With more studies and clinical trials underway, we will make advances in the field of gene therapy and this will hopefully result in more diseases being cured.

Do you have any thoughts on gene therapy or possible vectors? Contact to discuss.
  1. In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector.
  2. Gene Therapy Using Adeno-Associated Virus Vectors
  3. Immune responses to adenovirus and adeno-associated virus in humans

Contributed by Rea Dabelic, PhD.
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