Researchers are turning to the past to help better improve gene therapy with the hope of curing modern diseases. Ancient viruses were resurrected to effectively deliver gene therapy to the liver, muscle and retina. These viruses were not only safer, but were more potent than therapies currently available.
The findings, detailed in the journal Cell Reports, could help researchers design the next generation of viruses used as vectors for gene therapy. Viruses are an ideal vector to deliver gene therapy as they can introduce a normal copy of the target gene into cells, replicate within the host and compensate for the abnormal, disease-causing gene.
Though gene therapy has the potential to revolutionize treatment for many debilitating diseases, there are still plenty of hurdles to overcome. One is that viruses need to infiltrate an organism, transfer their genetic material and replicate, all while not being detected by the host's immune system.
Adeno-associated viruses (AAVs) have previously shown promise as a vector for gene therapy; they don't cause disease and have demonstrated efficacy in a number of clinical trials. There are limitations to AAVs, though, as they naturally circulate throughout the human population. As a result, many of us have already been exposed to the virus and developed an immunity to it. Researchers need to therefore engineer a virus that can be used as a vector without being attacked by the immune system.
Simply changing the AAVs structure so it’s not detected by the immune system is quite a difficult task due to its sheer complexity. Altering proteins in the virus for one specific benefit can end up damaging the structure of the entire shell. Researchers from Harvard Medical School, Schepens Eye Research Institute, and Massachusetts Eye and Ear instead decided to uncover the virus’ evolutionary history to help them create a virus that can be an effective vector. Throughout evolutionary history, AAV ancestors have undergone a number of changes that have altered their function, but not destabilized their structure. This was the key for researchers in developing a virus with structural integrity that is unrecognizable to the host.
Researchers were able to retrace genetic changes in AAVs to their remote ancestors. By working their way backwards, researchers were able to develop nine synthetic ancestor viruses. In the study, the most ancient virus, known as Anc80, was able to successfully target the liver, muscle, and retina without toxic side effects in mice.
"The vectors developed and characterized in this study demonstrate unique and potent biology that justify their consideration for gene therapy applications," senior author Luk H. Vandenberghe said in a statement.
In future research, the scientists want to get a better understanding of Anc80 and examine its potential for treating liver disease and retinal forms of blindness.