In a new study in the journal Cell Reports, researchers show how they
successfully engineered an ancient virus and used it to deliver gene therapy to the
retina, liver and muscle tissue of mice.
Gene therapy uses viruses to insert healthy genes in the DNA of diseased cells.
Gene therapy is a relatively new and largely experimental approach that uses genes
instead of drugs or surgery to prevent and treat disease.
The team, including members from the Massachusetts Eye and Ear Infirmary and the
Schepens Eye Research Institute in Boston, MA, says the study should help make gene
therapies safer, more potent and available to more patients.
They also hope the findings will increase scientists’ understanding of the complex
structures of viruses that can be used as gene therapy “vectors” – vehicles that insert
genes into cells.
Senior author Luk H. Vandenberghe, an assistant professor at Harvard Medical School
who heads a lab at the Institute and Infirmary, says:
“We believe our findings will teach us how complex biological structures, such
as AAVs (adeno-associated viruses), are built. From this knowledge, we hope to design
next-generation viruses for use as vectors in gene therapy.”
Viruses make ideal delivery vehicles for genes. They survive by inserting themselves
into the genetic material inside the cells of the organisms they invade. They then hijack
the cell’s machinery to make copies of themselves and proliferate.
Engineered viruses not likely to be attacked by immune system
By inserting therapeutic genes into viruses, researchers can use them to ferry the
genes into the cells or tissue of patients. Adeno-associated viruses (AAVs) are small viruses that infect humans but do not cause
disease. This is one of the features that makes them ideal vectors for gene therapy.
So far, gene therapy developers have chosen AAVs that naturally circulate in the human
population. But the problem with this is that when a person is exposed to such a virus,
their immune system remembers it and tries to eliminate it next time it invades.
As a result, the effectiveness of gene therapy based on natural AAVs is limited if the patient’s
immune system has seen them before and attacks the vectors before they have had a chance
to insert sufficient genes into cells for the therapy to have effect.
The solution is to engineer new, benign AAVs that patients’ immune system will not
recognize, giving them time to insert the therapeutic genes into the target cells. This
would make the therapy available to many more patients.
But AAVs are not easy to engineer due their complex structure. The proteins of
the virus shell fit snugly together in unique, intricate patterns, like a
The pattern is so intricate and intermeshed that tweaking a protein to achieve a
benefit – such as more efficient transfer of the gene into the cell – could result in
destruction of the whole shell.
Ancestor virus successfully targeted tissue in mice without side effects
To solve the problem of engineering AAVs that have the benefits
without the drawbacks, the team looked to the ancestors of viruses that are around
By examining the lineages of viruses, the researchers were able to work backwards up their tree of ancestors, discovering the changes that have occurred in their
evolution. From this knowledge, they engineered nine viruses that had structural integrity
and also had features that might make them good vectors.
When they tested the engineered viruses in mice, they found Anc80, the most
ancient of them, was able successfully to target and enter liver, muscle and retina cells
without toxic side effects.
The next step for the researchers will be to look at the interaction between virus and
host throughout evolution in an effort to find improved vectors for clinical use. The team also plans to examine whether Anc80 could be used to treat liver diseases and
retinal forms of blindness.
Prof. Vandenberghe sums up their findings so far:
“The vectors developed and characterized in this study demonstrate unique
and potent biology that justify their consideration for gene therapy
Medical News Today recently reported how researchers used gene therapy to restore hearing in mice with a type of
deafness that is caused by a faulty gene.
To deliver the healthy gene, the team created an AAV
together with a promoter that only turned the gene on in certain cells of the inner
Written by Catharine Paddock PhD
Copyright: Medical News Today
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