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Bespoke Is Often Better: How Scientists Are Customizing Gene Therapy

When it comes to products from suits to kitchen cabinetry, bespoke often means better. That’s because custom-designed goods are more likely to fit your specific needs.

The same principle holds true when it comes to current research fueling the creation of better viral vectors, the tools used in gene therapy to deliver DNA.

Vector-mediated gene therapy exploits the natural proclivity of viruses to invade human cells, insert their genetic material and then use the cell’s own internal machinery to replicate. By designing vectors that can deliver working copies of therapeutic genes to patients’ cells, scientists hope to develop treatments for devastating single-gene disorders such as hemophilia B and Duchenne muscular dystrophy. 

But, while the theory is promising, in practice, the quest has been challenging: the human body has evolved to fight off viruses, not welcome virus-derived particles as healing therapies. 

“What we’re trying to do with gene therapy is to use vectors derived from viruses to deliver genetic material. Being able to engineer around our bodies natural ability to combat viruses is our biggest challenge,” says Sury Somanathan, an Associate Research Fellow in Translational Gene Therapy at Pfizer’s Kendall Square site.

An inflection point

In recent years, scientists have pinned their hopes on adeno-associated virus (AAV), a virus that doesn’t cause disease in humans. Scientists now know of hundreds of naturally occurring isolates, or variants, of AAV found in humans and animals, and are using this knowledge to help custom-build vectors to target specific diseases. 

“After investing over 50 years in studying vector biology, we’ve reached an inflection point, where we have the proper tool box to develop vectors that have the desired properties,” says Anna Tretiakova, Vice President of Gene Therapy Translational Sciences, who is also based in the Kendall Square, Cambridge site.

One of the most important components in AAV vector design is the capsid, the protein shell that surrounds its genetic material and acts as a “GPS” helping the vector reach its destination. Different variants of AAV are known for their abilities to target certain cell and tissues types. For example, AAV2, the most commonly studied vector, is known for targeting muscle, brain and kidney cells.  

Next-generation AAV

With a new generation of research tools, scientists are finding ways to optimize the vector’s protein shell to more efficiently target specific cell types and reduce potential toxicity. In one technique known as “capsid shuffling,” DNA encoding many different capsids from existing viruses is chopped up and mixed together to create new hybrid versions. Scientists then screen these “shuffled” capsids to see which ones are most efficient at targeting certain cell types. 

Another technique, rational design, uses structural data from X-ray crystallography, cryo-electron microscopy and machine learning to direct the design to specific regions of the vector surface creating entirely novel versions of AAV that can be tested for desired properties. "Rational design combines knowledge of the virus structures with how the virus interacts with the external environment to change an undesired trait by targeting specific amino acids on the virus surface with only minor changes to the 3-D structure of the virion,” says Joseph Rabinowitz, Senior Director, Capsid Development at Pfizer. 

An important area of research within rational design is engineering vector capsids to evade an immune response. Many people with pre-exposure to variants of AAV have existing neutralizing antibodies that prevent the vector from working effectively. And, in some cases, people with earlier exposure to that variant of AAV can develop an inflammatory response against the vector. But researchers are designing novel AAV vectors that have a reduction in neutralizing antibody binding and undesired receptor binding sites that may decrease inflammation. 

After investing over 50 years in studying vector biology, we’ve reached an inflection point, where we have the proper tool box to develop vectors that have the desired properties