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Engineered Virus Aids Gene Therapy Delivery

Adeno-associated virus

Adeno-associated virus diagram (Lawrence Berkeley National Lab)

(Updated) 29 Nov. 2019. A university bio-engineering lab and start-up company are developing synthetic variations of viruses to more reliably deliver gene therapies. A team from the lab of Harvard University geneticist George Church describes its advances in today’s issue of the journal Science (paid subscription required).

Church, with colleagues from Harvard’s Wyss Institute for Biologically Inspired Engineering and the spin-off enterprise Dyno Therapeutics in Cambridge, Massachusetts aim to produce better techniques for delivering gene therapies. The adeno-associated virus is a benign and naturally occurring microbe that infects cells, but does not integrate with the cell’s genome or cause disease, other than at most mild reactions. As a result, the virus has become a workhorse for delivering modified genes to treat inherited diseases, including therapies approved by FDA.

In their natural state, however, adeno-associated viruses, or AAVs, an imperfect and inefficient delivery vehicles, on which the researchers seek to improve. The team discovered it would not be an easy task, given the many properties of the virus needing refinements and enhancements. As a result, the researchers took a comprehensive and systematic approach to better understand the molecular components of the virus’s capsid, its outer protein shell.

That investigation meant revealing all of the possible mutations in the 735 amino acids making up the capsid’s proteins. Eric Kelsic, a postdoctoral researcher in Church’s lab, led the project, which genetically sequenced and uniquely identified some 200,000 variations of those protein components. In addition, the team uncovered a previously unknown protein, confirmed by a search of an authoritative database, that helps bind AAVs to their target cells. They call their discovery the membrane-associated accessory protein.

The researchers collected these capsid protein variations in a library, made available through GitHub. “With the information generated by this library,” says Church in a Wyss Institute statement, “we were also able to design capsids with more mutations than previous natural or synthetic variants, and furthermore with efficiencies of generating viable capsids that far exceed those of AAVs created by random mutagenesis approaches.”

The researchers, as Church notes, then used this library to design AAVs with genetically-engineered capsids for improving their performance, including their targeting to different organs in the body and viability. The team used a data-driven approach to design the engineered capsids for producing more specialized and targeted AAVs. That process includes machine-learning algorithms that the researchers say are made possible by the size and detail of the capsid protein library.

The researchers tested their redesigned AAVs in lab mice, targeting specialized viruses to the animals’ spleen, liver, kidneys, heart, and lungs. The results show AAVs with engineered capsids delivered and remaining viable at higher rates than would be expected from natural mutations.

Church, along with first-author Kelsic and co-author Sam Sinai, are among the founders of Dyno Therapeutics that licenses the capsid engineering process from Harvard; Kelsic is now the company’s CEO. The company, started last year, is developing specialized engineered capsids for AAV delivery of gene therapies to precise tissue locations in the body. As reported earlier this month in Science & Enterprise, Rejuvenate Bio — another company spun-off from Church’s lab — is developing gene therapies delivered with AAVs to treat multiple age-related diseases at once.

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