Scientists Develop Safer Gene Editing Drug Delivery System

Genetic engineering, GMO and Gene manipulation concept. Hand is inserting sequence of DNA.  3D illustration of DNA.

A team of scientists at Harvard and the Broad Institute have developed a novel drug delivery system using engineered DNA-free virus-like particles (eVLPs) for encapsulating and delivering gene-editing proteins to animal models of disease. According to the researchers, eVLPs allow for the safer delivery of gene-editing therapies than other methods that can lead to prolonged expression in transduced cells—which increases the frequency of off-target editing—and viral vector integration into the genome of transduced cells, both of which can lead to oncogenesis.

In their research, published in the journal Cell, the team described both the delivery of base editors and CRISPR-Cas9 using eVLPs and detailed factors that influence virus-like particle delivery efficiency, while demonstrating that engineering virus-like particles can overcome multiple structural limits to their potency.

“The delivery of therapeutic macromolecules into mammalian cells in animals and eventually in patients is one of the most important challenges in life sciences.” said David Liu, a professor at the Broad Institute and the paper’s senior author. “There is often a very steep drop-off between in vitro and in vivo delivery, so we made the decision early on that our new delivery technology would need to show good efficacy in animal models.”

Virus-like particles (VLPs) have long been studied as a drug delivery method since they have the ability to infect cells, but don’t have viral genetic material. Because they lack viral genetic material, they have the advantage of having many of the same efficiency and tissue targeting advantages of viral delivery without the drawbacks of live viruses which can potentially insert their genetic material into a cell’s genome. Until now, though VLPs have shown very limited efficacy in delivering therapeutic agents in vivo.

In order to overcome this, the Liu lab team sought to understand the limitations of VLPs which included cargo packaging, release, and tissue localization. The result, was fourth-generation eVLPs capable of carry 16 times more cargo proteins than previous iterations and an eight- to 26-fold increase in editing efficiency in cells and animals.

To test their new eVLP design, the researchers used them to deliver base to edit a gene to lower “bad” cholesterol levels in mouse models. After a single injection of the eVLPs, the showed and average of 63% editing of the targeted gene, and 78% drop in its protein levels. The team also used a single eVLP injection to correct a disease-causing point mutation in mice with a genetic retinal disorder and partially restored vision with fewer off-targeting editing compared with other delivery techniques.

“The cholesterol target is particularly interesting because it is not only relevant to patients with a rare genetic disease,” said Broad researcher Aditya Raguram. “We are hopeful this is one example of genome editing being able to benefit a large population because cholesterol levels impact the health of billions of people.”

Postdoctoral fellow Samagya Banskota from the Broad hopes there will be significant uptake of this new gene-editing delivery method. “Because our system is relatively simple and easily engineered, it allows other scientists to adopt and build upon this technology quickly,” Banskota said. “Beyond carrying gene-editors, eVLPs have the ability to transport other macromolecules with lots of therapeutic potential.”

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