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New drug delivery system shown to effectively deliver therapeutic levels of gene-editing proteins

A Harvard research team has developed a new generation of virus-like particles, capable of delivering gene-editing proteins in vivo with high-specificity.

Gene-editing has been an exciting and emerging field in biotechnology for the better part of the last decade. Proteins such as CRISPR-Cas9 and various base editors, have been well studied and shown to be promising in providing a mechanism for curing genetic diseases. To put it in very general terms, these gene editing proteins act like scissors that cut out undesirable portions of DNA, and replace them with desirable ones. One drawback is that this technique requires extreme specificity. Getting these proteins to act preferentially on specific portions of DNA is crucial to their efficacy.

In a new study, a Harvard research team has demonstrated the ability to deliver gene-editing macromolecules through the use of enveloped virus-like particles (eVLP). Previous studies assessing VLPs have shown that although they effectively exploit the virus-like properties of protein transportation, they lack evidence of therapeutic efficacy in vivo, specifically, in mice.

David Liu, the paper’s senior author, stated in a Harvard news release, “The delivery of therapeutic macromolecules into mammalian cells in animals and eventually in patients is one of the most important challenges in life sciences. 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.”

Postdoctoral Fellow Samagya Banskota (Left) and Graduate Student Aditya Raguram (Right), co-lead authors, investigate in vivo delivery of therapeutic proteins at the Liu Lab. (Credit: Julia McCreary/ Harvard graduate student)

The team created a new generation of eVLPs capable of carrying 16-fold more base-editing proteins, with an eight to 26-fold increase in editing efficiency in animal cells.

The researchers demonstrated that their new generation of eVLPs were effective in editing genes in multiple tissues. They used the eVLPs to edit out a gene which provides the instructions for how to make a certain protein that is associated with “bad” cholesterol, PCSK9, known for regulating the levels of LDL cholesterol in the blood. By doing so, they lowered PCSK9 levels by 78%. Additionally, they used the eVLPs to edit a gene associated with genetic blindness, which resulted in partial restoration of visual function in the mice.

“The cholesterol target is particularly interesting because it is not only relevant to patients with a rare genetic disease,” co-author and graduate student Aditya Raguram said. “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.”


The study was published in Cell, on January 20th, 2022.

Abstract. Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.

Banskota S, Raguram A, Suh S, Du SW, Davis JR, Choi EH, Wang X, Nielsen SC, Newby GA, Randolph PB, Osborn MJ, Musunuru K, Palczewski K, Liu DR. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell. 2022 Jan 20;185(2):250-265.e16. doi: 10.1016/j.cell.2021.12.021. Epub 2022 Jan 11. PMID: 35021064.

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