Gene therapies and other molecular therapies may soon be packaged and delivered more effectively, suggest researchers affiliated with MIT. These researchers have developed a system called—appropriately enough—SEND. SEND stands for Selective Endogenous eNcapsidation for cellular Delivery. It harnesses PEG10, a retrotransposon-derived protein found in human cells.
Ordinarily, PEG10 molecules form a virus-like particle to protect PEG10 mRNA. The PEG10 protein, however, has been modified by the MIT scientists to encapsulate other RNAs. What’s more, it has become part of a more elaborate molecule-packing system, one that incorporates fusogens, proteins that help fuse cells together.
SEND could be advantageous for at least two reasons. First, it uses proteins that are already inherent to human cells. So, it could reduce the risk of adverse immune reactions. Second, it could be enhanced with engineered fusogens that are capable of targeting specific cell types. Such fusogens could bring therapeutic cargo to the cells that need it, and only those cells, further reducing the likelihood and severity of side effects.
Details about SEND appeared in Science, in an article titled, “Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery.” The article pointed out that certain retroelements have been domesticated in human cells. Of particular interest are neutralized or repurposed capsid-forming elements such as Gag homologs.
“We identified several mammalian Gag homologs that form virus-like particles and one LTR retrotransposon homolog, PEG10, that preferentially binds and facilitates vesicular secretion of its own mRNA,” the article’s authors wrote. “We showed that the mRNA cargo of PEG10 can be reprogrammed by flanking genes of interest with Peg10’s untranslated regions. Taking advantage of this reprogrammability, we developed SEND by engineering both mouse and human PEG10 to package, secrete, and deliver specific RNAs.”
The scientists used SEND to deliver the CRISPR-Cas9 gene editing system to mouse and human cells to edit targeted genes. In the cell models, the new delivery platform worked so efficiently that the investigators were encouraged it could open up a new class of delivery methods.
“The biomedical community has been developing powerful molecular therapeutics, but delivering them to cells in a precise and efficient way is challenging,” said CRISPR pioneer Feng Zhang, PhD, senior author on the study and a core institute member at the Broad Institute. “SEND has the potential to overcome these challenges.” Zhang is also an investigator at the McGovern Institute.
“By mixing and matching different components in the SEND system,” Zhang added, “we believe that it will provide a modular platform for developing therapeutics for different diseases.” The new findings suggest that SEND technology could complement viral delivery vectors and lipid nanoparticles to expand the toolbox of ways to deliver gene and editing therapies to cells.
Next, the team will test SEND in animals and further engineer the system to deliver cargo to a variety of tissues and cells. They will also continue to probe the natural diversity of these systems in the human body to identify other components that can be added to the SEND platform.
“We’re excited to keep pushing this approach forward,” Zhang concluded. “The realization that we can use PEG10, and most likely other proteins, to engineer a delivery pathway in the human body to package and deliver new RNA and other potential therapies is a really powerful concept.”