Programmable systems, made up of components found in the human body, are a step towards safer targeting and delivery of genetic editing and other targeted therapies.
Researchers from MIT, MIT’s McGovern Institute for Brain Research, Howard Hughes Medical Institute, and MIT and Harvard’s Broad Institute have developed new ways to provide molecular therapy to cells. A system called SEND can be programmed to encapsulate and deliver a variety of things. RNA cargo. SEND utilizes intrinsically disordered proteins in the body that form virus-like particles and bind to RNA, and may not elicit an immune response more than other delivery approaches.
The new delivery platform works efficiently in cell models, and further development opens up new classes of delivery methods for a wide range of molecular medicine, including gene editing and gene replacement. Existing delivery vehicles for these therapeutic agents are inefficient, can be randomly integrated into the cell’s genome, and some can stimulate unwanted immune responses. SEND is committed to overcoming these limitations that may open new opportunities for the development of molecular medicine.
Researchers at MIT, MIT’s McGovern Institute for Brain Research, Howard Hughes Medical Institute, and MIT and Harvard’s Broad Institute have developed new ways to provide molecular therapy to cells. Credits: McGovern Institute and Opus Design collaborated with Feng Zhang, Rhiannon Macrae and Broad Institute.
“The biomedical community has developed powerful molecular therapies, but it’s difficult to deliver them to cells in an accurate and efficient way,” said CRISPR pioneer Feng Zhang. He is an author, a Core Institute member of the Broad Institute, and a researcher at McGovern. Institute and Professor of Neuroscience at MIT, James and Patricia Poitras. “SEND has the potential to overcome these challenges.” Zhang is also a researcher at the Howard Hughes Medical Institute and a professor of brain and cognitive science and bioengineering at MIT.
Report in Chemistry, The team is SEND (NSElective subjects EUnique eNSCapsidation for cells NSDelivery) utilizes molecules made by human cells. At the heart of SEND is a protein called PEG10. It usually binds to its own mRNA and forms a spherical protective capsule around it. In their study, the team designed PEG10 to selectively package and deliver other RNAs. Scientists used SEND to provide a CRISPR-Cas9 gene editing system to mouse and human cells to edit target genes.
Michael Siegel, a postdoctoral fellow in Zhang’s lab, the first author, and Blake Rush, a second author and graduate student in the lab, said PEG10 is not unique in its ability to transfer RNA. “That’s very exciting,” Segel said. “This study shows that there are probably other RNA transfer systems in the human body that can also be used for therapeutic purposes. It is also some really fascinating about what the natural role of these proteins is. I will ask you a question. “
Inspiration from the inside
The PEG10 protein is naturally present in humans and is derived from “retrotransposons” (virus-like genetic elements) that were integrated into the genome of human ancestors millions of years ago. Over time, PEG10 has been adopted by the body to become part of a repertoire of vital proteins.
Four years ago, researchers showed that another retrotransposon-derived protein, ARC, forms a viral-like structure and is involved in RNA transfer between cells. These studies suggested that retrotransposon proteins could be designed as delivery platforms, but scientists have used these proteins to package specific RNA cargo into mammalian cells. And did not succeed in delivering.
The SEND package is introduced into affected cells to deliver therapeutic mRNA and restore health. Credit: McGovern Institute
Knowing that some retrotransposon-derived proteins can bind to and package molecular cargo, Zhang’s team used these proteins as a possible delivery medium. They systematically searched these proteins in the human genome for proteins that could form protective capsules. In their first analysis, the team found 48 human genes that code for proteins that may have that ability. Of these, 19 candidate proteins were present in both mice and humans. In the cell lines studied by the team, PEG10 stood out as an efficient shuttle. The cells released far more PEG10 particles than any other protein tested. Most PEG10 particles also contain their own mRNA, suggesting that PEG10 may be able to package specific RNA molecules.
Development of modular system
To develop SEND technology, the team identified the molecular sequence or “signal” of the PEG10 mRNA that PEG10 recognizes and uses to package its mRNA. Researchers then used these signals to manipulate both PEG10 and other RNA cargoes, allowing PEG10 to selectively package those RNAs. The team then decorated the PEG10 capsules with additional proteins called “fusion factors” on the surface of the cells to help them fuse.
By manipulating the fusion factors of PEG10 capsules, researchers should be able to direct the capsules to specific types of cells, tissues, or organs. As a first step towards this goal, the team used two different fusion factors, including those found in the human body, to enable delivery of SEND cargo.
“We are confident that the combination of the various components of the SEND system will provide a modular platform for developing treatments for different diseases,” Zhang said.
Advances in gene therapy
SEND is composed of proteins that are naturally produced in the body and may not provoke an immune response. If this is demonstrated in further studies, researchers say SEND may open up opportunities to repeatedly provide gene therapy with minimal side effects. “SEND technology complements viral delivery vectors and lipid nanoparticles to further expand the toolbox of methods for delivering genes and editorial therapy to cells,” Rush said.
The team then tests SEND on animals and further designs the system to deliver cargo to various tissues and cells. We will also continue to explore the natural diversity of these systems in the human body to identify other components that can be added to the SEND platform.
“We are excited to keep this approach moving forward,” Zhang said. “The recognition that PEG10 and possibly other proteins can be used to design delivery pathways in the human body and package and deliver new RNA and other potential therapies is a very powerful concept.”
Reference: “Mammalian retrovirus-like protein PEG10 can package and pseudotype unique mRNA for mRNA delivery” Michael Segel, Blake Lash, Jingwei Song, Alim Ladha, Catherine C. Liu, Xin Jin, Sergei L. Mekhedov, Rhiannon K. Macrae, Eugene V. Koonin, Feng Zhang, August 20, 2021 Chemistry..
DOI: 10.1126 / science.abg6155
This work was made possible with the help of MIT’s Simons Center for the Social Brain. National Institutes of Health’s On-Campus Research Program; The National Institutes of Health grants 1R01-HG009761 and 1DP1-HL141201. Howard Hughes Medical Institute; Open philanthropy. G. Harold and Leila Y. Mothers Charitable Foundation; Edward Marincrok Jr. Foundation; MIT’s Poitras Center for Mental Illness Research. Hook E. Tan and K. Lisayan Autism Research Center at MIT. MIT’s Yang-Tan Center for Molecular Therapeutics; Lisayan; Philips Family; R. Metcalf; and J. and P. Poitras.
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