Bone marrow targeted nano-particle

RNA interference is a strategy that could potentially be used to treat a variety of diseases by delivering short strands of RNA that block specific genes from being turned on in a cell. So far, the biggest obstacle to this kind of therapy has been the difficulty in delivering it to the right part of the body. When injected into the bloodstream, nanoparticles carrying RNA tend to accumulate in the liver, which some biotech companies have taken advantage of to develop new experimental treatments for liver disease.

Anderson's lab, working with MIT Institute Professor Robert Langer, who is also an author of the new study, has previously developed a type of polymer nanoparticles that can deliver RNA to organs other than the liver.

The particles are coated with lipids that help stabilize them, and they can target organs such as the lungs, heart, and spleen, depending on the particles' composition and molecular weight.

"RNA nanoparticles are currently FDA-approved as a liver-targeted therapy but hold promise for many diseases, ranging from COVID-19 vaccines to drugs that can permanently repair disease genes," Anderson says. "We believe that engineering nanoparticles to deliver RNA to different types of cells and organs in the body is key to reaching the broadest potential of genetic therapy."

The researchers began with the particles they had previously used to target the lungs and created variants that had different arrangements of a surface coating called polyethylene glycol (PEG). They tested 15 of these particles and found one that was able to avoid being caught in the liver or the lungs, and that could effectively accumulate in endothelial cells of the bone marrow. They also showed that RNA carried by this particle could reduce the expression of a target gene by up to 80 percent.

The researchers tested this approach with two genes that they believed could be beneficial to knock down. The first, SDF1, is a molecule that normally prevents hematopoietic stem cells from leaving the bone marrow. Turning off this gene could achieve the same effect as the drugs that doctors often use to induce hematopoietic stem cell release in patients who need to undergo radiation treatments for blood cancers. These stem cells are later transplanted to repopulate the patient's blood cells.

The second gene that the researchers targeted for knockdown is called MCP1, a molecule that plays a key role in heart disease. When MCP1 is released by bone marrow cells after a heart attack, it stimulates a flood of immune cells to leave the bone marrow and travel to the heart, where they promote inflammation and can lead to further heart damage.

"We now know that immune cells play such a key role in the progression of heart attack and heart failure," Mitchell says. "If we could develop therapeutic strategies to stop immune cells that originate from bone marrow from getting into the heart, it could be a new means of treating heart attack. This is one of the first demonstrations of a nucleic-acid-based approach of doing this."

 

 

Reference

Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche, Nature Biomedical Engineering (2020). DOI: 10.1038/s41551-020-00623-7 , www.nature.com/articles/s41551-020-00623-7