Developing effective treatments for hereditary lung diseases such as cystic fibrosis has proven challenging. Scientists are developing a new type of nanoparticle that can deliver gene-editing technology directly to the lungs of mice, so it may not be around for long.
With the mapping of the human genome and subsequent genome-wide association studies linking defined genetic mutations to known diseases, much research has focused on developing gene therapies that target the genetic causes of disease. rice field.
Messenger RNA (mRNA) is a relatively new therapeutic agent that is used to prevent and treat certain genetic diseases. But to function effectively in the body, the mRNA, which carries the genetic information that instructs the cell to make a protein, must be stable, protecting it from degradation and allowing it to enter the cell and deliver the genetically modified payload. Requires a delivery system. Nanoparticles have proven to be effective vehicles for delivering mRNA.
However, nanoparticle delivery of mRNA presents challenges. It can be difficult to get it to the correct body part and avoid affecting other organs. It has previously been proven to be effective when encased in a sphere. Researchers at the Massachusetts Institute of Technology (MIT) and the University of Massachusetts School of Medicine have developed promising lung-targeting lipid nanoparticles.
The researchers developed nanoparticles containing a positively charged head group that helps the particle interact with negatively charged mRNAs and a long lipid tail that helps the particle cross the cell membrane and enter the cell. bottom. They experimented with 72 head groups and 10 lipid tails with different chemical structures before identifying nanoparticle structures that could reach the lungs.
Once a working lipid nanoparticle structure was discovered, researchers tested it in mice. They found that nanoparticles could be used to deliver mRNA encoding the CRISPR/Cas9 gene-editing component to the lungs of animals. This method allows better dose control than inhalation using a method called intratracheal instillation that introduces the substance directly into the windpipe (trachea).
The provided CRISPR/Cas 9 component “cuts” the genetically encoded stop signal and turns on the gene for green fluorescent protein, allowing researchers to determine the percentage of lung cells that successfully express the mRNA. will do so.
The researchers found that approximately 40% of lung epithelial cells were transfected after a single dose of mRNA. Transfection is the process of introducing genetic material into cells. Two doses of mRNA increased the percentage to over 50% of his, and three doses increased him to 60%. Epithelial cells (clavate cells and ciliated cells), which are key to the treatment of lung disease, were each approximately 15% transfected.
“This means that the cells we’ve been able to edit are really the cells of interest for lung disease,” said Bowen Li, lead author of the study. “This lipid allows mRNA to be delivered to the lung much more efficiently than other delivery systems reported to date.”
The use of lipid nanoparticles instead of adeno-associated virus (AAV) offered distinct advantages over alternative vehicles used to deliver gene therapy. Although AAV is effective, it cannot be used repeatedly on the same person because it causes an immune response in the body. Lipid nanoparticles do not cause such an immune response, so they can be administered multiple times if necessary.
The researchers also found that the new nanoparticles disintegrated rapidly and were cleared from the lungs within days, thereby reducing the risk of inflammation. Their development could be used in the future to correct genetic mutations that cause cystic fibrosis and other hereditary lung diseases.
“This is the first demonstration of highly efficient delivery of RNA to the mouse lung,” said Daniel Anderson, corresponding author of the study. fibrosis. ”
The research team is working to make the new nanoparticles more stable and aerosolizable so that they can be inhaled via a nebulizer, as well as to develop an mRNA vaccine that can be delivered directly to the lungs.
The study was published in a journal nature biotechnology.
Source: MIT News
