New gene editing nanoparticles can heal your lungs using magic mRNA

New-age lipid nanoparticles can directly target genetic anomalies causing various types of incurable lung diseases in humans. Here is how they work.
Rupendra Brahambhatt
Liposome encapsulation for nanomedicine
Liposome encapsulation for nanomedicine

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A team of scientists from MIT and Massachusetts Medical School (UMass) has proposed that complex lung disorders that arise due to faulty genes and proteins can be treated using nanoparticles carrying messenger RNA (mRNA) particles. 

They also tested this approach in mice, and it delivered promising results. Daniel Anderson, one of the study authors and a professor of chemical engineering at MIT, said,  “This is the first demonstration of highly efficient delivery of RNA to the lungs in mice. We are hopeful that it can be used to treat or repair a range of genetic diseases, including cystic fibrosis.”

This is a big achievement, as currently, there is no cure for bronchiectasis, cystic fibrosis, sarcoidosis, and many other lung diseases that are caused by genetic factors. 

Delivering life-saving mRNA to mice lungs    

In their recently published study, researchers from MIT and UMass claim that they have created lipid nanoparticles that can deliver mRNA encoding healthy proteins to the lungs. This foreign mRNA actually encodes CRISPR/Cas9 gene editing components that replace the faulty disease-causing genes in the lungs with healthy proteins. 

Each nanoparticle molecule has a positively charged head and a lipid tail. The former stay linked to the negatively charged mRNA and enables it to escape the cellular structures that eat up foreign particles. Meanwhile, the lipid tail facilitates passage across the cell membrane. 

Interestingly, the study authors developed 72 alternative headgroups and 10 different chemical structures for the lipid tails. To determine which of these were most likely to reach the lungs, they checked various combinations of these nanoparticle structures in mice.

Once they figured out the correct nanoparticle structure to target mice lungs, they checked the success rate of the mRNA-carrying molecules using a “stop signal,” which was genetically encoded in mice lungs.

They designed the mRNA CRISPR/Cas9 components to cut the stop signal. Every time the mRNA did this, it triggered a measurable fluorescent signal that indicated the percentage of successful mRNA cell expressions in mice lungs.

The researchers noted that foreign mRNA was expressed by about 40 percent of all lung epithelial cells only after one dose of the nanoparticle molecules. The level increased to more than 50% after two doses and 60% after three treatments. 

Moreover, two epithelial cell types, club cells and ciliated cells, that are considered the most crucial targets for treating lung illness, also expressed the foreign mRNA encoding healthy proteins at roughly 15 percent.

Bowen Li, the first author of the study, said, “This means that the cells we were able to edit are really the cells of interest for lung disease,” He further added, This lipid can enable us to deliver mRNA to the lung much more efficiently than any other delivery system that has been reported so far.”

Time to make the nanoparticles inhalable

Unlike conventional mRNA delivery methods that involve innocuous adenoviruses, the lipid nanoparticles are reusable, meaning that they can be used to deliver mRNA multiple times. Moreover, they don’t cause any inflammatory reactions in the body or trigger the immune system like adenoviruses. 

Due to these advantages, the authors claim that their nanoparticles represent the best mRNA therapeutic approach discovered so far. They have the potential to offer treatment for various untreatable lung disorders, and therefore, they now look forward to testing them in humans. 

During the study, they delivered the nanoparticle to mice lungs via intratracheal instillation, a popular drug delivery method in which the medication is directly put into the trachea of the subject using a needle or a catheter.

However, Li and his team suggest that the gene editing nanoparticles will be delivered to human patients using a nebulizer or some other inhaling device. 

This is why they are currently finding ways to further stabilize and aerosolize the molecules so that these can be utilized in inhalers. 

The study is published in the journal Nature Biotechnology.

Study Abstract:

The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for messenger RNA and CRISPR–Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.

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