In Vivo Stem Cell Gene Editing Using Novel Lipid Nanoparticles Could Treat Lung Disease

Imagine if there was a technology that could directly modify our DNA to cure or prevent genetic diseases that are currently untreatable. This is no longer a plot in science fiction, but a reality with gene editing therapy. By precisely editing the genome, we can correct or eliminate problematic genes and provide long-lasting treatments for genetic diseases.

Last year, the U.S. Food and Drug Administration (FDA) approved a gene editing therapy using CRISPR technology to treat sickle cell disease, which was a major milestone in the field of gene editing. However, most of these therapies require an expensive and time-consuming stem cell transplant process: stem cells are extracted from the patient, genetically modified to repair the defect, and then these modified stem cells are returned to the patient. Although this method is effective, it is costly and complicated.

So, is there a way to genetically modify stem cells directly in the patient's body without taking them out? Researchers at the University of Texas Southwestern Medical Center are working on this and have made some exciting progress. Recently, they published their research results titled "In vivo editing of lung stem cells for durable gene correction in mice" in the journal Science.

The researchers developed a new type of lipid nanoparticle (LNP) that can effectively deliver gene-editing molecules to specific organs, especially the lungs. They found that after a one-time treatment with this nanoparticle, the gene-editing effects in the lungs of mice lasted for nearly two years. In addition, this technology is expected to correct an untreatable mutation in cystic fibrosis.

Due to the success of mRNA COVID-19 vaccines, lipid nanoparticles have become a popular drug delivery method. Traditional lipid nanoparticles are usually composed of four different lipids that encapsulate the therapeutic cargo. However, these nanoparticles tend to concentrate in the liver after infusion into the human body. This is because traditional lipid nanoparticles are very similar to low-density lipoprotein (LDL), which naturally enters the liver to be broken down.

To overcome this limitation, Siegwart and his team developed a new type of nanoparticle, called Selective Organ Targeting (SORT) nanoparticles. In addition to the traditional four lipids, SORT nanoparticles also contain a special fifth lipid that can guide the nanoparticles to specific organs. The fifth lipid changes the physical and chemical properties of the SORT nanoparticles and attracts different plasma proteins to attach to their surface, thus affecting the uptake of the nanoparticles by different tissues.

Delivering lipid nanoparticles to the right organ is only the first step; it is more important to ensure that they can target the right cell types, especially stem cells and progenitor cells. These cells can differentiate into multiple types of cells, so gene editing them can achieve lasting effects.

To verify whether SORT nanoparticles can achieve lasting gene editing in the lungs, the researchers used a genetically engineered mouse model. This mouse has the ability to make red fluorescent protein, but only if its genome is edited in a specific way. By injecting SORT nanoparticles filled with gene editing molecules and evaluating lung tissue at multiple time points after injection, the researchers found that at each time point, the red fluorescence was evenly distributed in the lungs, indicating that the gene editing persisted.

Figure 1. Lung SORT LNPs mediated efficient delivery into diverse lung cell types with enhanced delivery to VtnR-expressing cells. (Sun Y, et al., 2024)

With this method for long-term gene editing, the researchers turned their attention to cystic fibrosis. Cystic fibrosis is caused by mutations in the chloride pump, a protein that regulates the concentration of salt inside and outside cells. When this protein malfunctions, it causes thick mucus to accumulate in the lungs, triggering a series of breathing problems, infections and persistent lung damage.

About 90% of cystic fibrosis patients can improve their symptoms with a breakthrough drug, but for some patients whose genetic mutations result in a non-functional truncated protein, there is currently no effective treatment. The researchers used SORT nanoparticles loaded with a gene editor that can correct this mutation, turning the truncated chloride pump into a normal version. Experimental results showed that the nanoparticles can achieve gene correction in nearly 50% of lung stem cells and restore more than 50% of the function of the chloride pump.

These early research results suggest that this technology may one day revolutionize the daily lives of people with cystic fibrosis. Although more animal model research and clinical trials are needed, this technology brings new hope to patients with genetic diseases. As Dr. Jermont Chen of the National Institute of Biomedical Imaging and Bioengineering said, "Through a clever modification of standard lipid nanoparticles, the team has laid the foundation for an in vivo gene editing platform in the lungs that could potentially be applied to other tissues. The approach described in this study has the potential to lead to long-lasting treatments for patients with genetic diseases."

Reference

Sun Y, et al. In vivo editing of lung stem cells for durable gene correction in mice. Science, 2024, 384(6701): 1196-1202.