Using Nanotechnology to Deliver Genetic Medicines

Synthetic lipid nanoparticles developed at UT Southwestern show promise in delivering therapies to the lungs, bone marrow, and beyond.

For decades, scientists have strived to harness the potential of genetic medicines – nucleic acid therapies that treat diseases by prompting cells to produce therapeutic proteins or correcting genetic defects. However, effectively delivering genetic medicines where they’re needed has proved challenging, says Daniel Siegwart, Ph.D., Professor of Biomedical Engineering, of Biochemistry, and in the Harold C. Simmons Comprehensive Cancer Center.

As a materials chemist housed within an academic medical center, Dr. Siegwart is using his expertise to solve this problem. He and his colleagues have developed synthetic lipid nanoparticles to serve as delivery vehicles, showing in a series of studies that adjusting the composition of these nanocarriers can direct genetic medicines to the lungs, spleen, bone marrow, liver, and other organs of animal models. Different formulations of these nanocarriers can also be utilized for imaging, suggesting that this strategy could be used for “theranostics,” which combines therapy and diagnostics into a single modality.

“Dr. Siegwart’s discoveries have made great strides in bringing nucleic acid therapies for diseases including cystic fibrosis and cancer closer to clinical use,” says Carlos L. Arteaga, M.D., Director of the Harold C. Simmons Comprehensive Cancer Center and Professor of Internal Medicine. “His approaches for drug targeting and development are some of the most novel in the field and likely to have high impact.”

Unlocking Entry Into Cells

The nucleic acids DNA and RNA hold instructions that cells use to make proteins for performing every vital function in the body. However, their properties make it difficult for them to enter cells. Bare nucleic acids have a highly negative charge that repels them from negatively charged cell membranes, and the immune system quickly clears this genetic material from circulation since it views standalone nucleic acids as a threat.

Researchers have used several strategies over the years to usher nucleic acids into cells, but each has had significant drawbacks, Dr. Siegwart explains. For example, packaging DNA or RNA into viruses can be effective, but they can’t be mass-produced, and viruses can stimulate an undesirable immune response. Researchers have also had success with packaging nucleic acids inside lipid nanoparticles with formulations similar to cholesterol particles. But the body treats these nanocarriers as it would natural cholesterol and directs them only to the liver. Although these lipid nanocarriers are currently being investigated for genetic medicines to treat liver diseases, they aren’t effective delivery vehicles for diseases that affect other organs.

To solve this problem, Dr. Siegwart and his colleagues – including biochemists, biomedical engineers, physicians, and pharmaceutical scientists – developed nanoparticles made from a mix of synthetic lipids. Through trial and error and rational design, these researchers have developed a system they named SORT – short for Selective Organ Targeting – in which these synthetic lipid nanocarriers direct genetic medicines to desired organs by changing the lipid mix.

“At UT Southwestern, our researchers’ work is not siloed. Discoveries like SORT require extensive collaborations with different labs, diverse departments, and multiple investigators,” says Samuel Achilefu, Ph.D., Professor and Chair of Biomedical Engineering, Professor of Radiology and in the Harold C. Simmons Comprehensive Cancer Center. “The interdisciplinary research environment here allows this integration to happen organically.”

Extraordinary Potential

Dr. Siegwart and his colleagues have recently published a series of papers that show SORT’s broad potential. In one study, the researchers packaged messenger RNA (mRNA) inside SORT nanoparticles that contained instructions to convert immune cells called T cells into cancer-fighting agents called chimeric antigen receptor T cells (CAR T cells).

Although CAR T cells have shown significant promise in fighting malignancies, the conventional process to produce this therapy includes extracting the patient’s immune cells and inducing them to become CAR T cells in cell culture. Then, the cancerfighting cells are reintroduced to the body. This process costs hundreds of thousands of dollars and can take weeks or months to complete successfully, time that many cancer patients don’t have. The study showed that SORT particles prompted cells in the spleen of lab animals to produce their own CAR T cells that could kill cancer cells and extend survival.

In another study, Dr. Siegwart’s team used a similar strategy to direct genetic medicine to the bone marrow of animal models of sickle cell anemia. These bone marrow-homing nanoparticles contained geneediting machinery that corrected the genetic defect that causes this condition, offering a potential cure.

The researchers also used SORT to direct genetic medicines to the lungs. Using this approach, they were able to prompt cells there to produce proteins to replace defective ones in animal models of a condition called primary ciliary dyskinesia (in which hair-like protrusions in the lungs called cilia stay stationary, rather than beating rhythmically to move contaminants out of the lungs) and cystic fibrosis. In addition, the researchers used gene-editing machinery to repair the genetic defect that causes cystic fibrosis, a strategy that could eventually offer patients a lifelong cure.

“My team and I are excited to wake up in the morning and go to work because our research has such extraordinary potential to help patients,” Dr. Siegwart says. “We are contributing the basic knowledge needed to make a whole new category of medicine.”

Samuel Achilefu, Ph.D., Professor and Chair of Biomedical Engineering, Professor of Radiology and in the Harold C. Simmons Comprehensive Cancer Center

Carlos L. Arteaga, M.D., Director of the Harold C. Simmons Comprehensive Cancer Center and Professor of Internal Medicine

Daniel Siegwart, Ph.D., Professor of Biomedical Engineering, of Biochemistry, and in the Harold C. Simmons Comprehensive Cancer Center