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A gene-editing delivery system developed by UT Southwestern Medical Center researchers simultaneously targeted the liver and lungs of a preclinical model of a rare genetic disease known as alpha-1 antitrypsin deficiency (AATD), significantly improving symptoms for months after a single treatment, a new study shows. The findings, published in , could lead to new therapies for a variety of genetic diseases that affect multiple organs.

"Multi-organ diseases may need to be treated in more than one place. The development of multi-organ-targeted therapeutics opens the door to realizing those opportunities for this and other diseases," said study leader Daniel Siegwart, Ph.D., Professor of Biomedical Engineering, Biochemistry, and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Gene editing—a group of technologies designed to correct disease-causing mutations in the genome—has the potential to revolutionize medicine, Dr. Siegwart explained. Targeting these technologies to specific organs, tissues, or cell populations will be necessary to effectively and safely treat patients.

In 2020, the Siegwart Lab reported a called Selective Organ Targeting, or SORT, which uses specific components in the lipid nanoparticles (LNPs) that encapsulate gene-editing molecules to target certain organs. Although the researchers have demonstrated that SORT can edit genes selectively in specific organs, such as the liver, lungs, and spleen, the team had yet to demonstrate that this system could target multiple organs simultaneously.

Genetic therapies aimed at more than one organ will be critical to treat diseases like AATD, in which a mutation that affects a single nucleotide—one "letter" in the genetic code—causes buildup of a toxic protein in the liver. Because the healthy version of this protein also plays a role in inhibiting an enzyme that breaks down a key protein in the lungs, AATD patients' lungs are also affected, leading to a form of emphysema.

To correct the causative mutation in both organs simultaneously, Dr. Siegwart and his colleagues re-engineered the SORT nanoparticles to carry large gene-editing proteins necessary to replace the single affected nucleotide with a healthy one. They also developed new formulas for the liver- and lung-targeting nanoparticles, changing their ingredients to more efficiently reach these organs.

Tests in liver cells derived from patients showed these new nanoparticles effectively edited the mutated gene, known as SERPINA1. In a mouse model of AATD that carries the mutated human gene in each cell, a single dose of the liver- and lung-targeting SORT nanoparticles resulted in gene editing of about 40% of liver cells and about 10% of AT2 lung cells—those primarily affected by AATD. Evaluation of liver cells showed that editing remained stable in this organ for at least 32 weeks, reducing levels of the mutated protein by 80%.

Within four weeks of this treatment, aggregates of the toxic protein in the liver had faded away. Although this mouse model doesn't develop the same lung pathology as human patients, the researchers found that the damaging lung enzyme left unchecked in AATD was inhibited by 89%.

Together, Dr. Siegwart said, these results show that SORT can be used to treat multi-organ diseases. He and his colleagues continue to develop SORT into clinical therapies for various diseases through ReCode Therapeutics, which has licensed intellectual property from UT Southwestern. Dr. Siegwart is a co-founder and member of the scientific advisory board of the company. He has financial interests in ReCode Therapeutics, Signify Bio, and Jumble Therapeutics.