Dual-Target Gene Therapy Shows Promise for Treating Multi-Organ Genetic Disorders.

A pioneering gene-editing system developed by scientists at UT Southwestern Medical Center has successfully targeted both the liver and lungs in a preclinical model of alpha-1 antitrypsin deficiency (AATD), a rare genetic condition. Published in Nature Biotechnology, the study highlights a breakthrough that could pave the way for treating other complex diseases affecting multiple organs.

Led by Dr. Daniel Siegwart, Professor of Biomedical Engineering and Biochemistry, the research builds on a previous discovery from 2020 in which his team introduced a platform called Selective Organ Targeting (SORT). SORT leverages lipid nanoparticles (LNPs) tailored with specific chemical compositions to deliver gene-editing tools to select organs. Until now, SORT had been shown to edit genes in individual organs such as the liver or lungs. This latest study marks the first time SORT has effectively edited genes in more than one organ simultaneously.

“Diseases involving multiple organs often require coordinated therapeutic strategies,” said Dr. Siegwart. “This work opens new possibilities for addressing such conditions with precision.”

AATD results from a single-nucleotide mutation in the SERPINA1 gene, leading to the accumulation of a misfolded, toxic protein in the liver. At the same time, the deficiency of a properly functioning protein in the lungs leaves patients vulnerable to a form of emphysema.

To counteract this, researchers redesigned the SORT nanoparticles to transport large gene-editing proteins capable of correcting the mutated nucleotide. New formulations were developed to target both liver and lung tissue more effectively, optimizing the delivery of these editing tools.

Tests on liver cells from AATD patients demonstrated that the updated nanoparticles successfully corrected the SERPINA1 mutation. In genetically modified mice carrying the defective human gene, a single dose of the dual-targeting SORT nanoparticles resulted in gene editing in approximately 40% of liver cells and 10% of lung alveolar type 2 (AT2) cells—the primary lung cell type affected in AATD.

The therapeutic effects were notable: editing in liver cells remained stable for over 32 weeks, reducing toxic protein accumulation by 80%. Within four weeks post-treatment, liver damage markers had subsided. Although the mouse model does not mimic human lung pathology exactly, researchers observed an 89% inhibition of the enzyme responsible for lung tissue breakdown, indicating improved lung function.

“These promising results demonstrate that SORT is capable of delivering gene-editing therapies to multiple organs simultaneously,” Dr. Siegwart said.

The technology is being further developed into clinical treatments by ReCode Therapeutics, a company that has licensed the intellectual property from UT Southwestern. Dr. Siegwart is a co-founder and serves on the scientific advisory board of ReCode, and he also holds financial interests in ReCode, Signify Bio, and Jumble Therapeutics.

This advancement sets the stage for new therapeutic avenues targeting complex genetic conditions that impact more than one organ system.

Source:https://phys.org/news/2025-06-gene-nanoparticle-multiple-simultaneously.html

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