Dual SORT LNPs for multi-organ base editing.

Area of Science:

• Genetics and Genomics
• Nanotechnology
• Gene Therapy

Background:

• Alpha-1 antitrypsin deficiency (AATD) stems from SERPINA1 gene mutations, leading to liver damage and lung emphysema.
• Current treatments for AATD are limited, necessitating novel therapeutic strategies.
• Effective AATD treatment requires targeting both the liver and lungs, which is challenging.

Purpose of the Study:

• To develop a dual-target delivery system for base editors to address AATD.
• To create Dual Selective ORgan-Targeting lipid nanoparticles (SORT LNPs) for simultaneous liver and lung delivery.
• To evaluate the efficacy of base editing delivered by SORT LNPs in correcting the AATD-causing mutation.

Main Methods:

• Development of Dual SORT LNPs for targeted delivery of base editors.
• Administration of Dual SORT LNPs to correct the PiZ mutation in liver and lung cells.
• Assessment of gene editing efficiency, Z-A1AT levels, liver phenotype, and neutrophil elastase activity.

Main Results:

• Dual SORT LNPs achieved 40% editing in liver cells and 10% in lung AT2 cells.
• Stable liver editing was maintained for 32 weeks, reducing Z-A1AT by over 80% and restoring normal liver phenotype.
• Significant neutrophil elastase inhibition (89%) was observed in lung bronchoalveolar lavage fluid.

Conclusions:

• Dual SORT LNP therapy demonstrates effective genome correction for AATD in preclinical models.
• This approach offers a promising strategy for treating multi-organ genetic diseases like AATD.
• The developed dual-target delivery system shows potential for long-lasting therapeutic effects.