CHEST Guidelines-Editing-Approaches-to-Treat-Alpha-1-Antitrypsin-De

Editing-Approaches-to-Treat-Alpha-1-Antitrypsin-De

Pdf Summary

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder primarily caused by the E342K mutation in the SERPINA1 gene, leading to impaired secretion of alpha-1 antitrypsin (AAT) and increased protease activity that damages lung tissue. This results in conditions such as emphysema and chronic obstructive pulmonary disease (COPD), as well as liver disease due to the accumulation of mutated AAT in hepatocytes. Current treatments for lung manifestations include weekly intravenous AAT augmentation therapy, but there is no approved treatment for liver diseases caused by AATD. Emerging genomic medicine approaches, specifically RNA and DNA editing techniques, are being explored to address these deficiencies.<br /><br />RNA editing, particularly the reprogramming of endogenous adenosine deaminases acting on RNA (ADARs), offers a novel strategy to treat AATD by converting the mutated E342K RNA back to wild-type sequences. This method harnesses ADARs to edit RNA transcripts in a reversible manner, potentially repairing both the liver and lung disease phenotypes without permanently altering the DNA. RNA editing can temporarily bypass the genetic mutations and produce functional AAT.<br /><br />In parallel, DNA editing technologies like CRISPR-Cas9 are being explored, allowing for a permanent fix by either correcting the mutation or knocking in a healthy copy of the SERPINA1 gene. These approaches, although promising, face challenges such as potential off-target effects and immune responses. Delivery methods like lipid nanoparticles (LNPs) and GalNAc conjugates are critical in effectively targeting liver cells, where AAT is synthesized.<br /><br />These cutting-edge therapies could significantly improve the quality of life for individuals with AATD by not only managing symptoms but potentially addressing the root cause of the deficiency, offering hope for both lung and liver disease improvements.

Keywords

Alpha-1 antitrypsin deficiency

E342K mutation

SERPINA1 gene

emphysema

chronic obstructive pulmonary disease

RNA editing

DNA editing

CRISPR-Cas9

lipid nanoparticles

GalNAc conjugates