Epigenetic activation of the SERPINA3 gene as a compensatory strategy for alpha-1 antitrypsin deficiency: proposal of a model with CRISPRa
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Abstract
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder mainly associated with pathogenic variants in SERPINA1, which cause misfolded protein accumulation in the liver and reduced pulmonary antiprotease protection. This article reviews recent advances in gene therapies for AATD and proposes an alternative model based on epigenetic activation of SERPINA3 using CRISPRa. The strategy would use mRNA encoding dCas9-VP64 or dCas9-p300core and sgRNAs targeting the SERPINA3 promoter, delivered through GalNAc-functionalized lipid nanoparticles. The approach would be evaluated initially in hepatocytes derived from induced pluripotent stem cells and subsequently in humanized liver mouse models. Gene expression, alpha-1 antichymotrypsin secretion, antiprotease activity, cell viability, and potential off-target effects would be assessed. The model seeks to determine whether controlled SERPINA3 activation can partially compensate for the protease-antiprotease imbalance associated with AATD without directly modifying the DNA sequence, thereby providing a potentially reversible compensatory strategy for further preclinical investigation and validation in relevant experimental systems.
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