Gene therapy for alpha-1 antitrypsin deficiency: an update

IntroductionAltering the human genetic code has been explored since the early 1990s as a definitive answer for the treatment of monogenic and acquired diseases which do not respond to conventional therapies. In Alpha-1 antitrypsin deficiency (AATD) the proper synthesis and secretion of alpha-1 antitrypsin (AAT) protein is impaired, leading to its toxic hepatic accumulation along with its pulmonary insufficiency, which is associated with parenchymal proteolytic destruction. Because AATD is caused by mutations in a single gene whose correction alone would normalize the mutant phenotype, it has become a popular target for both augmentation gene therapy and gene editing. Although gene therapy products are already a reality for the treatment of some pathologies, such as inherited retinal dystrophy and spinal muscular atrophy, AATD-related pulmonary and, especially, liver diseases still lack effective therapeutic options.Areas coveredHere, we review the course, challenges, and achievements of AATD gene therapy as well as update on new strategies being developed.Expert opinionReaching safe and clinically effective expression of the AAT is currently the greatest challenge for AATD gene therapy. The improvement and emergence of technologies that use gene introduction, silencing and correction hold promise for the treatment of AATD.

Automated summary

Since the early 1990s, altering the human genetic code has been explored as a definitive treatment for monogenic and acquired diseases. Alpha-1 antitrypsin deficiency (AATD) is one such disease that has been targeted for gene therapy due to its single gene mutation. AATD gene therapy faces challenges in achieving safe and effective expression of the AAT protein.