The Role of Gene Therapy as an Emerging Treatment Strategy for Alpha-1 Antitrypsin Deficiency-Associated Lung...

Monogenetic disease alpha-1 antitrypsin deficiency (AATD) is the leading cause of emphysema, which is a major life-limiting chronic obstructive pulmonary disease (COPD). The current standard of care for severely affected individuals with lung disease is the periodic intravenous infusion of human AAT protein to restore circulating AAT levels to a protective level, known as augmentation therapy.  We did a systematic review to see the effect of gene therapy as a potential therapeutic option for AATD-related lung diseases. MEDLINE (via PubMed), SCOPUS, Web of Science, Cochrane Library, and EMBASE have been searched following PICO (Population, Intervention, Comparison, Outcome) criteria. After duplication removal, abstract and title screening, full-text screening was done by two individual reviewers. Then, the data were extracted, tabulated, and analyzed. A total of 1094 articles were found in the primary search. After a comprehensive review following strict inclusion and exclusion criteria, 14 articles have been included in the review. Evidence shows the response of gene therapy depends on multiple factors, e.g., what vector is used, route of therapy administration, duration of therapy, etc. The AAV8-CASI-luc vector, delivered intratracheally (IT), achieved sustained lung transgene expression for at least 52 weeks, but 29% of mice had persistent expression up to 72 weeks, providing therapeutic AAT protein levels, reducing experimental emphysema severity in mice. Intratracheal AAV8 in mice showed the highest AAT expression in the lung, outperforming AAV9, AAV5, AAV2, and AAV2 capsid mutants, providing long-term expression up to 4 months. Intrapleural administration of AAV5-hA1AT achieved higher lung and serum A1AT levels than intramuscular delivery, with AAV5 yielding 10 times higher levels than AAV2. Gene therapy using viral vectors has a potential role in producing AAT protein, which can be beneficial for AATD-related lung diseases. Human trials are necessary to establish the effectiveness and safety of gene therapy. In conclusion, while initial studies are encouraging, more research is needed to confirm the role of gene therapy.