Advances in Alpha-1 Antitrypsin Gene Therapy

Area of Science:

• Pulmonary Medicine
• Gene Therapy
• Genetic Disorders

Background:

• Alpha-1 antitrypsin deficiency (AATD) causes lung damage due to low AAT levels.
• Gene therapy is a promising treatment for inherited disorders like AATD.
• Current AATD gene therapy faces challenges in achieving local lung protection and avoiding liver toxicity.

Purpose of the Study:

• To review gene therapy strategies for AATD, focusing on pulmonary manifestations.
• To explore novel vector-based approaches for localized AAT delivery to the lungs.
• To assess the potential of gene editing technologies in advancing AATD treatment.

Main Methods:

• Review of adeno-associated virus (AAV) and adenoviral vector-mediated gene therapy for AATD.
• Discussion of nonhepatic AAT sourcing strategies, including pulmonary endothelium-targeted vectors.
• Examination of CRISPR/Cas9 integration with gene delivery for sustained AAT expression.

Main Results:

• Viral vector-mediated liver transduction successful for hemophilia, but not yet for AATD.
• Ongoing trials utilize various AAV administration routes (intramuscular, intrapleural) for nonhepatic AAT production.
• Pulmonary endothelium-targeted adenovirus vectors offer potential for local AAT augmentation and reduced liver toxicity.

Conclusions:

• Targeted gene therapy approaches are crucial for effective AATD treatment.
• Pulmonary endothelium-targeted vectors and CRISPR/Cas9 hold significant potential for AATD gene therapy.
• Advancements in gene editing will facilitate direct human translation of AATD therapies.