Alpha-1 Antitrypsin Deficiency (AATD)

Alpha-1 antitrypsin deficiency (AATD) can cause lung and liver manifestations. Specific molecular approaches can potentially treat lung and liver manifestations at an early stage of development. Some of the clinical manifestations of AATD involve emphysema, liver disease, and chronic lung disease. Experimental therapeutic approaches involving intravenous AAT augmentation therapy are considered a viable option to reduce the progression of emphysema. Therapies targeting AATD are based upon protease imbalances in the lung and polymer burden in the liver. Clinical trials to mitigate liver disease include small interfering RNA to reduce transcription of the mutant protein, and lead to polymer formation. Drugs like carbamazepine are also effective to enhance the degradation of mutant protein through degradation.

Intravenous Augmented Therapy

Intravenous augmented therapy is derived from the human plasma, which has the potential to raise the concentration of alpha-1 antitrypsin (AAT) concentration in the epithelial lining fluid of the lung. It restores normal AAT concentration levels. A definitive 4-year clinical trial showed the benefit of intravenous augmented therapy on emphysema progression. Radiological imaging of the lung using CT densitometry shows disease severity in COPD and emphysema. Change in density of the lower zone and its relationship with forced expiratory volume (FEV1) were measured. Questions were raised regarding the infusion frequency and dosage. Overall, as per randomized placebo trial conducted, it showed efficacy to reduce the progression of pulmonary emphysema for adults diagnosed with AATD.¹

Gene Therapy for AATD

Gene therapy relies on recombinant viral vectors for the transfer of nucleic acid into target cells. Most of the studies were performed using recombinant adeno associated viral (rAAV) vectors. Several other studies have experimented with lentiviral, retroviral, and adenoviral vectors. Retroviral vectors have shown an increased risk of mutagenesis. AAV vectors are critical for AATD gene therapy. AAV is part of a single-stranded DNA virus from the Parvoviridae family. It avoids the risk of insertional oncogenesis as rAAV vectors do not integrate into the genome of the target cells. It can persist for a longer duration in both dividing and non-dividing cells. It offers a humoral response with the activation of neutralizing antibodies but it does not activate cytotoxic T-cells. rAAV can be optimized for transgene response. This approach has led to the successful delivery of AAV-based recombinant plasma encoding the human alpha-1 antitrypsin (hAAT) gene. The AADT augmented therapy has led to the satisfactory expression of the transgene. It led to acceptable AAT concentration in the serum without any potential immune response as seen in murine models.²

Investigational Drugs for Treatment of AADT

There are various experimental therapies such as oral neutrophil elastase inhibitor, Alvelestat (NCT03636347),³ recombinant AAT with a fusion protein (NCT03815396)⁴, and carbamazepine (Tegretol-XR) which have shown effectivity in emphysema leading to normal spirometry. These experimental therapies have also shown efficacy with mild COPD (FEV1 > 80%) in clinical trials. New treatment options for AADT are being reviewed extensively.

Synthetic recombinant AAT (rAAT) has shown reduced immune reaction when it is fused with other molecules. It requires intravenous infusion which is not popular among asymptomatic patients. In Phase 3 clinical trials, researchers are considering inhaled augmentation instead of intravenous. The experimental therapies have led to the increase of AAT levels, it prevents polymerization, and is effective in early lung disease.⁵

Alpha-1 Antitrypsin Augmentation Therapy

AAT augmentation therapy uses human plasma components to prevent lung destruction in deficient individuals. An insufficient level of AAT is responsible for emphysema. Studies suggest that it is related to the degenerative pulmonary disease as well. Infusion of AAT purified from a pool of human plasma can raise the AAT to normal levels as per lung epithelial fluid. The initial trial evaluated the safety and biochemical efficacy of infusing a purified concentrate of AAT. As per the trial, the lung lining fluid’s anti elastase activity was maintained during the trial as the subjects also underwent bronchoalveolar lavage.⁶

Gene Therapy to Treat Liver Disease Associated with AADT

An accumulation of AAT protein in the liver hepatocytes can lead to devastating impacts on the liver. Some studies suggest intercellular vector administration. It carries the coding sequence of fully active AAT molecules which silences the expression of the Z form of the protein and allows the recovery of protective serum AAT levels. In the study, it was noticed that Z-AAT expression was reduced by 90% while circulating AAT levels increased by 13% to 30%.

The therapy enabled successful treatment of liver pathology as the AAT concentrations in the peripheral blood were corrected. It is more efficient than retrovirus vectors due to its ability to encode genes in multiple cell lines including non-dividing cells. It led to a decrease in the production of the deficient Z-AAT variant and established a human hepatoma-derived cell line. The safety profile of this therapy needs to be evaluated further. Overall, the dual approach of decreasing Z-AAT expression and increasing the by circulating level of AAT in blood has led to successful treatment possibilities for liver disease associated with AADT.²


  1. Pye A, Turner AM. Experimental and investigational drugs for the treatment of alpha-1 antitrypsin deficiency. Expert Opin Investig Drugs. 2019 Oct;28(10):891-902. doi: 10.1080/13543784.20191672656. Epub 2019 Oct 11 
  2. Wozniak J, Wandtke T, Kopinski P, Chorostowska-Wynimko J. Challenges and prospects for alpha-1 antitrypsin deficiency gene therapy. Hum Gene Ther. 2015;26(11):709-718. doi:10.1089/hum.2015.044
  3. A 12-week study treating participants who have alpha1-antitrypsin-related COPD with alvelestat (MPH966) or placebo. (ASTRAEUS). Accessed July 8, 2021
  4. Phase 1 Study to Assess the Safety, PK, and PD of INBRX-101 in Adults With Alpha-1 Antitrypsin Deficiency (rhAAT-Fc). Accessed July 8, 2021
  5. Quinn M, Ellis P, Pye A, Turner AM. Obstacles to early diagnosis and treatment of alpha-1 antitrypsin deficiency: current perspectives. Ther Clin Risk Manag. 2020;16:1243-1255
  6. Wewers MD, Crystal RG. Alpha-1 antitrypsin augmentation therapy. COPD. 2013 Mar;10 Suppl 1:64-7. doi: 10.3109/15412555.2013.764402

Reviewed by Harshi Dhingra, MD, on 7/1/2021.