By Friedrich Kueppers, MD
With awareness of alpha-1 antitrypsin deficiency (AATD) increasing, more patients with lung and liver disease are being tested. However, conventional quantitative methods are not specific enough to detect some deficiencies and uncommon deficiency-associated variants. New testing and treatment methodologies may change the game for this disease.
AATD is relatively rare (1-3% of COPD patients), but it sharply increases the risk of lung diseases like COPD and emphysema, especially for smokers. Alpha-1 antitrypsin (AAT) protects lung tissue from attack by the enzyme neutrophil elastase. In the most common deficiency, AAT accumulates in the liver, leading to liver damage and to low levels of AAT in the lung.
Conventional testing for AATD relies on immunological methods to measure blood levels of AAT. However, because these levels rise in response to inflammation, injury or other stimuli, simple quantitative testing may not accurately diagnose AATD.
Even the conventional genotypic technique of isoelectric focusing identifies only a limited number of deficiency alleles; novel mutations that may be associated with disease remain unrecognized. Luckily, next-generation sequencing, consisting of rapid parallel sequencing of large numbers of DNA fragments in a single reaction, can identify new mutations rapidly and inexpensively, thereby opening up new treatment options.
The only currently available therapy that specifically addresses AATD is augmentation therapy with AAT preparations that have been isolated from normal blood plasma.
Fundamentally different new therapies are currently in clinical trials. One involves using gene transfer methodology: a non-replicating, non-pathogenic, genetically engineered virus introduces the normal AAT gene into the patient’s liver cells, where it will start to produce normal AAT.
The second potential therapy uses a synthetic elastase inhibitor that can be taken by mouth as a pill. Absorbed into the bloodstream, it could reach the lungs and limit the destructive effect of excessive elastase, slowing the development of emphysema.
Although these therapies are still in their preliminary stages, we believe they are promising. The Temple Lung Center has been selected as a clinical site for both studies, and we expect to initiate the studies in the very near future. ■