Background of AAT
Alpha-1 antitrypsin (AAT) is a protease inhibitor produced in the liver. As a crucial protein to human health, irregularities in its function can lead to a number of diseases, but it also has potential therapeutic applications.
Discovered in the mid-twentieth century, AAT is synthesized in the liver and mainly functions to protect the lungs by inhibiting proteolytic enzymes such as neutrophil elastase. The AAT gene, termed SERPINA1, is located on the q arm of chromosome 14 at position 32.1. This single-copy gene spans 12.2 kbp and comprises seven exons and six introns. The protein structure of AAT is composed of three beta sheets and nine alpha helices. Its signature feature is the reactive center loop (RCL), which transiently collides with elasin.
AAT protein function
AAT's principal function is to protect the lungs from an enzyme called neutrophil elastase. This enzyme, which can degrade elastin, a key component of the connective tissues, is released from inflammatory and immune cells, primarily neutrophils, to fight infection. Without the balancing effect of AAT, elastase can wreak havoc on the delicate connective tissues of the lungs, leading to damage and development of lung-related disorders.
AAT protein-related signaling pathways
In addition to its primary function, AAT is involved in a variety of signaling pathways. As a broad-spectrum protease inhibitor, AAT can modulate a myriad of activities such as apoptosis, cell proliferation, and immunity. In particular, it suppresses the NF-κB pathway, which regulates the inflammatory response. It can also inhibit caspase-3, preventing the apoptosis of pulmonary cells. The PI3K/AKT signaling pathway, critical in cell proliferation and survival, can likewise be modulated by AAT.
AAT protein-related diseases
However, AAT dysfunction can also lead to several diseases. AAT deficiency, often resulting from SERPINA1 mutations, is a genetic condition that puts individuals at risk for lung diseases like chronic obstructive pulmonary disease (COPD) and emphysema, particularly if they are exposed to smoke or pollutants. Mutation-induced misfolding of AAT can cause the protein to aggregate in the liver, leading to liver diseases including neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. Studies also suggest that an imbalance between AAT and neutrophil elastase may contribute to the pathogenesis of rheumatoid arthritis and possibly other inflammatory conditions.
The role of AAT in these diseases has precipitated its use in medicine. Purified AAT from human plasma has been used in augmentation therapy for AAT deficiency. Clinical trials have demonstrated a potential benefit in slowing the progression of emphysema. In recent years, researchers have also been exploring applications of recombinant AAT and engineered AAT molecules with improved therapeutic properties. For non-deficient individuals, there is also potential for using AAT to treat diseases influenced by inflammation, such as rheumatoid arthritis and cystic fibrosis.
List of drug candidates related to AAT protein
Given these applications, several drug candidates have been related to AAT. Aralast NP and Prolastin-C, both plasma-purified AAT, are commercially available for augmentation therapy. Recombinant versions like AAT-Fc fusion and rAAVrh.10hAAT are being investigated. An exciting discovery is the synthetic peptides mimicking the RCL of AAT, which can harness its anti-inflammatory and tissue-protecting properties.
