Medicine has a curious ability to stagnate, like quicksand. Although research is always happening, at some point, certain diagnostic and treatment protocols become codified, memorized, and passed down. Ask any medical student or doctor what the medications for diabetes are and the answers are likely to be identical to that of 10 years ago. 

One reason for this is that doctors are taught to think in terms of protocols, flowcharts, and differential diagnoses. There is little room in the busy hustle of a doctor’s life for much imagination and creativity. Those belong in the research lab – and it is only when what is discovered there reaches a tipping point of irrefutable evidence does it trigger an actual change in how patients are diagnosed and treated. 

Oftentimes researchers spend years and years just to make inch-by-inch progress in their field. As doctors, we owe them an immense debt of gratitude for their perseverance and dedication to improving the lives of our patients. 

Continue Reading

A researcher, Franck F. Rahaghi, from the Advanced Lung Disease Clinic, Cleveland Clinic Florida in Weston, published a fascinating study on the current state of alpha-1 antitrypsin deficiency (AATD) research as well as emerging treatment strategies. We will discuss some of his findings in this article.

Gene Repair 

Gene repair technology, such as CRISPR-Cas9 (clustered regularly interspersed short palindromic repeats-CRISPR-associated nuclease 9) is making huge waves in the world of medicine. This gene repair technique is already used in diseases as diverse as human immunodeficiency virus (HIV), hepatitis B, and Duchenne muscular dystrophy. 

How does CRISPR-Cas9 work in the context of AATD? In a nutshell, CRISPR-Cas9 can be utilized to insert a normal SERPINA1 gene into the genome of AATD patients with the PI*ZZ mutation. This is achieved by having a guide RNA target the insertion site, which then allows the Cas9 endonuclease enzyme to cut host genomic DNA at particular PAM (protospacer adjacent motif) sequences. In AATD, the repair sequence is the normal SERPINA1 gene. It can then be inserted into the genomic DNA of AATD patients with the PI*ZZ mutation, allowing translation of normal PI*MM AAT. 

Read more about AATD diagnosis

This method has already been trialed in mouse models. CRISPR gene editing performed in PI*ZZ mice resulted in the reduced aggregation of the mutant Z protein and the restoration of modest amounts of AAT expression. 

Another method for gene editing is the employment of recombinant adeno-associated viral (rAAV) vectors to deliver the normal SERPINA1 to AATD patients with the PI*ZZ genotype. A phase I study injected rAAV vectors expressing normal AAT protein into 9 AATD patients with the PI*ZZ mutation. This trial managed to increase AAT levels, but they were still 200-fold below the therapeutic target of 11 µM. A phase II study used rAAV vectors designed specifically to increase normal AAT expression substantially.

However, although AAT levels did increase, they were still below the therapeutic target. Despite these disappointing results, it is clear that rAAV vectors can indeed play a role in increasing normal AAT expression, however, further work needs to be done to refine this method so that the AAT expression reaches a putative therapeutic target. 

Chemical Chaperones 

An alternative to gene therapy is the use of chemical chaperones to aid in the proper folding of mutant AAT protein. There is something poetic in the term “chaperone,” which describes proteins that are present when the process of protein folding occurs. Researchers are investigating their use to increase serum AAT levels in patients with AATD. 

Studies have found 4-phenyl butyrate (4PBA) to be the most effective chemical chaperone for increasing AAT levels; it increased serum AAT levels by 50% in both normal humans and mice. Further studies were carried out to investigate its usefulness as prophylaxis against lung and liver injury. However, the results show no increase in serum AAT levels. Why? Scientists believe it is because an incredible amount of 4PBA needs to be delivered to the hepatocyte endoplasmic reticulum to match the therapeutic levels of 4PBA given in mouse models. 

Read more about AATD prognosis

Another chemical chaperone, VX-814, has been investigated to determine its efficacy in facilitating the proper folding of the PI*ZZ variant. VX-814 is administered orally, making it less invasive than medications administered intravenously (IV). However, clinical trials for this drug were halted for the same reason that 4PBA failed; it was not feasible to safely increase VX-814 administration to therapeutic levels to cause a meaningful rise in AAT levels. 

Moving Forward 

Currently, the only licensed treatment that significantly slows AATD progression is the weekly administration of IV plasma-derived AAT. The goal of this therapy is to delay emphysema onset, reduce exacerbations, and improve quality of life. However, it costs a pretty penny; in the United States, it can cost around $82,000 per year. 

The problem is that IV plasma-derived AAT has many weaknesses. Besides its cost, it imposes a heavy disease burden on patients because it is a lifelong medication. Furthermore, it only addresses AATD-associated lung disease and not extrapulmonary manifestations. As we can clearly see, the AATD treatment landscape is ripe for improvement. 

In this article, we discussed two emerging therapies that could potentially replace current treatment protocols if researchers can find ways to modify them to clinically improve the disease burden of patients with AATD. Perhaps a few more years will give sufficient time for these and other emerging therapies to be refined enough to demonstrate promising findings in human trials.


Rahaghi FF. Alpha-1 antitrypsin deficiency research and emerging treatment strategies: what’s down the road? Ther Adv Chronic Dis. 2021;12_suppl:20406223211014025. doi:10.1177/20406223211014025

Sieluk J, Levy J, Sandhaus RA, Silverman H, Holm KE, Mullins CD. Costs of medical care among augmentation therapy users and non-users with alpha-1 antitrypsin deficiency in the United States. Chronic Obstr Pulm Dis. 2018;6(1):6-16. doi:10.15326/jcopdf.6.1.2017.0187