In 1963, the groundbreaking link between familial emphysema and alpha-1 antitrypsin deficiency was first discovered, setting the stage for decades of investigation into this genetic condition. From the discovery of human neutrophil elastase’s role in lung damage to the development of life-saving treatments, read on to learn about the history of Alpha-1 and find out how our evolving understanding of Alpha-1 continues to shape both clinical approaches and patient outcomes today.

The first scientific article describing the association between familial emphysema and the deficiency of alpha-1 antitrypsin was published in 1963 by Doctors Sten Eriksson and Carl-Bertil Laurell of Sweden. Before then, no one knew of the existence of alpha-1 antitrypsin deficiency (Alpha-1). Around the same time investigators in the US were also evaluating emphysema in a laboratory setting.

In 1964, Dr. Paul Gross found that rats developed emphysema when a substance called papain was placed into their lungs. Other investigators went on to show that the reason papain was able to cause emphysema was that it was able to destroy one particular protein in the lung, the protein elastin. Enzymes that can destroy elastin are called, by scientific convention, elastase. Many kinds of elastase had been identified before the mid-1960s, so scientists tested each of these elastases in animals, and each was able to cause emphysema.

In 1968, Dr Aaron Janoff described a new elastase he had found within a particular kind of human white blood cell. This white blood cell was called a neutrophil, and the elastase was named human neutrophil elastase (HNE). Dr. Janoff and his colleagues showed that HNE was very potent at causing emphysema in laboratory animals. They also showed that HNE’s activity against elastin could be totally blocked by mixing in human alpha-1 antitrypsin (AAT).

Dr. Janoff and his colleagues proposed that the lungs are constantly exposed to HNE by white blood cell activity in the lungs. They suggested that, in normal individuals, AAT is the primary defense against this destructive enzyme, but in individuals with a genetic deficiency of the AAT protein, the HNE can attack normal lung tissue, leading to emphysema. This group of scientists then went on to show that certain chemicals in tobacco smoke, called oxidants, could inactivate the protective function of AAT. (In fact, a single cigarette is capable of inactivating most of the AAT in a normal lung.)

This finding led to the suggestion that all emphysema is due to AAT deficiency in one way or another. In individuals with normal AAT genes who smoke regularly, the AAT deficiency is a functional deficiency, due to the action of tobacco smoke oxidants on AAT. In individuals with Alpha-1, the deficiency is genetic. Since individuals with Alpha-1, in general, have some circulating AAT (people with a severe deficiency usually have about 10 to 20 percent of the normal level), the combination of Alpha-1 and smoking can cause greatly increased risk of lung destruction.

Approximately six years after the initial description of Alpha-1 as a condition that predisposes to hereditary emphysema, Dr. Harvey Sharp published the first description of liver disease of the newborn in association with Alpha-1. This so-called neonatal cirrhosis led to liver failure and death in the infants he described. We now know that liver disease in children can range from very mild to life-threatening, and that liver disease in adults with Alpha-1 is not uncommon. Severe liver disease due to Alpha-1 in infants, children and adults is treated today with liver transplantation.

During the 1970s, a large number of different genetic patterns were identified for Alpha-1. These are called mutations of the AAT gene. First 10, then 50, and now over 140 different mutations of the AAT gene have been discovered. About one-third of these alleles are associated with a deficiency or dysfunction of the AAT gene. The rest are slight variations from the normal AAT gene that seem to cause no problems.

In the 1980s, investigators started to test whether it would be possible to replace or augment the deficient AAT protein in individuals with Alpha-1. This work was carried out primarily at the National Institutes of Health (NIH) facilities in Bethesda, MD. Investigators there isolated and purified AAT from normal volunteers, then administered it intravenously to patients with Alpha-1. They identified a dose that, when administered every week, could maintain AAT blood and lung levels at or above the level thought to protect against lung injury. This therapy became Prolastin®.

The 1990s saw the emergence of our understanding of Alpha-1 as a liver condition. Studies looking at the production of AAT determined that most of the AAT protein is made in liver cells. The liver cells make normal amounts of AAT; the problem is that the liver cells have problems transporting this protein out into the blood. The abnormal AAT gets hung up in the transport mechanism of the liver cells, and only a small fraction of the AAT protein made in the liver gets released into the blood. It is assumed that this clogging of the transport mechanism may explain how the liver injury develops in some Alpha-1 patients. Research is still progressing in this area.

In 2003, two additional intravenous drugs were approved for the treatment of Alpha-1 in the U.S, Aralast, currently manufactured by Takeda, and Zemaira, manufactured by CSL Behring. In 2010, Glassia, manufactured by Kamada and distributed by Takeda, was approved in the U.S. Prolastin, mentioned above, is currently called Prolastin-C Liquid and is manufactured by Grifols. Other medications may be approved in the future.

Currently, Alpha-1 is known to be a condition affecting the release of alpha-1 antitrypsin into the blood, causing low levels of this important protein in many tissues of the body. In the lungs, these low levels of Alpha-1 protein make them more likely to be injured by the body’s own defense mechanisms. Therefore, the next chapter of therapies for the lung will improve blood levels of Alpha-1 protein. The next therapies for liver disease will target ways to decrease the abnormally folded protein in the liver. Whether these medications will be the same medication or two different medications is not currently known.

There is much yet to be written in the history book of Alpha-1.

 

Sources:

https://subscriber.alphanet.org/s/article/3-3-1-overview-of-the-history
https://www.ncbi.nlm.nih.gov/books/NBK53021/