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Alpha-1 Antitrypsin Deficiency—From Genes to Therapies

NIH-funded research over the past decades has helped to decipher the genetic underpinnings and clinical manifestations of alpha-1 antitrypsin (AAT) deficiency, an inherited disorder associated with liver disease, as well as disease in other organs such the lungs. Although the disease is caused by a single abnormal gene, its manifestations vary greatly depending upon the specific mutation a person has, whether a person inherits copies of the abnormal gene from one or both parents, and also on other genetic and environmental factors. With knowledge gained from research has come an expanded understanding of AAT deficiency, the differences among its various forms, and development of new therapeutics based on this scientific foundation.

The AAT enzyme is synthesized in the liver and secreted into the bloodstream, where it is transported throughout the body to help protect against tissue damage. It plays a particularly important role in the lungs, where it prevents the breakdown of proteins in connective tissue that help the lungs remain flexible.

AAT deficiency is a genetic disorder in which the gene encoding AAT is mutated, resulting in lower levels of this protein in the blood and diminished AAT activity in the lungs. AAT deficiency is a major contributor to chronic obstructive pulmonary disease and emphysema due to lung damage. The lower levels of AAT in the lungs are a consequence of the retention of malformed AAT protein in the liver, where its accumulation can cause tissue damage. AAT deficiency is the most common genetic cause of liver disease in children and an uncommon but important cause of liver disease in adults, sometimes leading to chronic liver disease and liver cancer. Patients with AAT deficiency thus face potential health risks on two fronts: lung disease, due to insufficient circulating AAT, and liver disease, due to accumulation of AAT in this organ. Research has greatly increased scientists’ understanding of the molecular processes involved in AAT deficiency, and recent studies have highlighted a promising new approach to addressing the sometimes life-threatening consequences of this serious condition.

Molecular and Cellular Features of AAT Deficiency

Since the mid-1960s, scientists have identified over 120 variants of the AAT gene. These variants are grouped into three categories based on the level of AAT they release into the bloodstream—normal, deficient, or virtually undetectable. About 100,000 Americans have the most severe form of AAT deficiency. In these patients, a significant fraction of the mutant AAT protein does not complete its journey from the interior of a liver cell, where it is assembled, to the cell surface, where it would normally be released into the bloodstream. Rather, the mutant protein forms polymers—chains of AAT molecules—which aggregate within liver cells at a site that acts as a checkpoint for quality control of proteins. The retention of polymerized AAT within the liver has two adverse consequences: first, the accumulation of AAT polymers results in tissue damage, including inflammation and fibrosis, in this vital organ; second, it results in lower levels of AAT in the bloodstream, which means that this protein cannot perform its important protective role of keeping in check the tissue-degrading enzymes in distal organs, especially the lungs.

Clinical Characterization of AAT Deficiency

The importance of AAT was originally recognized in studies of blood proteins in 1963, when scientists found that some patients with emphysema lacked sufficient amounts of AAT in their blood. In 1969, other researchers observed that patients with a particular variant of the AAT gene had a high frequency of liver disease, including neonatal jaundice and cirrhosis. In addition, the patients had high concentrations of the variant AAT in their liver cells. These and other observations about the disease enabled fundamental research to begin uncovering underlying mechanisms—a prelude to the development of treatments.

Scientists supported by the NIH have focused vigorous research efforts on liver damage arising from AAT deficiency. Because not all people with variant AAT develop liver disease, researchers have searched for factors that might predispose some patients to be susceptible to or protected from this liver damage. To this end, in 1994, researchers grew skin cells from AAT-deficient individuals who had never suffered from liver disease and who therefore might be “protected.” Similar cultures were made with cells from AAT-deficient individuals who had severe liver disease and were therefore considered “susceptible.” While cells from both cultures accumulated the variant AAT protein, only the “susceptible” cells exhibited a delay in degrading this abnormal protein, suggesting that some AAT-deficient patients have alterations in the degradation pathway for the protein in their liver cells—alterations that may predispose them to developing liver disease.

Possible Treatments for AAT Deficiency

In the 1980s, scientists demonstrated that increasing a patient’s levels of functional AAT by administering the normal form of the protein was feasible and beneficial. AAT-deficient patients achieved an increase in their blood levels of the normal protein following the intravenous transfusion of purified AAT from the blood of healthy individuals. Further research led to the FDA approval of a purified form of the enzyme for the treatment of AAT-related lung disease in 1987. Related therapies on the horizon are intravenous AAT augmentation products, inhalation delivery systems, and synthetic augmentation therapies. However, while these therapies for AAT-related lung disease are promising, they do not address the other manifestation of AAT deficiency: liver disease.

In the late 1980s, a study of mice engineered to produce a mutant human form of AAT secreted sufficient AAT into their bloodstream to protect them from lung disease but still suffered from a build-up of AAT in their liver cells and showed signs of liver damage. In 1989, additional research supported by the NIH substantiated that the aggregation of AAT protein within liver cells caused disease. Subsequent studies showed that patients with AAT deficiency sustain liver damage due to inflammatory immunological responses to the aggregated protein, and that the immunosuppressive drug cyclosporin A could help prevent AAT liver damage—a proof-of-principle for immune mechanism-based therapeutic approaches to AAT deficiency. All of these studies point to the accumulation of AAT as a key factor in the development of liver disease in AAT deficiency.

Building on these findings, more recent studies have focused on strategies to limit the accumulation of malformed protein in the liver to address the manifestations of AAT deficiency in this organ. One approach has targeted “autophagy”—literally, “self-eating”— the process by which a cell breaks down and recycles its components. In 2010, basic research studies demonstrated that, in liver cells, increased autophagy affords limited protection from damage caused by AAT aggregates. Treatment with the drug carbamazepine markedly reduced the amount of accumulated protein in cultured cells by boosting autophagy activity, and this drug also reduced liver fibrosis in a mouse model of AAT deficiency. Notably, carbamazepine has been used as an anticonvulsant and mood stabilizer in humans for over 40 years and its safety and tolerability are well known. Using a system to screen large numbers of drugs, investigators are searching for agents that improve autophagy and reduce the AAT aggregates in cells. Targeting the autophagy pathway may be a promising strategy for future therapeutic approaches.

Looking Forward

Despite recent progress toward new therapies, the only effective treatment for liver failure due to AAT deficiency is liver transplantation, for which donor organs are severely limited. Therefore, there remains a need for alternative therapies that can treat or prevent the serious liver disease that often accompanies AAT deficiency. By combining basic research on cellular processes underlying disease with knowledge of existing therapeutics that target these processes, researchers are striving to identify promising treatments that may work for multiple diseases. While autophagy-enhancing drugs are a promising potential treatment for liver disease associated with AAT deficiency, further studies will be needed to test the benefits and risks of this treatment in pediatric and adult patients with this serious form of liver disease.

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