To treat lung disease by correcting the folding of a protein that has gone wrong

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Alpha-1 Antitrypsin Deficiency (AATD), a hereditary lung condition that affects more than 100,000 people in the United States and results in one kind of chronic obstructive pulmonary disease (COPD), may now be treated thanks to research from Scripps Research. The human variation-based discovery technique, as detailed in Cell Chemical Biology, works by enhancing a broadly functioning protein quality control process already found in all cells and may be helpful for treating a range of different genetic illnesses.

According to senior author William Balch, PhD, professor of Molecular Medicine at Scripps Research, the path to discovery involves a major shift.  It is unknown of for a drug to be found that not only restores a protein’s function but also, in the case of AATD, prevents it from aggregating by precisely defining the function of the quality control mechanism in converting a misfolded state to a folded state through a comprehensive understanding of the variation causing the disease.

A genetic disorder known as AATD is brought on by changes in the alpha-1-antitrypsin gene (AAT). AAT is produced in the liver of healthy individuals and then circulates via the blood to the lungs, protecting them from damage and inflammation. However, when the mutant AAT protein is created by liver cells in individuals with AATD, it does not fold into the proper three-dimensional shape. By the time a person reaches middle age, the abnormal protein has damaged the liver and caused serious lung inflammation (COPD) due to accumulation over a long period of time in the liver.

The unfolded protein response (UPR) is triggered when a healthy cell detects a misfolded protein. This reaction eliminates misfolded proteins, decreases protein synthesis, and raises levels of chemicals that aid in proper protein folding. AAT variants do not activate the UPR at normal levels for unexplained reasons.

Variation spatial profiling (VSP), a study technique created by Balch’s team over the past ten years, seeks to better understand specific illness-associated proteins by examining how the dynamic, flexible, three-dimensional structures of proteins connected to disease change among several individuals. They found a novel therapy strategy to address the biggest problem in cystic fibrosis last year using VSP.

In the latest study, the researchers employed a similar machine learning technique powered by artificial intelligence to examine how 71 types of AAT react to a medication that activates one of the three main UPR pathways in cells. Each of the 71 types had previously been connected to AATD in humans, and Jeffery Kelly and Luke Wiseman of Scripps Research had already produced the medication.

According to Chao Wang, PhD, senior staff scientist at Scripps Research and co-first author of the new research, they found that when you modify the UPR, you can not only prevent these AAT variations from clumping in the liver, but you can also repair their function in the lungs.  Without changing the gene sequence, the researchers can fix the folding and activity of this protein.

Nearly all 71 of the AAT variations’ functions may be fixed by the medication. Although the mutation is present, activating the UPR successfully drives the problematic variants into functional protein structures. The reason for this success is still unknown to the researchers. According to their current thinking, when the UPR is activated, the environment in which proteins fold is very different from what is usual. This suggests that even when an AAT protein has a mutation, it may still be driven into the proper functional shape, presumably because the molecule’s structuring process is more flexible.

According to co-first author Shuhong Sun, PhD, for most AATD patients, the depletion of the protein in the lungs is the most serious matter, and while many available medicines are designed to prevent the accumulation of AAT in the liver, they don’t really make it functional in the lungs. Thus, it is quite amazing that the researchers were able to do both.

The studies also revealed one region of the protein that is crucial to its function; this “gate” region of the protein must be able to fold and flex in specific ways for the protein to move from the liver and carry out its function in the lungs. Together, these results show an existing compound that may be used to treat AATD. The production of additional specialized medications that treat AATD by affecting this special aspect of the AAT fold design may result after this new knowledge. This line of research is already being done by Balch’s team.

The study’s success also indicates that activating the UPR could aid in the treatment of other hereditary illnesses, including as cancer and neurodegenerative diseases in which genetic mutations result in improperly folded proteins. Additionally, the conversion of harmful AAT folds provides fresh perspectives on how natural selection generally works in response to population variation.


(2023). Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis. Cell Chemical Biology. 10.1016/j.chembiol.2022.12.004.