Alpha-1 antitrypsin deficiency (Alpha-1) is a significant and treatable cause of COPD and emphysema, yet despite clear guidelines recommending screening of all individuals diagnosed with COPD for this genetic disorder, Alpha-1 continues to be significantly underrecognized.

During the ATS President’s Symposium: Alpha-1 Breakthroughs: New Discoveries in Mechanisms, Diagnosis & Treatment of Lung Disease in Alpha-1 Antitrypsin Deficiency on Monday morning at the ATS 2025 International Conference, seven experts explored the critical gaps in the understanding of patient needs, disease pathogenesis, and applications of screening guidelines for Alpha-1, which can cause liver damage as well as lung damage.

“This is a protein-misfolding disease, and misfolded proteins can form polymers, which accumulate in the endoplasmic reticulum of hepatocytes. That then results in byproduct injury and cirrhosis in a subset of individuals, and at the same time is responsible for reductions in the secreted alpha-1 antitrypsin that is then present in the circulation in low quantities, and therefore present in the lung in low quantities, which predisposes the lung to injury through a loss of toxic function mechanism,” explained Andrew A. Wilson, MD, a critical care clinician-scientist and professor at Boston University.

Craig P. Hersh, MD, MPH, ATSF, associate professor at Harvard Medical School and a physician at Brigham and Women’s Hospital, discussed the mechanism of injury in Alpha-1 lung disease.

“Most of the therapies in development to treat lung disease from Alpha-1 still are targeting the loss of function, the protease and protease hypothesis, whereas the therapies targeting liver disease are targeting the gain of function of the liver,” he noted. “So, just think about how important these mechanisms might be and how that might affect these therapies.”

Gerry Mcelvaney, BM, professor of medicine at Beaumont Hospital and the Royal College of Surgeons in Ireland, gave a retrospective look at what has been learned from augmentation therapy trials from 1988 to the present.

“There is consistent evidence that augmentation therapy decreases loss of lung tissue in Alpha-1, as measured by CT lung density,” Dr. Mcelvaney explained. “There is consistent evidence that augmentation therapy has a beneficial effect on lung function within specific groups.”

Additionally, there is real-world evidence that lung function data is less useful as an evaluation tool in people with advanced disease, and that augmentation therapy confers a survival advantage, he said.

However, several therapeutics are in development that target multiple steps of normal protein production, said Dr. Wilson, who outlined next-generation therapies for monogenic lung disease, including recombinant AAT, small molecules, RNA interference/siRNA, RNA editors, DNA editors, and gene therapy.

“Those different modalities will differentially benefit lung and/or liver disease-affected patients based on their mechanisms of action,” Dr. Wilson noted. “And physicians are going to need to be able to understand these implications and to explain them to patients, which sounds trivial, but actually, it takes quite a bit of time in the clinic.”

Education and awareness are important components in the effort to reduce the number of undiagnosed Alpha-1 cases. Social media could help in this regard.

“We should be aware that 80 percent of cases of COPD are not diagnosed, so that’s increasing our challenge,” said Michael A. Campos, MD. “So, how can we improve these testing rates? For years, we have been giving lectures, providing educational material, and sending kids to physicians’ offices. Now, with social media, you can find Alpha-1 on almost every platform.”

Dr. Campos, professor of clinical medicine at the University of Miami and section chief of pulmonary medicine at the Miami Veterans Affairs Medical Center, highlighted progress toward targeted detection and screening for Alpha-1. While researchers are not close to this goal, Dr. Campos said the progress toward it was swift, bolstered by novel detection tools that are cheaper and efficient, as well as the communication channels provided by social media.

Monocyte-endothelial crosstalk in COPD and Alpha-1 could illuminate a new pathway to treatment, said Karina A. Serban, MD, associate professor of medicine at the University of Florida.

“One potential therapeutic target is the endothelial cells, and if we find a better and more target-based inhibitor, maybe we can prevent the inflammation in the Alpha-1 lung and COPD lung,” she said.

Francesca Polverino, MD, PhD, ATSF, a professor at Baylor College of Medicine, outlined adaptive immune dysregulation in Alpha-1 lung disease, explaining that Alpha-1 emphysema is characterized by blunted tolerance, increased antigen presentation, and humoral immunity.

“Wild-type emphysema has B-cell hyperactivation and autoimmune disease, but this is even more pronounced in alpha-1 antitrypsin deficiency,” Dr. Polverino said. “We believe that the polymers of alpha-1 antitrypsin get into the macrophages and other immune cells, and they become the source of antigen, activating a self-perpetuating loop of immunity within the alpha-1 antitrypsin deficiency lung.”

Charlie Strange, MD, ATSF, professor of pulmonary and critical care medicine at the Medical University of South Carolina, discussed clinical trial endpoints for Alpha-1, CT densitometry, and the Alpha-1 Biomarkers Consortium (A1BC).

The nine-center consortium, with funding from the National Institutes of Health (NIH), is a partnership with the Alpha-1 Foundation to find biomarkers that correlate with emphysema progression and define the natural history of the disease, with the inclusion of genetics. In 18 months, 275 individuals have enrolled to participate and comprehensively endotype their COPD.

“Only about half of these individuals have an airflow obstruction, and only half of these individuals are receiving augmentation therapy,” Dr. Strange said. “What that means is that we really have the full distribution of lung disease.”

The A1BC cohort has the potential to be a large natural history cohort that can be used as a control population for emerging clinical trials, but it is not there yet.

“The A1BC will be limited in its impact until we can make it a 10-year study to really study the longitudinal, slowly progressive emphysema that is part of this community,” Dr. Strange said.