The 28th Gordon L. Snider (GLS) Critical Issues Workshop entitled, “AAT Polymers: Disease Pathogenesis, Detection, and Therapeutic Targeting” took place on Friday, October 3, 2025, in London, England. The overall goal of this workshop chaired by Dr. Andrew Wilson and Dr. David Lomas was to focus on the alpha-1 antitrypsin (AAT) polymer, the structure that is potentiated when AAT monomers misfold and that is a significant contributor to clinical disease in AATD.
A1F welcomed 80 attendees from around the world who joined the workshop to contribute their Alpha-1 expertise on this topic. The goal of GLS topical workshops is to provide new information that speeds the journey to a cure for Alpha-1 Antitrypsin Deficiency (AATD).
“I was delighted with the success of the workshop which provided a platform to discuss the role of antitrypsin polymers in many aspects of antitrypsin deficiency: their role in the pathogenesis of the liver and lung disease, as a biomarker of liver disease and as a marker of the response to therapies that target the liver. I am hopeful that the sharing of information will stimulate new developments in this exciting field of research,” – Dr. David Lomas, workshop co-chair.
We are now fortunate to be entering a period in which multiple distinct therapeutic approaches are being developed and tested in patients for the first time. The success of these interventions will likely hinge upon their ability to alter the formation, clearance, or destructive potential of AAT polymers, making it a good time to revisit the molecular basis of the disease. This GLS workshop will therefore survey the field, reviewing what is known about polymer structure and formation, how we can detect and quantify AAT polymers, what is known about their presence in organs affected in AATD, how they contribute to cellular dysfunction, their prognostic significance in disease, how cells compensate to degrade polymers, and how we can contemplate targeting polymers as a therapeutic intervention.
It has been nearly 40 years since David Lomas and his colleagues found that the “Z” mutation in alpha-1 antitrypsin facilitates the formation of AAT polymers. Since that time, we have learned that AAT polymers play a central role in cellular dysfunction and tissue injury that leads to disease in AATD. The success of emerging therapeutic approaches now in development will likely hinge upon their ability to alter the formation, clearance, or destructive potential of AAT polymers, making it a good time to revisit the molecular basis of the disease. I was honored to plan this meeting with Dr. Lomas and to hear from the outstanding speakers about polymer structure and formation, how we can detect and quantify AAT polymers, what is known about their presence in organs affected in AATD, their prognostic significance in disease, how cells compensate to degrade polymers, and how we can contemplate targeting polymers as a therapeutic intervention. I am hopeful that data and discussion from the meeting will help to focus our priorities and as we work to enable the development of treatments and a cure for Alpha-1 patients,” – Dr. Andrew Wilson, A1F Scientific Director and workshop Co-chair.
A1F aims to accomplish the following actionable items from this robust workshop:
(i) to establish a standard protocol for measuring polymers in cohorts and clinical studies.
(ii) to share academic and industry data in a precompetitive space to assess whether we can validate circulating polymers as a biomarker for liver disease and response to therapy in alpha-1 antitrypsin deficiency.
(iii) to evaluate whether the measurement of circulating polymers is useful in detecting individuals with antitrypsin deficiency. This will be done with AlphaDetect.
An understanding of the basis of antitrypsin polymerization is critical as it is the basis of the accumulation of mutant protein as inclusions within the liver. It was this understanding that allowed the recognition that polymers may play a role in the associated emphysema, that their level in the circulation may predict individuals at risk of liver disease and that their suppression is the basis for novel therapies to treat the cirrhosis associated with antitrypsin deficiency.
“The A1F was proud and honored to hold our first GLS conference in Europe. AAT Polymers as a topic represents the innovative spirit of Alpha-1 Researchers and Scientists, and their commitment to advancing the field on behalf of patient,” – Scott Santarella, A1F President and CEO.
A1F thanks the workshop’s co-chairs, Dr. Andrew Wilson and Professor David Lomas, for their input into the meeting program and for inviting and securing the participation of this group of experts.
