2. Academic Validation
  3. Susceptibility of alpha-1 antitrypsin deficiency variants to polymer-blocking therapy

Susceptibility of alpha-1 antitrypsin deficiency variants to polymer-blocking therapy

  • JCI Insight. 2025 Jul 8;10(15):e194354. doi: 10.1172/jci.insight.194354.
Riccardo Ronzoni 1 2,  Ibrahim Aldobiyan 1 2 3,  Elena Miranda 4,  Narinder Heyer-Chauhan 1 2,  Emma Lk Elliston 1 2,  Juan Pérez 5,  Annamaria Fra 6,  James A Irving 1 2,  David A Lomas 1 2
Affiliations

Affiliations

  • 1 UCL Respiratory, Division of Medicine, and.
  • 2 Institute of Structural and Molecular Biology, University College London, London, United Kingdom.
  • 3 Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
  • 4 Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy.
  • 5 Department of Cellular Biology, Genetics, and Physiology, University of Malaga, Faculty of Science, Malaga, Spain.
  • 6 Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
PMID: 40627447 DOI: 10.1172/jci.insight.194354
Abstract

The Z variant (Glu342Lys) causes alpha-1 antitrypsin (AAT) to self-assemble into polymer chains that accumulate within hepatocytes, causing liver disease and exposing a cryptic epitope recognized by the 2C1 monoclonal antibody (mAb). They can be blocked by the small molecule GSK716 ('716) that stabilizes an intermediate on the polymerization pathway. We have characterized 23 mutants of AAT in a cellular model to establish: (a) their ability to form intracellular Polymers, (b) whether polymer formation could be prevented by '716, and (c) whether the Polymers expose the 2C1 cryptic epitope. Most of the variants, including Mprocida (Leu41Pro), Mherleen (Pro369Leu), Mduarte (Asp256Val), Lfrankfurt (Pro255Thr), Yorzinuovi (Pro391His), Mwurzburg (Pro369Ser), and p.289S accumulated as intracellular Polymers. Eleven formed Polymers that were resistant to '716, including Mprocida, Mmalton (ΔPhe51), Lfrankfurt, Mduarte, S (Glu264Val), Mherleen, and Yorzinuovi. The '716 resistant mutants localize to a region of the AAT molecule separate from the binding site of the small molecule and form Polymers that are less well recognized by the 2C1 mAb. They are fully recognized by a novel 8A7 mAb that we developed to have a broader specificity. Our data suggest that individuals with these mutations are unlikely to benefit from treatment with '716 or its derivatives.

Keywords

Cell biology; Cell stress; Clinical Research; Genetic diseases.

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