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

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 intracellul

SUBMITTER: Ronzoni R 

PROVIDER: S-EPMC12333946 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature