Functional Alpha-1 Antitrypsin Reference Interval Established in Healthy Donors to Guide AATD Therapy Assessment
Background
Individuals with Alpha-1 antitrypsin deficiency (AATD) suffer from a genetic disorder characterized by insufficient functional alpha-1 antitrypsin (AAT), a critical protease inhibitor. This deficiency leads to unchecked neutrophil elastase activity, primarily damaging lung tissue and causing emphysema. Current standard-of-care involves weekly infusions of plasma-derived AAT, which is burdensome. Novel recombinant therapies, such as efdoralprin alfa, are in clinical trials. A precise reference interval for functional AAT (fAAT) is essential to accurately evaluate how effectively these therapies restore protective levels and mitigate disease progression.
Study Design
Researchers recruited 237 self-reported healthy individuals from Massachusetts to establish a reference interval (RI), with a requirement for ≥75% White participants. Blood samples were analyzed by the Mayo Clinic to confirm wildtype Pi*MM phenotype using the A1ALC test and assess total AAT protein via a Siemens nephelometry assay. Functional AAT (fAAT) was measured at BioAgilytix using a validated anti-neutrophil elastase capacity assay calibrated with WHO International AAT standards. Verification cohorts from Florida and California were subsequently recruited to confirm the representativeness of the Massachusetts cohort.
Results
Of the 237 initial donors, 211 with confirmed wildtype Pi*MM phenotype were used to calculate the reference interval. The central 95% range for functional AAT (fAAT) concentration was determined to be 23.8-42.4 µM. The lower limit of normal (LLN) for fAAT was designated as 23.8 µM.
This established LLN of 23.8 µM for fAAT was consistent with findings from two geographically distinct verification cohorts, despite one Florida cohort being excluded due to unverified sample-handling procedures. Additionally, the lower bound for total AAT protein from the RI cohort was 106 mg/dL, a value consistent with two other laboratory reference ranges, further validating the cohort's utility.
Key Findings
- A functional AAT (fAAT) reference interval was established in 211 healthy
Pi*MMdonors. - The central 95% range for fAAT concentration was determined to be 23.8-42.4 µM.
- The lower limit of normal (LLN) for fAAT was designated as 23.8 µM.
- The fAAT LLN was consistent across two independent verification cohorts.
- The lower bound for total AAT protein was 106 mg/dL, aligning with other lab references.
Why It Matters
This precisely defined reference interval for functional alpha-1 antitrypsin (fAAT) provides a critical benchmark for evaluating the efficacy of both existing and emerging AATD therapies. Clinicians can now objectively assess if therapeutic interventions, including novel agents like efdoralprin alfa, are restoring fAAT levels to a protective range, moving beyond just total AAT measurements. This standardization is vital for clinical trial design, patient monitoring, and optimizing treatment protocols to prevent or slow the progression of emphysema. It offers a clearer target for therapeutic goals, potentially improving outcomes for individuals living with AATD.
alpha-1 antitrypsin
aatd
reference interval
functional aat
emphysema
preclinical-animal