NTLA-3001 in Adults with Alpha-1 Antitrypsin Deficiency-Associated Lung Disease

This study consists of 2 parts: Phase 1 is an open-label, single-arm ascending dose study to characterize the safety and activity of NTLA3001 and identify the dose for evaluation in Phase 2. Phase 2 will follow as an open-label, dose expansion study to further characterize the safety and clinical activity of NTLA-3001 and provide an initial assessment of the effect of NTLA-3001 on clinical measures of pulmonary function.

• Biological NTLA-3001 (Biological): IV administration of AAV and CRISPR/Cas9 gene editing system

Primary outcomes

• Safety and Tolerability [From NTLA-3001 infusion up to week156 post infusion]: To evaluate the safety and tolerability of NTLA-3001 as determined by adverse events (AEs) and dose limiting toxicities (DLTs)

Secondary outcomes

• Pharmacodynamics [From NTLA-3001 infusion up to week 156 post infusion]: To evaluate the PD effect of NTLA-3001
• Immune Response [From NTLA-3001 infusion up to week 156 post infusion]: To evaluate the immune response to NTLA-3001
• Vector Shedding [From NTLA-3001 infusion up to week 156 post infusion, only during phase 2.]: To evaluate vector shedding following administration of NTLA-3001

Sex: All, ages: 18 Years to 75 Years

Inclusion:

1. Age 18 years to 75 years
2. Diagnosis of AATD ZZ/ZNull genotypes
3. FEV1 ≥35% and ≤65%
4. No evidence of liver cirrhosis
5. Adequate chemistry and hematology measures at screening
6. Participants must agree not to participate in another interventional study for the duration of this trial.
7. Participants must be capable of providing signed informed consent

Exclusion Criteria:

1. AATD genotypes outside of ZZ or ZNull
2. Participants with total antibodies to adeno-associated virus (AAV) serotype above laboratory assay cut off
3. Participants who have known negative reaction or hypersensitivity to any lipid nanoparticles (LNP) component.
4. Any condition that, in the Investigator's opinion, could adversely affect the safety of the participant.
5. Unwilling to comply with study procedures.