Inclusion Criteria:
- Males or females who are 18 to 70 years of age, inclusive, at the time of signing the informed consent
- Body mass index of 18 to 37 kg/m2, inclusive
- Confirmed diagnosis of AATD and PiZZ genotype
- At least one previous measure of blood total AAT level <11 µmol/L
- Nonsmoker for at least 6 months before screening and must remain nonsmoking for the entire study duration
- Either AAT treatment-naïve or washed out of all investigational or approved treatments that modify AAT levels for 5 half-lives or at least 4 weeks, whichever is longer, before TSRA-196 administration
Parts 1A and 2A (AATD lung disease with no or minimal liver fibrosis)
- Clinically significant lung disease, defined as 1) evidence of emphysema or bronchiectasis by computed tomography or 2) DLCO <70% of the predicted value or 3) ppFEV1 <80%
- ppFEV1 ≥35%
- METAVIR fibrosis score F0 or F1 confirmed by liver biopsy at screening, or a liver stiffness measure by FibroScan ≤7 kPa at screening
- FIB-4 index score ≤3.25 at screening
- ALT and/or AST <ULN at screening
Parts 1B and 2B (AATD liver disease with significant or severe liver fibrosis, with or without AATD lung disease)
- METAVIR fibrosis score F2 or F3 confirmed by liver biopsy at screening. A liver biopsy conducted within 12 months before screening is acceptable as a substitute.
- Liver stiffness measure by FibroScan >7 and ≤15 kPa at screening
- ALT and/or AST <2 x ULN at screening
Exclusion Criteria:
- Presence of genetic variation in SERPINA1 gene that may disrupt the function of TSRA-196, determined by screening genotyping
- History of liver disease unrelated to AATD, or history of or clinical signs of cirrhosis
- Significant lung disease not attributable to manifestations of AATD, as determined by the investigator
- History of one or more hospitalizations due to severe exacerbation of underlying lung disease during the year before screening or received IV antibiotics for treatment of a pulmonary infection within 6 months before screening
- Unstable AATD-related COPD, as determined by the investigator, or severe bronchiectasis
- Lung volume reduction surgery within 1 year before screening or plan to receive lung volume reduction surgery during the study period
- Documented chronic need for positive airway pressure therapy beyond nocturnal use
- Seropositive for human immunodeficiency virus (HIV) (HIV-1 or HIV-2)
- Seropositive for hepatitis B (hepatitis B surface antigen \[HBsAg\] or hepatitis B core antibody \[HBcAb\] positive) with detectable HBV DNA
- Hepatitis C virus (HCV) RNA positive at screening (Parts 1A and 2A), or HCV RNA positive and/or HCV antibody positive at screening (Parts 1B and 2B)
- Has received an organ transplant or is on a waiting list for an organ transplant
- Prior treatment with gene therapy using viral vectors or intended to permanently change the patient's DNA
- Any investigational products within 30 days before dosing or plan to take an investigational product before the end of study