A Study of the Safety and Efficacy of Prime Editing (PM647a) in Participants With Alpha-1 Antitrypsin Deficiency

The purpose of this study is to evaluate the safety, tolerability, biological activity, and initial efficacy of PM647a, an investigational Prime Editing therapy, in adults and adolescents with Alpha-1 Antitrypsin Deficiency (AATD). AATD is caused by a mutation (change) in a gene called SERPINA1 that prevents the cells in your liver from producing a functional protein (alpha-1 anti-trypsin; AAT) that helps protect your lung tissue. PM647a is designed to precisely correct the prevalent disease-causing mutation (SERPINA1 Pi\*Z (E342K)) with the goal of restoring functional AAT. This is the first study of PM647a in humans. Participants will receive a single intravenous (IV) infusion of PM647a and will be monitored closely to evaluate safety, how the body responds to treatment, changes in AAT protein levels, and whether treatment may improve signs and symptoms of AATD.

Inclusion Criteria: * Participants at least 18 years of age at the time of consent and able to provide written consent * Confirmed diagnosis of AATD as determined by medical history consistent with AATD, and diagnostic genetic testing performed by the designated central laboratory demonstrating homozygous presence of the SERPINA1 Pi\*Z (E342K) allele * Blood total AAT level \< 11 μM or history of total AAT levels \< 11 μM a) For individuals receiving augmentation therapy, willingness to stop augmentation therapy for at least 5 half-lives or 4 weeks, whichever is longer, prior to the planned infusion of PM647a through Week 16 post-PM647a infusion * Group A only: Postbronchodilator FEV1 ≥ 30% of predicted (or ≥ 40% of predicted for participants on augmentation therapy) and at least ONE of the following: 1. FEV1/FVC \ 3 L/min supplemental oxygen to maintain SpO2 \> 88% * Body mass index (BMI) \>35 * Current or recent regular smoking history (within the past 12 months) or not willing to abstain from smoking (including vaporizers/e-cigarettes, marijuana) for the duration of the study * Liver disease with any of the following: 1. Total bilirubin \> 1.5 x ULN at screening, except for participants with documented Gilbert's Syndrome 2. Decompensated cirrhosis or advanced liver disease 3. Model for End-Stage Liver Disease (MELD) score \> 13 4. Group A only additional requirements: 1. ALT or AST \>1.5x upper limit of normal (ULN) at screening 2. Total bilirubin levels \>ULN at screening; if documented Gilbert's Syndrome, total bilirubin \>2 × ULN 3. FibroScan liver stiffness measurement ≥7.5 kilopascals (kPa) 4. Known history of liver cirrhosis or complications of cirrhosis 5. ≥F2 liver fibrosis if a patient has previously had a liver biopsy 6. Acute hemolytic anemia * Group A only: Significant burden of co-morbid liver disease or injury of any etiology (including AATD) * Group B only: Significant burden of co-morbid liver disease or injury not attributable to AATD, including but not limited to alcohol-related liver disease, autoimmune hepatitis, AIH, PBC, PSC, hemochromatosis * History of significant liver disease other than AATD, including but not limited to alcohol-related liver disease ('alcoholic hepatitis'), autoimmune hepatitis, or hemochromatosis. On-going hepatitis A, B, C or E viral infection is excluded, regardless of viral load. However, individuals with confirmed resolved hepatitis A, B or C viral infection may be enrolled (i.e., hepatitis B surface antibody positive and viral load negative, while not on antiviral treatment; hepatitis C viral load negative on at least 2 occasions at least 6 months apart, while not on antiviral treatment) * Evidence of Moderate or Severe Renal Impairment in the last 12 months since signing the ICF, defined as: 1. eGFR \< 30 mL/min/1.73m2 (CKD-EPI method) 2. Presence of Nephrotic Syndrome 3. Presence of Nephritic Syndrome * Clinically significant coagulopathy or disorder of platelet function (as evidenced by any of the following or as judged by the Investigator) 1. Requiring ongoing antiplatelet therapy (excepting low-dose acetylsalicylic acid \[ASA\]) that cannot safely be interrupted, or receipt of any such antiplatelet agent within the 14 days prior to PM647a administration 2. Requiring ongoing anticoagulant therapy that cannot safely be interrupted, or receipt of any anticoagulant within the longer of 7 days or 5 half-lives prior to PM647a administration 3. International Normalized Ratio (INR) \> 1.3 on at least 2 evaluations performed ≥ 1 week apart. If the most recent test exceeds these values, then a repeat test should be performed ≥ 1 week later to confirm * Absolute neutrophil count (ANC) \