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 \<70% at screening OR
2. Annualized decline in post-bronchodilator FEV1 of ≥100 mL, calculated from at least two spirometry assessments obtained at least 12 months apart
* Group A only: Radiologic or physiologic evidence of emphysema (obtained within 6 months of signing the ICF) defined as either:
1. Chest CT imaging demonstrating a clinically significant burden of emphysematous change consistent with AATD-related disease (as judged by the Investigator or interpreting radiologist)
2. DLCO ≤70% predicted (corrected for anemia, if present)
* Willingness to abstain from alcohol use and herbal medications from the start of the screening period through 28 days post-PM647a administration
* Willingness to avoid strenuous physical activity starting 1 week prior to PM647a infusion through 14 days after PM647a infusion
* Willingness to participate in a long-term extension study with the understanding that the total duration of participation is 15 years post-infusion
* Group B only: Liver histopathologic examination with a METAVIR fibrosis stage of F1, F2, or F3
* Group B only: FibroScan ≤12 kPa
Exclusion Criteria:
* Prior medically significant reaction to an LNP-based or PEG-containing product medication (e.g., severe hypersensitivity reaction, myocarditis)
* Use of any investigational product within 30 days (or 5 half-lives, whichever is longer) of signing ICF
* Prior receipt of genetic medicine for AATD
* History of lung or liver transplantation, or actively waitlisted,
* History of lung volume reduction surgery (LVRS) or endobronchial lung volume reduction (ELVR)
* Recent (within past 6 weeks) COPD exacerbation requiring antibiotic or steroid therapy, or requiring hospitalization
* Resting SpO2 ≤88% on room air or requiring \> 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) \<1500 cells/mm3 OR platelet count \< 70 × 109 cells/L OR hemoglobin \<10 g/dL for males or \<9 g/dL for females
* Congestive Heart Failure (NYHA Class III-IV)
* Known or clinically suspected ischemic heart disease (unless adequately revascularized, free of angina or anginal equivalent, on maximal guideline-directed medical therapy for at least 12 months prior to screening)
* For male participants aged ≥ 40 years, a current calculated 10-Year ASCVD risk ≥ 20% (UNLESS ischemic evaluation performed within the 12 months before signing the informed consent or at the time of screening was in the Investigator's judgment sufficient to reasonably exclude the presence of clinically significant obstructive CAD / ischemic heart disease). If a lipid panel has been performed within the prior 12 months, the most recent lipid panel data may be used for ASCVD calculation
* Known or strongly suspected acute coronary syndrome (UA, NSTEMI, STEMI) or other clinically significant cardiovascular event (new reduction in LV systolic function, transient ischemic attack, cerebrovascular accident) within the 12 months prior to screening
* Known history of clinically significant arrhythmia (e.g., poorly controlled pAF, sustained ventricular tachyarrhythmia, etc.) with cardiac conduction disorder including but not limited to: congenital long QT syndrome, acquired prolonged QT (\[QTcF\] \> 450 msec (males) or \> 470 \[females\]), AV block (1st degree AVB is excepted)
* Active infectious disease including:
1. Known or suspected active systemic infection
2. Receipt of systemic antimicrobial therapy within 30 days of screening
3. Positive for presence of human immunodeficiency virus (HIV)-1 or HIV-2 (evidence of infection, regardless of viral load)
* Prior or current malignancy (excluding Stage 1 or lower, fully treated/excised malignant and pre-malignant disease of the skin, cervix or colon. Additionally, any other malignant and pre-malignant disease that the Investigator, in consultation with the treating oncologist and Study Medical Monitor, deems to have been fully treated/excised for \> 5 years)
* Any condition, laboratory abnormality, or reason that could adversely affect participant safety or study results, as determined by the Investigator, including, but not limited to:
1. Significant neurological conditions within the prior 12 months which may impact participant safety or participation in the study, including ability to complete study requirements or procedures as outlined in the clinical study protocol in the opinion of the Investigator
2. Any severe clinical condition of limited life expectancy
* Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile participants
a) Females of childbearing potential and non-sterile male participants who are or may become sexually active with female partners of childbearing potential are required to use highly effective contraception from Screening through at least 84 days after DP infusion
* History of Alcohol Use Disorder (AUD) or Drug Use Disorder (DUD) with \< 3 years of continuous abstinence preceding the date of screening
