A Phase I/IIa，Open-label, Single Ascending Dose and Dose-expansion Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of YOLT-201 in Patients With Transthyretin Amyloidosis Polyneuropathy (ATTR-PN) or Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)

Inclusion Criteria:

1. Age 18 - 80 years old (including the critical values), regardless of gender;

2. Body weight at the time of screening is between 40 - 90kg (including the criticalvalues);

3. TTR gene mutation is confirmed by genetic testing;

4. At the time of screening, the following laboratory standards must be met:

5. AST, ALT, and TBIL ≤ the upper limit of the normal value (ULN);

6. For subjects with Gilbert syndrome, TBIL ≤ 2 times ULN;

7. Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73m2 (calculated according tothe CKD-EPI formula);

8. Platelet count ≥ 100 × 109/L;

9. Partial thromboplastin time (APTT), prothrombin time (PT), and thrombingeneration time (TGT) are all within the reference value range, fibrinogen (FIB) ≥ the lower limit of the normal value (LLN) and ≤ 1.5ULN, theinternational normalized ratio (INR) ≤ ULN, and if taking anticoagulant drugs,it is ≤ 2.5ULN;

10. Vitamin A and vitamin B12 ≥ the lower limit of the reference value (LLN);

11. Low-density lipoprotein cholesterol (LDL) < 200 mg/dL (5.17 mmol/L).

12. Drugs approved for the treatment of ATTR are not accessible (Criterion A) and/or thedisease still progresses despite the use of drugs approved for the treatment of ATTR (Criterion B):

• Criterion A: Meeting one or more of the following criteria:

1. Drugs for the treatment of ATTR are not marketed in China;
2. Unable to receive the approved drugs for ATTR treatment (e.g., intoleranceor other medical, cost and/or other reasons);

• Criterion B: Subjects have received ATTR drug treatment for at least 3 months,but the subject's condition has progressed as assessed by the investigator, andmeets any of the following criteria: ATTR-CM: a. Increased number of hospitalizations related to heart failure; b.Worsening of NYHA classification; c. Decrease in KCCQ score by at least 5 points; d.Decrease in 6-MWT by at least 30m; e. Increase in NT-proBNP by 30%; f. Increase inTroponin I by 30%; g. Echocardiography indicates an increase in left ventricularwall thickness by 2mm; h. Echocardiography indicates a decrease in left ventricularejection fraction by ≥ 5% or a decrease in global longitudinal strain by ≥ 1% or adecrease in stroke volume by ≥ 5%; i. New conduction block appears; ATTR-PN: a. PNDscore increase by ≥ 1 point; b. FAP increases by 1 stage; c. NIS score increase by ≥ 5 points; d. NIS-Lower Limb score increase by ≥ 5 points; e. mBMI decrease by ≥ 25kg/m2×g/L; f. 10-MWT decrease by ≥ 0.1 m/s; g. Electroneurophysiological examination (electromyography) worsens compared to the previous.

6. Agree to stop drinking alcohol within the screening period to 28 days afteradministration;

7. Female subjects need to be menopausal (absence of menstruation for at least 1 year)or have undergone uterine/ovarian resection surgery; Male subjects and theirpartners have no fertility plans from the screening period to 6 months after the endof the trial and agree to take effective non-pharmaceutical contraceptive measuresduring the trial;

8. The subject himself/herself (or his/her legally recognized representative)understands and signs the informed consent form;

9. Agree not to receive other ATTR drug intervention treatment within at least 8 weeksafter administration of YOLT-201; For ATTR-PN only:

10. Diagnosed as ATTR-PN according to the "Consensus on the Diagnosis and Treatment ofTransthyretin Amyloidosis Polyneuropathy", and the NIS score at the screening is ≥ 5and ≤ 130, and the PND score is ≤ IIIb;

11. NT-proBNP < 600pg/ml at the screening; For ATTR-CM only:

12. Diagnosed as ATTR-CM according to the "Expert Consensus on the Diagnosis andTreatment of Transthyretin Cardiac Amyloidosis";

13. The New York Heart Association (NYHA) cardiac function classification is grade II -III;

14. The 6-minute walk test (6-MWT) is ≥ 150 m at the screening;

15. NT-proBNP is ≥ 600pg/mL and ≤ 3000pg/mL at the screening;

16. At the screening, echocardiography suggests evidence of cardiac involvement: thethickness of the interventricular septum and/or the posterior wall of the leftventricle is ≥ 12 mm.

Exclusion Criteria:

1. Amyloidosis is not caused by TTR protein, such as light chain amyloidosis;

2. There is meningeal transthyretin amyloidosis;

3. Allergic to any lipid nanoparticle (LNP) component or has previously received LNPand experienced treatment-related laboratory abnormalities or adverse events;

4. Use any of the following ATTR treatments within the prescribed time:

• In the dose escalation stage of the first stage, the use history of Patisiran,Inotersen, and Vutrisiran is excluded;

• In the dose expansion stage of the second stage, the following are excluded:Patisiran is used within 90 days before the administration of theinvestigational drug; Inotersen is used within 160 days before theadministration of the investigational drug; Vutrisiran has a previous usehistory;

• Tafamidis: used within 10 days before the administration of the investigationaldrug;

• Diflunisal: used within 3 days before the administration of the investigationaldrug;

• Doxycycline and/or taurodeoxycholic acid: used within 14 days before theadministration of the investigational drug;

• Previous use history of investigational gene editing drugs;

• Other drugs for the treatment of ATTR: the last use is less than 30 days or 5half-lives before the administration of the investigational drug, whichever islonger.

5. Unable or unwilling to supplement vitamin A during the trial;

6. History of multiple myeloma;

7. Ophthalmological examination results at the screening are consistent with vitamin Adeficiency;

8. Abnormal thyroid function test with clinical significance judged by theinvestigator;

9. Known or suspected systemic infection (viral, parasitic or fungal infection) within 14 days before screening;

10. History of past hepatitis B virus, hepatitis C virus, acquired immunodeficiencysyndrome or positive HBsAg, HCV-Ab, and HIV-Ab at the screening;

11. History of previous liver, heart or other organ transplantation or bone marrowtransplantation or expected transplantation within 1 year (except for the history ofcorneal transplantation or planned corneal transplantation);

12. History of bleeding or coagulation disorders (such as cirrhosis, malignanthematological disease, antiphospholipid antibody syndrome);

13. History of acute thrombosis within 6 months before screening (such as acutemyocardial infarction, acute cerebral infarction), or positive Leiden factor Vand/or prothrombin gene test;

14. History of malignant tumor within 5 years before screening (except for basal cellcarcinoma of the skin, radicalized squamous cell carcinoma of the skin, andcarcinoma in situ of the cervix);

15. Planned invasive cardiovascular surgery during the trial (such as coronary arterystent/coronary artery bypass, pacemaker placement, etc.); those who have undergonecardiovascular invasive surgery within 90 days before screening or have beenhospitalized due to heart failure;

16. History of alcohol abuse within 3 years before screening (definition of alcoholabuse: women drink ≥ 4 glasses/day or 8 glasses/week, men ≥ 5 glasses or 15glasses/week, where 1 glass = 14g of pure alcohol);

17. Expected survival period is less than 1 year;

18. Other situations that the investigator deems inappropriate to enter this trial; For ATTR-PN only:

19. Other known diseases that cause motor or sensory neuropathy (such as diabeticneuropathy, neuropathy related to autoimmune diseases, etc.);

20. Diagnosed with type 1 diabetes or type 2 diabetes for ≥ 5 years;

21. NYHA cardiac function classification is grade III or IV within 90 days beforescreening; For ATTR-CM only:

22. NYHA cardiac function classification is grade IV within 90 days before screening;

23. PND score is grade IIIa, IIIb or IV at the screening;

24. Suffering from other cardiomyopathies not caused by TTR (such as hypertensivecardiomyopathy, valvular heart disease, cardiomyopathy caused by ischemic heartdisease, etc.).