YOLT-204 in Patients With Hemoglobinopathies

Inclusion criteria

• Aged 3-17 years (inclusive); any sex.
• The subject and/or his/her legally authorized guardian/representative must fully understand the study and voluntarily sign a written informed-consent form.
• Karnofsky Performance Status (KPS) ≥ 70 (if ≥ 16 years old) or Lansky Performance Scale (LPS) ≥ 70 (if < 16 years old).
• Detailed medical records of red-cell transfusions during the 2 years before informed-consent signature must be available, including volume or units transfused and pre-/post-transfusion red-cell and hemoglobin levels.
• No severe hematopoietic dysfunction; cardiac, pulmonary, hepatic, and renal function essentially normal.
• Coagulation: international normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × upper limit of normal (ULN).
• Renal function: serum creatinine ≤ 1.5 × ULN; if creatinine > 1.5 × ULN, calculated creatinine clearance > 50 mL/min by the Schwartz formula.
• Hepatic function: alanine aminotransferase (ALT) ≤ 3 × ULN and aspartate aminotransferase (AST) ≤ 3 × ULN.
• Cardiac function: left-ventricular ejection fraction (LVEF) ≥ 50 %.
• Good compliance; willing to adhere to visit schedules, study procedures, laboratory tests, and other protocol requirements.
• Agrees to use at least one highly effective contraceptive method from informed-consent signature through the end of the main study (Week 52 visit).
• Willing to participate in long-term follow-up.
• Screening genotype shows HbSS or HbSβ0; prior reports acceptable if assessed as adequate by the investigator.
• If on L-glutamine, regimen must have been stable for ≥ 3 months before study-drug administration; if on hydroxyurea, must have discontinued ≥ 8 weeks before study-drug administration.
• Meets severe SCD criteria: despite optimal supportive therapy (including, but not limited to, analgesics and hydroxyurea), at least two of the following events occurred in the 12 months before screening:
• Severe intermittent acute pain requiring healthcare-provider management;
• Acute chest syndrome with new pulmonary infiltrate on chest imaging plus pneumonia-like symptoms, pain, or fever;
• Splenic sequestration crisis manifested by enlarged spleen, left upper-quadrant pain, and acute Hb drop > 20 g/L.

Exclusion criteria

• 1.History of multiple drug allergies or hypersensitivity to oligonucleotides or lipid nanoparticles (LNP).

2.Clinically significant active bacterial, viral, fungal, or parasitic infection at screening, as judged by the investigator.

3.White blood cell (WBC) count < 3 × 10⁹/L and/or platelet count < 100 × 10⁹/L at screening.

4.Uncorrected bleeding diathesis. 5.Massive splenomegaly at screening (spleen edge below the umbilicus or > 4 cm below the costal margin) deemed by the investigator to preclude enrollment.

6.Serum ferritin ≥ 5 000 ng/mL, or MRI T2* evidence of severe cardiac or hepatic iron overload.

7.Positive for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus antibody, anti-HIV antibody, or specific anti-Treponema pallidum antibody.

8.Prior hematopoietic stem-cell transplantation, gene therapy, or gene-editing therapy.

9.Participation in another clinical trial and receipt of investigational product within 3 months before first dose of study drug.

10.Current or prior malignancy, myeloproliferative disorder, or immunodeficiency disease.

11.Severe psychiatric illness precluding cooperation; clinically significant pulmonary hypertension requiring medical intervention; recent malaria; first-degree relative with hematologic malignancy.

12.Positive pregnancy test, pregnancy, or lactation in female subjects at screening.

13.Any condition (past or present) that, in the investigator's opinion, could confound results, compromise participation, or render the patient unsuitable for the study.

14.Use within 3 months before study drug: erythropoietin (EPO), thalidomide, hydroxyurea, luspatercept, or similar agents.

15.In subjects ≥ 12 years, abnormal transcranial Doppler (TCD) with middle cerebral or internal carotid artery velocity ≥ 200 cm/s.

16.History of moyamoya disease or imaging findings consistent with moyamoya at screening, assessed by the investigator as conferring bleeding risk.