Exploring Nasal Drop Therapy With Small Extracellular Vesicles for ALS

Inclusion Criteria:

• Age: 18-80 years, inclusion of both genders;

• Disease duration: ≥6 months and ≤2 years (counted from the onset of any ALSsymptoms);

• Subjects must meet the El Escorial revised criteria (2000) for the diagnosis of ALS,with a diagnosis of Definite ALS, Probable ALS, Probable laboratory-supported ALS,or Possible ALS;

• A score of ≥2 on each item of the revised ALS Functional Rating Scale (ALSFRS-R),with a score of 4 for items related to dyspnea, orthopnea, and respiratoryinsufficiency;

• BMI: Between 18 and 30 kg/m²;

• Subjects must have a baseline forced vital capacity percentage (%FVC) ≥70%;

• Allowed concomitant treatments: Oral administration of riluzole/edaravone atstandard doses for ≥30 days; regular intravenous edaravone with planned sequentialoral treatment. During the trial and follow-up period, the dosage and type ofconcomitant medications must remain unchanged;

• Subjects of childbearing potential must use appropriate and effective contraceptionfrom 2 weeks prior to trial enrollment until the end of the follow-up period;

• The subject or legal representative must be able to sign an informed consent formand comply with the study requirements for medication administration and follow-up.

Exclusion Criteria:

• Diagnosed as non-ALS based on clinical presentation and available clinicalexaminations (e.g., neurophysiological tests, MRI, or other imaging, laboratorytests);

• Abnormal nasal anatomy, nasal cavity damage, severe rhinitis, or nasal diseaseaffecting the administration of the study drug;

• Requires nasal insertion of a gastric tube;

• Peripheral venous hemoglobin (HGB) < 100 g/L, absolute neutrophil count (NEUT) < 1.5×10^9/L, platelet count (PLT) < 100×10^9/L, white blood cell count (WBC) < 4.0×10^9/L or ≥ 12×10^9/L, serum albumin < 30 g/L; alanine aminotransferase (ALT)and aspartate aminotransferase (AST) ≥ 3× the upper limit of normal (ULN);

• Severe renal insufficiency: Glomerular Filtration Rate (GFR) < 30 mL/min (Cockcroft-Gault formula), or other known severe renal diseases;

• Positive for hepatitis B surface antigen, e antigen, e antibody, or core antibodycombined with positive hepatitis B virus DNA; positive for hepatitis C virusantibody; positive syphilis serum antibody; or positive for HIV antibody;

• History of acute myocardial infarction or interventional treatment within the last 6months, or heart failure (classified as NYHA III-IV);

• Presence of severe localized or systemic infection, immunodeficiency, or currentlytaking immunosuppressants;

• Concurrent severe systemic diseases such as immunodeficiency diseases, coagulationdisorders, or malignancies;

• Vaccination within 1 month prior to the first administration or during the studyuntil the end of follow-up;

• Known allergy to the drugs used in this study or similar drugs;

• Participation in another study and administration of an investigational productwithin the last 3 months;

• Contraindications to MRI (e.g., presence of metal implants) or inability to tolerateMRI (e.g., claustrophobia);

• Pregnant or breastfeeding women, or women of childbearing potential who cannot orare unwilling to use appropriate contraception;

• Unwillingness or inability to comply with the procedures required by the protocol;

• Any other conditions deemed unsuitable for inclusion by the investigators.