Study on the Safety and Efficacy of RAG-21 in the Treatment of Amyotrophic Lateral Sclerosis Patients With FUS Gene Mutations

Study on the Safety and Efficacy of RAG-21 in the Treatment of Amyotrophic Lateral Sclerosis Patients With FUS Gene Mutations

Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disease that remains incurable, with limited existing therapies or drugs available. Familial ALS can be caused by mutations in various genes. In Asia, mutations in the FUS gene are relatively common among early-onset familial ALS patients. Reducing the levels of toxic FUS protein may be an effective therapeutic approach for such ALS patients without causing side effects.

RAG-21 is a small interfering ribonucleic acid (siRNA) with a molecular weight of 20 kDa. Through the RNA interference mechanism, it targets the FUS gene, recognizes the corresponding mRNA, and mediates its degradation, thereby downregulating FUS gene expression and reducing toxic FUS protein levels. Accordingly, this project plans to conduct a single-center, dose-escalation clinical study aimed at evaluating the safety, tolerability, and pharmacokinetics of intrathecal bolus administration of RAG-21 in ALS patients carrying FUS gene mutations.

Inclusion Criteria:

1. Age 18-75 years, gender unlimited.
2. Clearly identify amyotrophic lateral sclerosis (ALS) patients with FUS gene mutations (known FUS mutation sites and reported disease progression).
3. Forced vital capacity (FVC) during screening period ≥ 50% of expected lung capacity.
4. ALS patients diagnosed according to the Gold Coast criteria (2020) with limb-onset weakness.
5. The patient or their legal representative clearly understands and voluntarily participates in the study and signs an informed consent form.
6. The subjects (including male subjects) have no family planning throughout the entire study and within 3 months after, voluntarily take effective contraceptive measures and without any plans to donate sperm or ovum.

Exclusion Criteria:

1. FUS mutation sites located within nucleotides 928-970 (calculated from the translation of FUS protein).
2. Patients who have previously received or are currently receiving Ulefnersen treatment.
3. Human immunodeficiency virus (HIV) test positive or positive test history.
4. Patients with active hepatitis C or hepatitis B infection.
5. Other experimental drugs used within one month or within five drug half-lives.
6. Lumbar diseases and deformities.
7. ALS with bulbar-onset symptoms, or suffering from other diseases known to be related to motor neuron dysfunction, which may confuse or blur the diagnosis of ALS.
8. Other psychiatric disorders diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria, or obvious suicidal intentions.
9. Combined with severe liver dysfunction, renal dysfunction, or severe heart dysfunction (severe liver dysfunction refers to alanine aminotransferase (ALT) value ≥ 2.0 times the upper limit of normal value or aspartate aminotransferase (AST) value ≥ 2.0 times the upper limit of normal value; severe renal dysfunction refers to creatinine (CRE) ≥ 1.5 times the upper limit of normal value or estimated glomerular filtration rate (eGFR) < 40mL/min/1.73m^2; severe heart dysfunction refers to New York College of Cardiology (NYHA) 3-4 levels).
10. Permanent and sustained dependence on ventilator assisted ventilation.
11. History of combined alcohol and drug abuse.
12. Pregnant, lactating, or potentially pregnant patients, as well as those planning to conceive.
13. Patients participating in other clinical trials or applying other biologics, drugs, or devices under study.
14. Patients who have received any vaccination within 28 days.
15. Those who can't complete follow-up due to other reasons.