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

NCT07080801 | Not Yet Recruiting Early Phase 1 DMC

• 1 other identifier: HX-A-2025021
• Study Type: interventional
• Target: 6
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Amyotrophic Lateral Sclerosis (ALS)

Keywords

RAG-21; FUS gene mutations

Outcome Measures

Primary Outcomes (1)

• AE&SAE

  Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) after RAG-21 treatment.

  15±1, 29±2, 57±3, 85±3, 113±3, 141±3, 169±3, 197±7days after treatment

Study Arms (1)

RAG-21

EXPERIMENTAL

Drug: RAG-21

Interventions

RAG-21 DRUG

Intrathecal bolus administration of RAG-21 will be initiated at a dose of 120 mg, prepared with a dedicated solvent into a 10 mL sterile aqueous solution. Dosing will occur every 2 weeks, with the dose escalating to 180 mg after 3 administrations. Subsequently, the dosing interval will be extended to every 4 weeks. The investigator will then select an optimal dose from the completed dose cohorts or continue dose escalation until the maximum tolerated dose (MTD) is reached, with a predefined maximum dose of 210 mg. For continued treatment, the investigator-determined optimal dose will be administered as a fixed dose every 4 weeks, with a total treatment duration of 6 months (8 administrations).

RAG-21

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-75 years, gender unlimited.
• Clearly identify amyotrophic lateral sclerosis (ALS) patients with FUS gene mutations (known FUS mutation sites and reported disease progression).
• Forced vital capacity (FVC) during screening period ≥ 50% of expected lung capacity.
• ALS patients diagnosed according to the Gold Coast criteria (2020) with limb-onset weakness.
• The patient or their legal representative clearly understands and voluntarily participates in the study and signs an informed consent form.
• 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.

You may not qualify if:

• FUS mutation sites located within nucleotides 928-970 (calculated from the translation of FUS protein).
• Patients who have previously received or are currently receiving Ulefnersen treatment.
• Human immunodeficiency virus (HIV) test positive or positive test history.
• Patients with active hepatitis C or hepatitis B infection.
• Other experimental drugs used within one month or within five drug half-lives.
• Lumbar diseases and deformities.
• 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.
• Other psychiatric disorders diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria, or obvious suicidal intentions.
• 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).
• Permanent and sustained dependence on ventilator assisted ventilation.
• History of combined alcohol and drug abuse.
• Pregnant, lactating, or potentially pregnant patients, as well as those planning to conceive.
• Patients participating in other clinical trials or applying other biologics, drugs, or devices under study.
• Patients who have received any vaccination within 28 days.
• Those who can't complete follow-up due to other reasons.

Sponsors & Collaborators

• Beijing Tiantan Hospital: lead

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Central Study Contacts

Xinru Liu

CONTACT

13521588395; liuxinru0826@163.com

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Vice-President of Beijing Tiantan Hospital,Chief Scientist of Neurology Center

Study Record Dates

• First Submitted: July 6, 2025
• First Posted: July 23, 2025
• Study Start: August 1, 2025
• Primary Completion: August 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: July 23, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share