RAG-17 siRNA for SOD1-ALS – First-in-Human Data Published in Nature Medicine

China's first siRNA therapy for SOD1-associated amyotrophic lateral sclerosis (ALS) — RAG-17 — demonstrates favorable safety and objective efficacy in first-in-human trial, marking a zero-to-one breakthrough in domestic precision therapy for ALS.

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis, and death typically within 3–5 years of diagnosis.[reference:28]

SOD1 gene mutations, which cause a toxic gain of function, account for approximately 10–20% of familial ALS cases and 1% of sporadic ALS cases.[reference:29] These patients experience rapid disease progression with extremely limited treatment options.

On July 15, 2026, a collaborative team from Beijing Tiantan Hospital (Professor Wang Yilong) and Ractigen Therapeutics (Professor Li Longcheng) published the first-in-human clinical data for RAG-17, a siRNA therapeutic targeting SOD1-ALS, in Nature Medicine.[reference:30]

This marks the first siRNA therapy for SOD1-ALS developed and clinically validated entirely by a Chinese team, filling a critical gap in domestic precision therapy for ALS.[reference:31]

The RAG-17 siRNA Platform

RAG-17 is a small interfering RNA (siRNA) designed to specifically and efficiently target and silence SOD1 gene mRNA expression.[reference:32]

The drug leverages Ractigen's proprietary SCAD™ (Smart Chemical-Assisted Delivery) platform, which enables efficient delivery of oligonucleotides into the central nervous system.[reference:33]

Key features of the SCAD™ platform:

• Enhanced CNS penetration — optimized oligonucleotide conjugation improves blood-brain barrier crossing and distribution within the CNS[reference:34]
• Durable target silencing — sustained SOD1 gene suppression with intermittent dosing[reference:35]
• Favorable safety profile — reduced off-target effects and immunogenicity

RAG-17 has received FDA Orphan Drug Designation and has been included in the NMPA CDE's "Patient-Centered Rare Disease Drug Development Pilot Program."[reference:36]

Preclinical Studies

Preclinical data published alongside the clinical results demonstrated:

• In SOD1G93A ALS mouse models — RAG-17 significantly delayed disease progression, protected motor function, and extended survival[reference:37]
• In cynomolgus monkeys — intrathecal administration achieved dose-dependent and durable SOD1 gene silencing in the CNS[reference:38]

First-in-Human Clinical Trial

The first-in-human study was a 6-patient, open-label, dose-escalation trial conducted at Beijing Tiantan Hospital.[reference:39]

Study Design

Parameter	Details
Lead Institution	Beijing Tiantan Hospital
Principal Investigator	Professor Wang Yilong
Number of Patients	6 SOD1-ALS patients
Administration	Intrathecal injection
Follow-up	240 days

Safety Results

RAG-17 demonstrated an acceptable safety and tolerability profile:[reference:40]

• Treatment-emergent adverse events occurred in 33% (2/6) of patients
• All adverse events were mild to moderate — muscle tremor (2 patients) and elevated alanine aminotransferase (1 patient)[reference:41]
• All adverse events resolved without sequelae[reference:42]
• No serious adverse events were reported[reference:43]

Efficacy Results

Key secondary endpoints showed compelling target engagement and disease modification:[reference:44]

• CSF SOD1 protein — reduced by 56–69% from baseline to day 240
• Plasma neurofilament light chain (NfL) — reduced by 52–62%, indicating slowed axonal degeneration
• Clinical outcomes — no patients required invasive mechanical ventilation or died by the end of the study[reference:45]

These biomarker data are particularly significant as they represent the first demonstration in a Chinese population that intrathecal siRNA administration can safely and effectively silence the SOD1 gene.[reference:46]

Comparison with Tofersen

Tofersen, an antisense oligonucleotide (ASO) developed by Biogen, is the only other SOD1-targeting therapy approved for ALS. RAG-17 offers several potential advantages:

Feature	Tofersen (ASO)	RAG-17 (siRNA)
Mechanism	RNase H-mediated mRNA degradation	RISC-mediated mRNA cleavage
Potency	Standard	Higher (catalytic mechanism)
Dosing frequency	Multiple loading doses	Potentially less frequent
Origin	Imported	China-developed

As the research team noted: "RAG-17, as the first siRNA drug for SOD1-ALS to enter human clinical trials globally, provides a new treatment option with improved accessibility for Chinese patients."[reference:47]

Phase II Trial: Enrollment Completed

On August 6, 2026, Ractigen Therapeutics announced that the Phase II clinical trial of RAG-17 had completed enrollment and first dosing of all subjects.[reference:48]

The Phase II study (NCT06556394) is a randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of repeated intrathecal RAG-17 administration. Participating centers include:[reference:49]

• Beijing Tiantan Hospital (Professor Wang Yilong)
• Second Affiliated Hospital of Zhejiang University School of Medicine (Professor Wu Zhiying)
• West China Hospital of Sichuan University (Professor Shang Huifang)
• Fujian Medical University Union Hospital (Professor Zou Zhangyu)
• The First Affiliated Hospital of Sun Yat-sen University (Professor Zeng Jinsheng)

Dr. Li Longcheng, founder and CEO of Ractigen Therapeutics, commented: "The completion of enrollment and first dosing in the Phase II trial marks a critical milestone in RAG-17's clinical development. Based on the positive data from the Phase I single-ascending-dose study — demonstrating efficient CSF SOD1 protein suppression and neurofilament light chain improvement — we are now taking a decisive step toward bringing this breakthrough therapy to ALS patients."[reference:50]

Significance for Chinese Patients

This breakthrough has particular significance for Chinese ALS patients:

• First domestic precision therapy — fills a critical gap in SOD1-ALS treatment options[reference:51]
• Improved accessibility — addresses challenges of drug availability, cost, and potential ethnic differences associated with imported therapies[reference:52]
• Platform validation — establishes the SCAD™ delivery platform for future CNS-targeted RNA therapies[reference:53]