China-based Ractigen Therapeutics has published Phase I clinical data for RAG-17, an intrathecally delivered siRNA targeting SOD1 mRNA in patients with SOD1-mutant amyotrophic lateral sclerosis (ALS). The six-patient study, published in Nature Medicine, reported mean cerebrospinal fluid SOD1 protein reductions of 69% and plasma neurofilament light chain (NfL) reductions of 62% at Day 240, with no serious adverse events, representing one of the most comprehensive first-in-human datasets yet reported for an RNA interference therapy in ALS.
The open-label, dose-escalation investigator-initiated trial evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple intrathecal RAG-17 doses. Individual NfL nadirs reached 85% below baseline in certain participants, and exploratory data suggested disease stabilization or decelerated functional decline, with forced vital capacity maintained or improved in specific patients. Treatment-emergent adverse events were mild to moderate and transient.
RAG-17 uses Ractigen's proprietary SCAD delivery platform, which conjugates the siRNA duplex to an accessory oligonucleotide designed to improve CNS distribution following intrathecal administration. In cynomolgus monkeys, a single dose reduced lumbar spinal cord SOD1 mRNA by 91%, with silencing persisting for at least 72 days, suggesting the potential for substantially longer dosing intervals than current monthly intrathecal therapies.
Why target SOD1
SOD1-ALS arises from toxic gain-of-function mutations rather than enzymatic loss. Over 150 pathogenic variants drive motor neuron death through protein misfolding, aggregation, mitochondrial dysfunction, and non-cell-autonomous glial toxicity — mechanisms unrelated to the protein's antioxidant function. The direct therapeutic implication is protein reduction, making SOD1 mRNA one of the most target-validated loci in neurodegeneration.
That validation was formalized in 2023 when the US FDA granted accelerated approval to tofersen (Qalsody), an antisense oligonucleotide (ASO) developed by Biogen and Ionis Pharmaceuticals that silences SOD1 mRNA via RNase H-mediated degradation. Tofersen demonstrated measurable biomarker responses but its pivotal VALOR trial did not meet its primary functional endpoint, and monthly intrathecal administration imposes a significant burden. The confirmatory Phase III ATLAS study continues in presymptomatic SOD1 variant carriers.
The mechanistic distinction between ASOs and siRNA therapeutics is significant. ASOs operate stoichiometrically — one molecule engages one mRNA target. siRNA, by contrast, is loaded into the RNA-induced silencing complex (RISC), which cleaves mRNA catalytically, enabling a single RISC-siRNA complex to silence multiple transcripts. Preclinical comparisons have suggested this translates to greater potency and durability: studies in SOD1-G93A mouse models have reported that siRNA-ASO conjugates produced more potent and longer-lasting SOD1 silencing than tofersen-like ASOs, with superior survival extension.