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FDA Gives Clearance for Phase 1/2 Trial of Novel TRIM72 Agent in ALS
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Key Takeaways
- SNUG01, a TRIM72-targeted gene therapy, received FDA clearance for phase 1/2 trials in ALS, focusing on safety and efficacy.
- The investigational therapy uses AAV vectors to deliver the TRIM72 gene, enhancing neuronal repair and reducing oxidative stress.
Backed by promising early data and mechanistic insights, SNUG01 enters clinical trials as the first TRIM72-based gene therapy candidate for ALS.
Jia Yichang, PhD
According to a recent announcement, the FDA has cleared SineuGene Therapeutics investigational new drug application (IND) to test SNUG01, a tripartite motif protein 72 (TRIM72)-targeted gene therapy, in patients with amyotrophic lateral sclerosis (ALS). The phase 1/2 study, the first such to test a TRIM72-targeted approach in ALS, will primarily focus on safety, tolerability, and preliminary efficacy, testing several different escalating doses of the agent.1
SNUG01 is an investigational therapy that uses adeno-associated virus (AAV) vectors to deliver the human TRIM72 gene intrathecally, aiming to enhance neuronal membrane repair, reduce oxidative stress, and restore mitochondrial function. Currently, it is the only TRIM72-targeted therapy in clinical development for ALS. Unlike mutation-targeting gene therapies, SNUG01 leverages multiple neuroprotective mechanisms, offering a critical advantage for most patients with sporadic forms of ALS, according to SineuGene.
The only clinical data regarding SNUG01 came from a small-scale, investigator-initiated trial led at Peking University Third Hospital, in Beijing, China. Overall, the study featured 6 patients with the disease, including 1 Caucasian patient. Findings announced in September 2024 showed that none of the participants experienced dose-limiting toxicity (DLT) events as well as drug-related adverse events above Grade 2 during the 28-day DLT observation period. Of note, both clinical function and biomarker assessments suggested potential therapeutic effects of SNUG01.2
"The results from this trial reinforce the potential of SNUG01 as a new treatment for ALS," Jia Yichang, PhD, founder of SineuGene and professor at Tsinghua University, said in a statement at the time. "We are deeply grateful to Professor Fan and his team at PUTH for their invaluable contributions to this study. We also want to express our heartfelt thanks to the patients and their families for their trust and participation. Their support has been critical to advancing this important research."
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Yichang was among the main researchers who originally identified TRIM72 as a multifunctional neuroprotectant. Published in 2024, preclinical research done by Yichang et al discovered that loss-of-function of TRIM72 significantly accelerates the ALS-like phenotypes in FUS-R521C knockout mouse spinal cord, which is a hallmark, like mislocalized TDP-43, shown in patients with ALS and other neurodegenerative diseases. Furthermore, the study demonstrated that Retriever/Commander complrex promotes membrane repair function mediated by TRIM72.3
In the study, Yichang and colleagues isolated spinal cords from wildtype and FUS-R521C KI mice at 2 age points, 1.5 and 7 months, and applied for RNA-sequencing. Compared with wildtype controls, only a few genes were differentially expressed in the mutant FUS spinal cords. Among them, TRIM72 was the only differentially expressed gene at both time points, with about 8-10 times upregulation in the mutant spinal cord. To examine the upregulation of TRIM72 in motor neurons, the investigators cultured the motor neurons from wildtype and FUS-R521C mutant animals and confirmed the motor neuron upregulation.
Additional data from the preclinical study revealed that TRIM72 is significantly upregulated in neural tissues–including the spinal cord, motor cortex, cerebellum, and hippocampus–of FUS-R521C mutant mice compared with wild-type controls, while expression in non-neural tissues remained unchanged. A unique, high-molecular-weight form of TRIM72 was detected specifically in the mutant neural tissue, not present in wild-type or non-neural samples, suggesting a FUS mutation-dependent, brain-specific alteration. This large TRIM72 form appeared structurally stable, as it was resistant to denaturation by DTT, urea, and ß-mercaptoethanol, indicating it likely forms through non-disulfide-based interactions.
