San Francisco-based Trace Neuroscience has dosed the first patients with TRCN-1023, an antisense oligonucleotide (ASO) targeting UNC13A protein restoration in amyotrophic lateral sclerosis (ALS), launching what the company describes as a coordinated global early-stage program. The announcement covers two parallel studies: the Phase I/II FUNCTION ALS trial, authorized in the UK and Netherlands, and LAUNCH ALS, an investigator-initiated trial underway in China in partnership with Tenacia Biopharmaceutical.
FUNCTION ALS is a randomized, double-blind, placebo-controlled study expected to enroll approximately 30 participants across North American and European sites, with 24 weeks of follow-up. Endpoints include safety, tolerability, pharmacokinetics, and pharmacodynamic activity, supplemented by biomarker analyses and digital movement and speech assessments. Eligible participants are aged 18–75, must have experienced symptom onset within the past two years, and must have slow vital capacity of at least 60%. Those carrying SOD1 or FUS mutations are excluded. LAUNCH ALS targets approximately 25 participants under consistent eligibility criteria. Trace Neuroscience anticipates expanding FUNCTION ALS to additional global regions later in 2026.
TRCN-1023 is administered intrathecally and binds directly to UNC13A messenger RNA, modulating its processing to promote formation of functional UNC13A protein — a synaptic regulator implicated in neuromuscular transmission.
Why UNC13A matters in ALS drug development
ALS is driven by the progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and death, typically within two to five years of diagnosis. Approved therapies — including riluzole, edaravone, and sodium phenylbutyrate-taurursodiol — modestly slow functional decline but do not halt neurodegeneration. The disease's heterogeneity has historically complicated target identification, but human genetic studies have increasingly pointed toward UNC13A as a broadly relevant vulnerability.
UNC13A encodes a presynaptic protein critical for neurotransmitter vesicle priming. Common variants in the UNC13A gene have been associated with ALS risk and survival in genome-wide association studies, and the protein's loss of function — driven in part by TDP-43 pathology, the hallmark of most ALS cases — disrupts synaptic transmission at the neuromuscular junction. Because TDP-43 dysfunction is present in approximately 97% of ALS cases regardless of genetic subtype, restoring UNC13A function represents a mechanistic intervention with unusually broad potential applicability. Trace Neuroscience's ASO approach targets this pathway directly by correcting aberrant UNC13A mRNA processing downstream of TDP-43 mislocalization.
This mechanism is distinct from SOD1-targeting ASOs such as tofersen (Qalsody), developed by Biogen, which received US FDA accelerated approval in 2023 but addresses only the roughly 2% of ALS patients carrying SOD1 mutations. The UNC13A strategy, if validated, would be applicable across sporadic and most familial ALS cases — a substantially larger population.