XL20 Extends ALS Mouse Survival at 50 mg/kg by Targeting TDP-43
Updated
Updated · Nature.com · Jul 3
XL20 Extends ALS Mouse Survival at 50 mg/kg by Targeting TDP-43
1 articles · Updated · Nature.com · Jul 3
Summary
A brain-penetrant small molecule called XL20 improved motor performance and extended survival in TDP-43 p.Ala315Thr ALS mice when dosing began at day 45 and continued at 50 mg/kg three times weekly.
Screening of 190,337 compounds identified XL20 as a binder of TDP-43’s conserved 320–340 region, where it reduced toxic condensation and aggregation without disrupting key RNA splicing activity.
In mice and human iPSC-derived motor neurons, XL20 lowered cytoplasmic and mitochondrial TDP-43, restored mitochondrial function, and reduced motor neuron loss, gait deficits and insoluble TDP-43 fragments.
Safety tests found the 50 mg/kg regimen was tolerated, with rapid CNS penetration and brain-to-plasma ratios above 0.5, while a 200 mg/kg single dose caused one death in five mice.
The study positions TDP-43’s conserved region as a drug target for ALS and potentially other TDP-43-linked neurodegenerative diseases, though XL20 remains a preclinical candidate.
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Overview
Amyotrophic Lateral Sclerosis (ALS) is a progressive and devastating neurodegenerative disease that attacks nerve cells, leading to muscle weakness, paralysis, and death within a few years of diagnosis. Current therapies offer only modest benefits, highlighting the urgent need for better treatments. Recently, preclinical studies introduced XL20, an experimental small-molecule drug designed to target TDP-43, a protein implicated in about 97% of ALS cases. XL20 shows remarkable promise by addressing a fundamental cause of ALS, offering hope for more effective therapies in the future.