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GCN2 Inhibitors Alleviate CMT Symptoms
Patients with Charcot-Marie-Tooth (CMT) disease, caused by genetic alterations in tRNA loading, predominantly suffer from motor neuropathy. This manifests as debilitating muscle weakness, which can ultimately lead to immobility. Mouse models of CMT also exhibit this dysfunction and can be assessed using the ‘latency to fall’ test, a measure of muscle strength.
Research has shown that pharmacological inhibition of GCN2 mimics the effects observed in GCN2 knockout models, offering a promising therapeutic approach to alleviate symptoms in CMT patients.
GENETIC GCN2 DELETION
> Cross-breading mice
PHARMACOLOGICAL GCN2 INHIBITION
> Pathogenic mutants induce CMT in mouse models, recapitulating human disease
＞GCN2 inhibition does not affect onset of disease, but progression and aggressivity of disease
GCN2 INHIBITORS EFFICIENTLY CONTROL TUMOR GROWTH
> GCN2 inhibitor causes synthetic lethality in cancers with amino-acids deficit
GCN2I DAYS OF TREATMENT
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Advancement
Breakthroughs in GCN2 Inhibition
for Cancer and CMT
GCN2 Inhibitors Efficiently Control Tumor Growth
GCN2 activation is crucial for cancer cell survival, enhancing autophagy, controlling proliferation, and inhibiting apoptosis. Many cancers face amino acid shortages due to genetic alterations, leading to unloaded tRNA that relies on GCN2 to compensate.
Advancements in CMT Biology
Our GCN2 inhibitors show promising efficacy in Charcot-Marie-Tooth (CMT) models. Studies demonstrate early and late therapy responses, wash-out effects, and improvements in functional and electrophysiology metrics.
We also observe efficacy in genetically cross-bred mice with various mutations and AARS enzymes, confirming the mechanism of action through ATF4 modulation. These findings support the expansion potential of GCN2 inhibitors for both monoallelic and biallelic disorders, paving the way for innovative treatments for CMT.
