Rescue of respiratory and cognitive impairments in Rett Syndrome mice using NLX-101, a selective 5-HT receptor biased agonist.

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene encoding the methyl-CpG-binding protein 2 (MECP2). Impaired function of this transcriptional regulator leads to profound neurological defects, among which respiratory distress, motor function and cognitive disorders are prominent. Despite great advances in understanding RTT neurobiology, therapies that can meaningfully improve patients' symptoms are still needed. Here, we focused on 5-HT receptor-mediated serotonergic signaling as a potential therapeutical route for RTT. We report the effects of a drug candidate, NLX-101, a highly selective, biased agonist of 5-HT post-synaptic receptors at brainstem and cortical regions, on key phenotypes of RTT. Unrestrained whole-body plethysmography studies confirmed and extended the previous observation that single i.p. administration of NLX-101 dose-dependently reduced the occurrence and length of apneic events in Mecp2 heterozygous female mice and largely corrected respiratory irregularity. Although no preservation of motor function was observed, early onset chronic administration of NLX-101 entirely prevented the cognitive deficits of the Mecp2 mice both in the short and the long-term memory paradigms of the Novel Object Recognition upon 10 weeks of treatment, an effect that was maintained throughout animals' age. Similar effects were observed in the Fear Conditioning paradigm, with treated Rett mice performing as well as wild-type controls, highlighting the procognitive properties of NLX-101. This work provides compelling evidence of the therapeutic potential of targeting post-synaptic 5-HT receptors to improve cognitive function in patients with RTT while supporting its respiratory-rescue properties.