Rett syndrome (RTT) is a severe neurodevelopmental disorder that is associated in most cases with mutations in the transcriptional regulator MECP2. At present, there are no effective treatments for the disorder. Despite recent advances in RTT genetics and neurobiology, most drug development programs have focused on compounds targeting the IGF-1 pathway and no pivotal trial has been completed as yet.

Thus, testing novel drugs that can ameliorate RTT's clinical manifestations is a high priority. ANAVEX2-73 (blarcamesine) is a Sigma-1 receptor agonist and muscarinic receptor modulator with a strong safety record and preliminary evidence of efficacy in patients with Alzheimer's disease. Its role in calcium homeostasis and mitochondrial function, cellular functions that underlie pathological processes and compensatory mechanisms in RTT, makes blarcamesine an intriguing drug candidate for this disorder.

Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. We tested blarcamesine in female heterozygous mice carrying one null allele of Mecp2 (HET) using a two-tier approach, with age-appropriate tests. Administration of the drug to younger and older adult mice resulted in improvement in multiple motor, sensory, and autonomic phenotypes of relevance to RTT. The latter included motor coordination and balance, acoustic and visual responses, hindlimb clasping, and apnea in expiration. In line with previous animal and human studies, blarcamesine also showed a good safety profile in this mouse model of RTT. Clinical studies in RTT with blarcamesine are ongoing.

雷特综合征 (RTT) 是一种严重的神经发育障碍，在大多数情况下与转录调节因子MECP2的突变有关。目前，该疾病尚无有效的治疗方法。尽管 RTT 遗传学和神经生物学最近取得了进展，但大多数药物开发项目都集中在针对 IGF-1 途径的化合物上，尚未完成任何关键试验。

因此，测试能够改善 RTT 临床表现的新药是当务之急。 ANAVEX2-73 (blacamesine) 是一种 Sigma-1 受体激动剂和毒蕈碱受体调节剂，具有良好的安全记录和对阿尔茨海默病患者有效的初步证据。其在钙稳态和线粒体功能、RTT 病理过程和补偿机制基础的细胞功能中的作用，使 blacamesine 成为治疗这种疾病的有趣候选药物。

缺乏 MeCP2 的小鼠会出现一系列模仿人类综合症的生理和神经异常。我们使用两层方法和适合年龄的测试，在携带Mecp2无效等位基因 (HET) 的雌性杂合小鼠中测试了布拉卡美辛。对年轻和年长的成年小鼠施用该药物可改善与 RTT 相关的多种运动、感觉和自主表型。后者包括运动协调和平衡、听觉和视觉反应、后肢紧握和呼气时呼吸暂停。与之前的动物和人体研究一致，blacamesine 在 RTT 小鼠模型中也显示出良好的安全性。 blacamesine 的 RTT 临床研究正在进行中。