Anavex Life Sciences Corp., 51 West 52nd Street, 7th floor, New York, NY 10019, USA; Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322.
Anavex Life Sciences Corp., 51 West 52nd Street, 7th floor, New York, NY 10019, USA.
Pharmacol Biochem Behav. 2019 Dec;187:172796. doi: 10.1016/j.pbb.2019.172796. Epub 2019 Nov 5.
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剂 MECP2 的突变有关。目前，该疾病尚无有效治疗方法。尽管 RTT 遗传学和神经生物学方面最近取得了进展，但大多数药物开发计划都集中在针对 IGF-1 途径的化合物上，目前尚未完成关键性试验。因此，测试可以改善 RTT 临床表现的新型药物是当务之急。ANA VEX2-73（blarcamesine）是一种西格玛-1 受体激动剂和毒蕈碱受体调节剂，具有良好的安全性记录，并有初步证据表明对阿尔茨海默病患者有效。其在钙稳态和线粒体功能中的作用，是导致 RTT 病理过程和代偿机制的细胞功能，使 blarcamesine 成为该疾病的一个有趣的候选药物。MECP2 缺失的小鼠具有一系列类似于人类综合征的生理和神经异常。我们使用两阶段方法，在携带一个 Mecp2 无效等位基因的雌性杂合子小鼠（HET）中测试了 blarcamesine，采用了适合年龄的测试。在较年轻和较年长的成年小鼠中给予该药物，可改善与 RTT 相关的多种运动、感觉和自主神经表型。后者包括运动协调和平衡、听觉和视觉反应、后肢扣紧和呼气暂停。与之前的动物和人类研究一致，blarcamesine 在这种 RTT 小鼠模型中也表现出良好的安全性。正在进行与 blarcamesine 治疗 RTT 的临床研究。
