Tetra Discovery Partners, Inc, Grand Rapids, MI, USA.
FRAXA-DVI, FRAXA, Santiago, Chile.
Sci Rep. 2017 Nov 7;7(1):14653. doi: 10.1038/s41598-017-15028-x.
Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling.
脆性 X 综合征（FXS）患者由于 X 连锁的脆性 X 智力低下 1 基因（FMR1）沉默而表现出智力障碍和自闭症谱系障碍。环磷酸腺苷代谢失调是患者以及小鼠和果蝇 FXS 模型中的一致发现。因此，我们探讨了 BPN14770（一种早期人类临床试验中的典型磷酸二酯酶 4D 负变构调节剂（PDE4D-NAM））是否可能为 FXS 模型中的小鼠提供治疗益处。在成年雄性 fmr1 C57Bl6 敲除小鼠中，每天用 BPN14770 治疗 14 天可减轻过度觉醒，改善社交互动，并改善筑巢和埋大理石等自然行为以及树突棘形态。用 BPN14770 治疗的对照 C57Bl6 小鼠的行为评分没有下降。停药两周后，BPN14770 的行为益处仍然存在。因此，BPN14770 可能对治疗脆性 X 综合征和其他 cAMP 信号降低的疾病有用。
