BPN14770 For Treatment of Fragile X Syndrome

主要合作者开发了一种磷酸二酯酶-4D(PDE4D)的小分子抑制剂(BPN14770)。在FXS中，FMR1基因内CGG重复序列的大量扩张导致其沉默，随后编码蛋白丢失。这种蛋白质产物FMRP在大脑中发挥调节作用，抑制对突触功能至关重要的mRNA的翻译。FMRP的缺失会导致cAMP的产生减少，其他严格调控的基因过度表达，以及FXS特有的突触功能障碍。通过抑制PDE4对cAMP信号的调制之前已经在FXS的果蝇模型中进行了测试，显示了拯救行为和结构表型的能力。FRAXA研究基金会在FXS的小鼠模型中测试了BPN14770，显示出行为活动和社交活动的增加，以及大脑cAMP水平的恢复。 该团队正在合作完成关于BPN14770的以下研究： -对幼年大鼠的IND直接毒理学和生殖毒性评估

The lead collaborators have developed a small molecule inhibitor (BPN14770) of phosphodiesterase-4D (PDE4D). In FXS, large expansions of CGG repeats within the FMR1 gene result in its silencing and subsequent loss of the encoded protein. This protein product, FMRP, plays a regulatory role in the brain, suppressing the translation of mRNA important for synaptic function. Loss of FMRP results in decreased production of cAMP, over-expression of otherwise tightly-regulated genes, and synaptic dysfunction characteristic of FXS. Modulation of cAMP signaling through PDE4 inhibition had previously been tested in fruit fly models of FXS, showing an ability to rescue behavioral and structural phenotypes. The FRAXA Research Foundation tested BPN14770 in mouse models of FXS, showing increases in behavioral activity and social interaction, as well as restoration of brain cAMP levels. The team is collaborating on the completion of the following studies on BPN14770: - IND-directed toxicology in juvenile rats with reproductive toxicity assessment