Development of self-delivering RNAi targeted to PTEN for treatment of spinal cord injury

对啮齿类动物轴突再生和恢复的研究表明， 并不是硬连线的，“学习”可以发生在脊髓回路中。化合物， 轴突再生和发芽有助于脊髓的可塑性， 至少在啮齿类动物中，可以改善创伤性损伤的恢复。内在的信号， 与正常神经元分化发挥了重要作用，防止轴突 再生已经鉴定了几种再生的内在负调节剂 通过对基因敲除小鼠的研究。抑制PTEN蛋白的合成可以 促进成年啮齿动物的轴突再生和运动功能恢复。一直 在SCI研究中，最有希望的目标缺乏翻译， 因此，我们决定创造一种具有治疗开发潜力的化合物。 我们选择了自递送RNA干扰（sd-rxRNAi）技术，因为 体内递送至中枢神经系统的简单性和经证实的功效。BA- 434作为一种新的sd-rxRNA，靶向编码PTEN的mRNA并抑制 PTEN蛋白的表达。该基因与大鼠、猪和人具有同源性， 从我们筛选的20个中选出我们建议进一步开发BA-434， 开展IND使能安全性和有效性实验，将这些发现转化为 临床研究我们将优化BA-434的稳定性，以及在脊髓中的剂量和功效 伤害模型我们还将确认猪脊髓中的适当药物递送， 猪脊髓的尺寸更接近于人脊髓的尺寸。的 拟议的研究将构成非GLP安全性和有效性研究的基础， 一个IND申请。

Studies on axon regeneration and recovery in rodents have revealed that the spinal cord is not hard wired and “learning” can occur in spinal cord circuits. Compounds that elicit axonal regeneration and sprouting help plasticity in the spinal cord and dramatically improve recovery from traumatic injury, at least in rodents. Intrinsic signals that progress with normal neuronal differentiation play a significant role in preventing axon regeneration. Several intrinsic negative regulators of regeneration have been identified through studies of knock-out mice. Suppression of synthesis of PTEN protein can promote axon regeneration and recovery of motor function in adult rodents. There has been a concerning lack of translation in SCI research for the most promising targets, and therefore we decided to create a compound with potential for therapeutic development. We chose the technology of self-deliverable RNA interference (sd-rxRNAi) because of the simplicity and proven efficacy of in vivo delivery to the central nervous system. BA- 434 as a novel sd-rxRNA that targets mRNA encoding PTEN and suppress the expression of PTEN protein. It has sequence homology to rat, pig and human, and was selected from 20 that we screened. We propose to further development of BA-434 and carry out IND-enabling safety and efficacy experiments to translate these findings to clinical study. We will optimize stability of BA-434, and dose and efficacy in spinal cord injury models. We will also confirm appropriate drug delivery in pig spinal cord because the size of pig spinal cord better approximates the size of human spinal cord. The proposed research will form the basis of non-GLP safety and efficacy studies in support of an IND application.