A Novel Therapeutic that Harnesses Microtubules to Promote Cavernous Nerve Regeneration after Radical Prostatectomy

根治性前列腺癌(RP)是一种治疗局限性前列腺癌的常用方法。 海绵体神经(CN)损伤导致勃起功能障碍(ED)的高风险。更新的， 保留神经的机器人手术并不能令人信服地改善RP术后的勃起功能(EF)结果。在……里面 此外，RP引起的ED通常对口服5型磷酸二酯酶治疗无效。 抑制剂(PDE5i)给患者带来了糟糕的治疗选择，这些选择具有侵入性，与副作用相关， 疗效有限，治标不治本。有一个真实而紧迫的需要 确定新的治疗策略来治疗与RP相关的ED。 作为CN损伤的结果，小体组织中神经元一氧化氮(NO)释放减少， 导致勃起的分子通路的主要激活剂。较低的NO释放水平会导致失败 在促进海绵体氧合的机制中，导致纤维化和海绵体平滑肌 细胞凋亡是EF恢复的潜在不可逆转的障碍，即使在CN再生后也是如此。自.以来 EF在CN损伤后48小时内受到影响，这一策略被称为“阴茎康复”，例如口服PDE5i 在RP后尽早开始给药，目的是增加基础躯体血流量和 保留阴茎结构，直到出现功能性CN再生。 基于CN损伤在RP后ED发生中的核心作用，我们的新治疗方法 战略利用siRNA技术靶向表达一种新发现的微管调节因子--fidgetin样蛋白 2(Fl2)促进CN再生。初步和已发表的研究表明，Fl2是一种负向调节因子 轴突生长和伤口修复；在第一阶段研究一种新的铅治疗配方(释放Fl2- SiRNA；siFi2)被鉴定为，当给进行双侧CN横断的大鼠注射时，可见 CN再生，改善勃起功能。与正在研究的其他临床前策略相比 对于CN再生，SiFi2在促进CN再生、诱导改革方面异常快速和有效 神经组织跨越几毫米的间隙，并导致勃起功能的显著改善 最早在横断后两周。然而，这一策略和其他正在探索的临床前策略 CN再生可能无法恢复最佳EF，因为阴茎结构可能发生不可逆转的变化 在神经再生所需的时间内。因此，我们将探索一种双管齐下的方法来加强 神经再生和减轻躯体组织损伤，同时神经正在愈合。 这一第二阶段提案的目标是启动研究新药申请(IND)的步骤 备案，超过三个具体目标：(1)评价口服PDE5i增强SiF2治疗的能力； (2)在合同制造组织(CMO)启动GMP启动计划；以及(3)评估 在CMO生产的SiFi2。

Radical prostatectomy (RP) is a commonly used treatment option for localized prostate cancer, which carries a high risk for development of erectile dysfunction (ED) because of cavernous nerve (CN) injury. Even newer, nerve-sparing, robotic procedures do not convincingly improve erectile function (EF) outcomes after RP. In addition, ED resulting from RP is often refractory to treatment by orally administered phosphodiesterase type 5 inhibitors (PDE5i) leaving patients with poor treatment options that are invasive, associated with side-effects, have limited efficacy, and treat symptoms rather than being curative. There is a real and urgent need to identify new therapeutic strategies to treat ED associated with RP. As a consequence of CN injury there is decreased neuronal nitric oxide (NO) release in corporal tissue, the primary activator of the molecular pathways leading to an erection. Lower levels of NO release lead to a failure in mechanisms that facilitate cavernosal oxygenation, resulting in fibrosis and cavernosal smooth muscle apoptosis, which then act as potentially irreversible barriers to recovery of EF, even after CN regeneration. Since EF is impacted within 48 hours of CN injury, a strategy called “penile rehabilitation” such as oral PDE5i administration, is initiated as early as possible after RP with the goal of raising basal corporal blood flow and preserving penile architecture until there is functional CN regeneration. Based on the central role that CN injury plays in the development of ED following RP, our novel treatment strategy uses siRNA technology to target expression of a newly discovered microtubule regulator, Fidgetin-like 2 (FL2) to enhance CN regeneration. Preliminary and published studies suggest FL2 is a negative regulator of axon growth and wound repair; in Phase I studies a novel lead therapeutic formulation (a “wafer” releasing FL2- siRNA; SiFi2) was identified that when administered to rats undergoing bilateral CN transection resulted in visible CN regeneration and improved erectile function. Compared to other pre-clinical strategies under investigation for CN regeneration, SiFi2 is exceptionally fast and effective in promoting CN regeneration, inducing reformation of nerve tissue across a gap of several millimeters, and resulting in significant improvement in erectile function as early as two weeks following transection. However, this and other preclinical strategies being explored for CN regeneration may fail to recover optimal EF because irreversible changes may occur in penile architecture during the time it takes for nerve regeneration. Therefore, we will explore a two-pronged approach enhancing nerve regeneration and mitigating corporal tissue damage while the nerve is healing. The goal for this Phase II proposal is to initiate steps towards an Investigational New Drug application (IND) filing, over three specific aims: (1) evaluate the ability of orally administered PDE5i to enhance SiFi2 treatment; (2) initiate a GMP start-up program at a contract manufacturing organization (CMO); and (3) evaluate toxicity of SiFi2 produced at the CMO.