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

一种利用微管促进根治性前列腺切除术后海绵体神经再生的新疗法

• 批准号: 10488264
• 负责人: Lisa Ann Baker
• 金额: $ 74.48万
• 依托单位: MICROCURES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488264
• 关键词: Apoptosis; Architecture; Autopsy; Bilateral; Biological Assay; Blood Preservation; Blood flow; Chemistry; Clinical Chemistry; Comparative Histology; Contracts; Development; Erectile dysfunction; Evaluation; Failure; Fibrosis; Formulation; Gene Expression; Goals; Hematology; Histologic; Hour; Investigation; Investigational New Drug Application; Lead; Malignant neoplasm of prostate; Microtubules; Modeling; Molecular; Nerve; Nerve Regeneration; Nerve Tissue; Neurons; Nitric Oxide; Oral; Outcome; Pathway interactions; Patients; Peripheral nerve injury; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Procedures; Publishing; Radical Prostatectomy; Rattus; Recovery; Refractory; Rehabilitation therapy; Reporting; Robotics; Role; Small Interfering RNA; Smooth Muscle; Technology; Therapeutic; Time; Tissues; Topical application; Toxic effect; Translating; axon growth; base; design; drug candidate; erection; healing; high risk; improved; inhibitor; manufacturing process; men; millimeter; nerve injury; nerve transection; novel; novel therapeutic intervention; novel therapeutics; penis; phase 1 study; phosphoric diester hydrolase; pre-clinical; prevent; programs; response; side effect; symptom treatment; treatment strategy; wound; wound healing

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.

根治性前列腺切除术（RP）是局部前列腺癌的常用治疗选择，其携带有 由于海绵体神经（CN）损伤，勃起功能障碍（艾德）发展风险高。更新的， 保留神经的机器人手术不能令人信服地改善RP后的勃起功能（EF）结果。在 此外，RP引起的艾德通常对口服磷酸二酯酶5型治疗无效 抑制剂（PDE 5i）给患者留下了较差的治疗选择，这些治疗选择是侵入性的，与副作用相关， 疗效有限，治标不治本。有一个真实的和迫切的需要， 确定治疗RP相关艾德的新治疗策略。 作为CN损伤的结果，在身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释放水平导致故障 促进海绵体氧合的机制，导致纤维化和海绵体平滑肌 细胞凋亡，其然后充当EF恢复的潜在不可逆屏障，甚至在CN再生之后。以来 EF在CN损伤后48小时内受到影响，这是一种称为“阴茎康复”的策略，如口服PDE 5i 在RP后尽可能早地开始给药，目的是提高基础身体血流量， 保持阴茎结构直到CN功能性再生。 基于CN损伤在RP后艾德发展中的核心作用，我们的新治疗方法 该策略使用siRNA技术靶向表达一种新发现的微管调节因子Fidgetin样 2（FL 2）以增强CN再生。初步和已发表的研究表明，FL 2是一种负调节因子， 轴突生长和伤口修复;在I期研究中，一种新的先导治疗制剂（释放FL 2的“晶片”， siRNA; SiFi 2）被鉴定为当给予经历双侧CN横断的大鼠时， CN再生和改善勃起功能。与正在研究的其他临床前策略相比 对于CN再生，SiF 12在促进CN再生、诱导重组 神经组织穿过几毫米的间隙，并导致勃起功能的显着改善 早在横切后两周。然而，这种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的变化 在神经再生的过程中。因此，我们会研究双管齐下的方法， 神经再生和减轻身体组织损伤，同时神经正在愈合。 该第二阶段提案的目标是启动新药研究申请（IND）的步骤 （1）评价口服给予的PDE 5i增强SiFi 2治疗的能力; (2)在合同生产组织（CMO）启动GMP启动计划;以及（3）评估 在CMO生产的SiFi 2。