Preclinical Development of an NT3-expressing HSV Vector

描述（由申请人提供）：预防神经病变的有效治疗的开发一直令人不安地缓慢，部分原因是难以将神经营养肽递送至靶组织。为了克服这一限制，我们构建了一系列基于非复制型单纯疱疹病毒（HSV）的载体，其有效地将基因递送从皮肤接种靶向背根神经节，以实现从转导的神经元释放神经保护肽。我们已经将表达前脑啡肽原的非复制型HSV载体用于患有癌症顽固性疼痛的患者的1期临床试验。对于限制癌症化疗的化疗诱导的周围神经病变的有效治疗存在大量未满足的需求，并且我们进行了临床前动物研究以证明表达神经营养蛋白-3（NT 3）的HSV载体在顺铂神经病变的啮齿动物模型中是有效的。因此，我们寻求资金以完成获得NT 3表达HSV载体的IND和IRB批准所需的临床前步骤，以便在将接受顺铂治疗的癌症患者中进行1/2期临床试验。 公共卫生相关性：通过这项申请，我们正在寻求资金，以推进临床前开发NT-3表达HSV载体，用于治疗将接受顺铂的癌症患者。化疗引起的周围神经病变是一种严重的治疗并发症，严重限制了我们有效治疗癌症患者的能力，目前还没有有效的治疗方法。 免责声明：请注意，以下评论是由审查员在研究部分会议之前准备的，并且以基本上未经编辑的形式提供。 虽然审查人员有机会根据小组讨论情况更新或修订其书面评价，但不能保证在会议讨论之后更新了个人评论。 因此，这些评论可能并不完全反映小组讨论结束时单个评审员的最终意见或小组的最终多数意见。因此，讨论的简历和摘要是评审员在会议上实际认为关键的最后一句话。

DESCRIPTION (provided by applicant): The development of effective treatments to prevent neuropathy has been disappointingly slow, in part because it is difficult to deliver neurotrophic peptides to the target tissue. To overcome this limitation we have constructed a series of non-replicating herpes simplex virus (HSV)-based vectors that efficiently target gene delivery to dorsal root ganglia from skin inoculation to effect release of neuroprotective peptides from transduced neurons. We have already taken a non-replicating HSV vector expressing preproenkephalin into phase 1 clinical trial in patients with intractable pain from cancer. There is a substantial unmet need for effective treatments chemotherapy-induced peripheral neuropathy that limits cancer chemotherapy, and we have preclinical animal studies to demonstrate that a neurotrophin-3 (NT3)-expressing HSV vector is effective in the rodent model of cisplatin neuropathy. Therefore we seek funding to complete the preclinical steps required to obtain IND and IRB approval of an NT3-expressing HSV vector in order to proceed with a phase 1/2 clinical trial in patients with cancer who will receive cisplatin treatment. Public Health Relevance: With this application we are seeking funding to move forward with the preclinical development of an NT-3- expressing HSV vector for treatment of cancer patients who will receive cisplatin. Chemotherapy-induced peripheral neuropathy is a serious complication of therapy that substantially limits our ability to effectively treat patients with cancer, and for which there is currently no effective treatment. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.