HSV GAD for Painful Diabetic Neuropathy

描述(由申请人提供)： 摘要：我们正在申请翻译研究中的RR&D合作计划，以寻求资金来完成临床前步骤，以获得IND和IRB对表达谷氨酸脱羧酶(GAD)的单纯疱疹病毒(HSV)载体的批准，用于痛性糖尿病神经病变(PDN)患者的1/2期临床试验。治疗慢性疼痛的新的有效疗法的开发速度慢得令人失望，部分原因是神经中神经递质、受体和离子通道的有限库的保守使用限制了我们使用全身给药的小分子选择性地阻断伤害性神经传递的能力。为了克服这一局限性，我们构建了一系列基于HSV的非复制型载体，通过皮肤接种将基因有效地靶向背根节，从而影响脊髓背角抗伤害感受性神经递质的释放。我们已经将其中的第一个载体--表达前脑啡肽原的非复制型单纯疱疹病毒载体--用于癌症顽固性疼痛患者的第一阶段临床试验。对神经性疼痛的有效治疗存在大量未得到满足的需求；临床前动物研究表明，表达GAD的单纯疱疹病毒载体在PDN啮齿动物模型中有效；退伍军人管理局拥有该载体专利的所有权股份(正在审查中)。拟议工作的成功完成将使该媒介能够在患者身上进行测试。

DESCRIPTION (provided by applicant): Abstract: We are applying to the RR&D Cooperative Program in Translational Research to seek funding to complete the preclinical steps required to obtain IND and IRB approval of a glutamic acid decarboxylase (GAD)-expressing herpes simplex virus (HSV)-based vector for a phase 1/2 clinical trial in patients with painful diabetic neuropathy (PDN). The development of novel effective treatments for chronic pain has been disappointingly slow, in part because the conservative use of a limited repertoire of neurotransmitters, receptors and ion channels in the nervous limits our ability to employ systemically administered small molecules to selectively interrupt nociceptive neurotransmission. To overcome this limitation we have constructed a series of non- replicating HSV-based vectors that efficiently target gene delivery to dorsal root ganglia from skin inoculation to effect the release of antinociceptive neurotransmitters in dorsal horn of spinal cord. We have taken the first of these vectors - a nonreplicating 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 of neuropathic pain; preclinical animal studies demonstrate that the GAD-expressing HSV vector is effective in a rodent model of PDN; and the VA has an ownership stake in the patent (under review) for this vector. Successful completion of the work proposed will allow the vector to be tested in patients.