HSV GAD for Painful Diabetic Neuropathy

描述（由申请人提供）： 摘要：我们正在申请RR&D转化研究合作计划，以寻求资金来完成临床前步骤，以获得IND和IRB批准表达谷氨酸脱羧酶（GAD）的单纯疱疹病毒（HSV）载体，用于疼痛性糖尿病神经病变（PDN）患者的1/2期临床试验。慢性疼痛的新型有效治疗方法的发展一直令人不安地缓慢，部分原因是保守使用神经中有限的神经递质、受体和离子通道库限制了我们采用全身给药的小分子来选择性地中断伤害性神经传递的能力。为了克服这一限制，我们构建了一系列基于非复制型HSV的载体，其有效地将基因递送从皮肤接种靶向到背根神经节，以实现脊髓背角中抗伤害感受性神经递质的释放。我们已经将这些载体中的第一个--表达前脑啡肽原的非复制型HSV载体--用于癌症顽固性疼痛患者的1期临床试验。神经性疼痛的有效治疗存在大量未满足的需求;临床前动物研究表明，表达GAD的HSV载体在PDN的啮齿动物模型中有效; VA拥有该载体专利的所有权（正在审查中）。成功完成拟议的工作将使该载体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.