Gene Therapy for Nerve Injury

神经损伤的基因治疗

基本信息

批准号：
7937535
负责人：
LUC JASMIN
金额：
$ 26.77万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-22 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7937535
关键词：
Absence of pain sensation Adverse effects Affect Afferent Neurons Analgesics Animals Area Axon Behavior Brain Stem Butyric Acid Butyric Acids Cell Nucleus Cells Chronic Clinical Code Condition Disinhibition Dose Enzymes Esthesia Face Facial Pain Functional disorder GABA Agonists Gene Expression Gene Transfer Genes Glutamate Decarboxylase Goals Hand Headache Health Care Costs Healthcare Heart Diseases Heating Human Hyperalgesia Individual Injury Label Life Link Malignant Neoplasms Mediating Methods Modeling Motor Nerve Nervous system structure Neuraxis Neurobiology Neurons Neurotransmitters Nociception Numbers Numbness Operative Surgical Procedures Oral Pain Pain management Patients Peripheral Pharmaceutical Preparations Phenotype Physicians Population Principal Investigator Protein Isoforms Protocols documentation Radiation Rattus Receptor Gene Resistance Route Sensory Site Structure of trigeminal ganglion Substance P Receptor Synaptic Vesicles Testing Thinking Translations Trigeminal Nuclei Trigeminal nerve structure Visit allodynia chronic pain cost desensitization gamma-Aminobutyric Acid gene therapy gene transfer vector injured nerve injury nerve supply painful neuropathy preclinical study prevent programs receptor

项目摘要

DESCRIPTION (provided by applicant): Nerve injury leads to many changes in the peripheral and central nervous system leading to altered somatic sensation. These sensory changes, including pain, are particularly resistant to treatment and the currently available drugs do not offer adequate relief in addition to having many unwanted side effects. Gene therapy offers a new and promising method of attacking pain because it can target specific areas of the nervous system and it has long-lived effects. We use a well-established method for transferring gene vector into sensory neurons that could eventually be used clinically. The gene we will transfer codes for the enzyme responsible for the synthesis of GABA, the main inhibitory neurotransmitter of the nervous system. Treatment with drugs that increase GABA in the nervous system is known to produce relief in a number of pain conditions. We use gene transfer to increase GABA in neurons of the trigeminal ganglion that supply the sensory innervations of the face and find that this results in analgesia in rats with nerve injury induced facial pain. This is an encouraging indication a similar gene transfer strategy would provide pain relief to the many patients with chronic intractable facial pain. Before contemplating a human trial, however, some key questions concerning the mechanism underlying the effect of the transferred genes need to be answered and are the subject of the present experimental protocol. Firstly, we will identify the site of action of the GABA synthesized by the transected genes. Secondly, we will see if inserting two versus only one of the two genes coding for the GABA producing enzyme results in more pain relief. Thirdly, we will determine if transferring the gene to different populations of sensory neurons can modify different components of pain sensation. Finally, we will determine if GABA therapy given before the nerve injury is more, or less, efficacious than therapy give after the injury in preventing or reversing some of the key changes linked to pain sensation occurring in the nervous system. Oral, facial, and head pain from trigeminal nerve dysfunction is a common clinical problem and one of the most challenging to treat. Gene therapy is a better method for pain control because it avoids many of the drawbacks of drugs or ablative treatments such as surgery or radiation. Our project is a pre-clinical study of the analgesic effects of correcting trigeminal nerve dysfunction by adding a gene that codes for GABA, a natural neurotransmitter to trigeminal nerve neurons.

描述（由申请人提供）：神经损伤导致周围和中枢神经系统发生许多变化，从而导致躯体感觉改变。这些感觉变化，包括疼痛，特别难以治疗，并且目前可用的药物除了具有许多不需要的副作用之外，还不能提供足够的缓解。基因疗法提供了一种新的、有前途的治疗疼痛的方法，因为它可以针对神经系统的特定区域，并且具有长期的效果。我们使用一种行之有效的方法将基因载体转移到感觉神经元中，最终可用于临床。我们将转移的基因编码负责合成 GABA 的酶，GABA 是神经系统的主要抑制性神经递质。众所周知，使用增加神经系统中 GABA 的药物治疗可以缓解多种疼痛症状。我们利用基因转移来增加三叉神经节神经元中的 GABA，这些神经元负责面部的感觉神经支配，并发现这可以对神经损伤引起的面部疼痛的大鼠产生镇痛作用。这是一个令人鼓舞的迹象，类似的基因转移策略将为许多患有慢性顽固性面部疼痛的患者提供疼痛缓解。然而，在考虑进行人体试验之前，需要回答一些有关转移基因作用机制的关键问题，这些问题也是本实验方案的主题。首先，我们将确定被横切基因合成的 GABA 的作用位点。其次，我们将看看插入编码 GABA 产生酶的两个基因中的两个与仅插入一个是否可以更好地缓解疼痛。第三，我们将确定将基因转移到不同的感觉神经元群体是否可以改变痛觉的不同组成部分。最后，我们将确定神经损伤前给予的 GABA 治疗在预防或逆转与神经系统中发生的痛觉相关的一些关键变化方面是否比损伤后给予的治疗更有效或更差。三叉神经功能障碍引起的口腔、面部和头部疼痛是常见的临床问题，也是最具挑战性的治疗问题之一。基因疗法是一种更好的疼痛控制方法，因为它避免了药物或手术或放射等消融治疗的许多缺点。我们的项目是一项临床前研究，通过添加编码 GABA（三叉神经元的天然神经递质）的基因来纠正三叉神经功能障碍的镇痛效果。