Gene Therapy for Nerve Injury

神经损伤的基因治疗

• 批准号: 7290381
• 负责人: LUC JASMIN
• 金额: $ 27.02万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 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/7290381
• 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

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，从而改变了体细胞感。这些感官变化（包括疼痛）特别抗药性，目前可用的药物除了具有许多不必要的副作用外，还没有足够的缓解。基因疗法提供了一种新的攻击疼痛方法，因为它可以针对神经系统的特定区域，并且具有长期的影响。我们使用良好的方法将基因载体转移到最终可以在临床上使用的感觉神经元中。我们将传递负责酶合成GABA的基因，GABA是神经系统的主要抑制性神经递质。已知用增加神经系统中GABA的药物的治疗可在许多疼痛条件下缓解。我们使用基因转移来增加三叉神经节神经神经元的GABA，该神经神经节提供了脸部的感觉神经的神经神经支配，并发现这会导致神经损伤引起的面部疼痛的大鼠镇痛。这是一种令人鼓舞的迹象，表明类似的基因转移策略将减轻许多慢性顽固性面部疼痛的患者。但是，在考虑人类试验之前，需要回答有关转移基因效果的基础机制的一些关键问题，并且是当前实验方案的主题。首先，我们将确定由跨基因合成的GABA的作用部位。其次，我们将看到插入两个编码为GABA产生酶的两个基因中的两个基因中的一个是否会导致更大的疼痛缓解。第三，我们将确定将基因转移到不同的感觉神经元种群中是否可以改变疼痛感觉的不同成分。最后，我们将确定在神经损伤之前给予的GABA治疗是否比治疗在预防或逆转某些与神经系统中发生疼痛相关的关键变化方面给予的疗法是否更有效。 三叉神经功能障碍引起的口腔，面部和头部疼痛是一个常见的临床问题，也是最具挑战性的治疗之一。基因治疗是一种更好的疼痛控制方法，因为它避免了许多药物的缺点或诸如手术或辐射等消融治疗的缺点。我们的项目是对校正三叉神经功能障碍的镇痛作用的一项临床前研究，该基因添加一个编码GABA的基因，该基因将天然神经递质（一种天然的神经递质）编码为三叉神经神经元。