Gene-based Neuromodulation: A New Paradigm for Functional Neurosurgery

基于基因的神经调节：功能神经外科的新范式

• 批准号: 7530554
• 负责人: NICHOLAS M BOULIS
• 金额: $ 17.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530554
• 关键词: Ablation; Adenovirus Vector; Affect; Anatomy; Architecture; Automobile Driving; Award; Axon; Basal Ganglia; Biological Assay; Biological Neural Networks; CMV promoter; Capsid; Cells; Cisplatin/Doxorubicin/Melphalan/Teniposide; Clinic; Clinical; Clinical Treatment; Clinical Trials; Complication; Corpus striatum structure; Data; Deep Brain Stimulation; Development; Devices; Digestion; Disease; Dose; Doxycycline; Electrodes; Electronics; Engineering; Epilepsy; Failure; Functional disorder; Funding; Gene Delivery; Gene Expression; Gene Transfer; Genes; Goals; Grant; Implant; In Vitro; Individual; Infection; Inflammation; Injection of therapeutic agent; Invasive; Journals; Laboratories; Left; Lesion; Light; Mediating; Medicine; Membrane; Mental Depression; Mental disorders; Mentors; Modeling; Molecular; Motor; Motor Neurons; Movement; Movement Disorders; Nervous system structure; Neural Inhibition; Neurons; Neurophysiology - biologic function; Neurosciences; Neurotransmitters; Obsessive-Compulsive Disorder; Operative Surgical Procedures; Pain; Parkinson Disease; Peripheral Nerves; Phase; Population; Potassium; Preparation; Presynaptic Terminals; Protein Fragment; Proteins; Pump; Rate; Refractory; Regulation; Research Personnel; Resource Development; Risk; Scientist; Site-Directed Mutagenesis; Specificity; Spinal Cord; Standards of Weights and Measures; Structure; Surface; Synapses; Synaptic Transmission; System; Techniques; Testing; Tetanus; Tetanus Helper Peptide; Tetanus Toxin; Tetracycline; Tetracyclines; Thalamic structure; Time; Tissues; Transgenes; Translations; Tropism; Vesicle; Viral; Viral Vector; Virus; adeno-associated viral vector; adenovirus mediated delivery; base; career; cell type; concept; gene therapy; human VAPA protein; immunogenic; implantable device; implantation; improved; in vitro Assay; in vivo; inward rectifier potassium channel; neural prosthesis; neuronal excitability; neurosurgery; programs; promoter; receptor; relating to nervous system; stem; synaptic function; synaptic inhibition; tool; vector; vesicle-associated membrane protein; viral vector development

DESCRIPTION (provided by applicant): The present proposal will continue the career development of Dr. Boulis as a clinician-scientist in the field of Functional Neurosurgery, focusing on an alternative to existing strategies for Neuromodulation. Neuromodulation, the manipulation of neural activity within anatomically discrete targets, is the principle tool of Functional Neurosurgery, finding application in the treatment of movement disorders, pain, spasticity, epilepsy and psychiatric disease. It has largely replaced the destruction of neural tissue as a means to treat refractory functional disorders. Nonetheless, the focused delivery of electric current is incapable of pharmacological specificity and requires electronic neural prostheses that carry a significant complication rate. Viral gene therapy has several advantages over implanted devices for the treatment of functional neural disorders. Neuronal gene expression can be achieved through minimally invasive stereotactic injection. Moreover, the tropism of viral vectors can be engineered through manipulation of the virus surface to target the vectors to individual cell types as well as limit and direct the spread of gene expression. Finally, viral gene expression can be achieved in a sustained fashion in neurons without disrupting their architecture or synaptic structure. Thus, gene transfer can be used to manipulate functioning neural structures in a fashion that current surgical procedures cannot achieve, providing the dual advantage of both pharmacologic and anatomic specificities. The following proposal explores the development of vectors to achieve controlled modulation of synaptic function using the best available inducible gene expression systems for regulated release of the clostridial tetanus toxin light (LC) gene and the inwardly rectifying potassium channel (Kir2.1) gene. Aims of the current proposal will test the following hypotheses: 1) AAV mediated LC synaptic inhibition is durable and less immunogenic than delivery mediated by Adenovirus, and that durable expression can be regulated by the Tet-on system. 2) Expression cassette modification, targeting expression to motor neurons and transgene delivery to axons, can improve the potency and specificity of LC gene-based neural inhibition. 3) The Rheoswitch(r) inducible expression system will improve controlled LC delivery. 4) Neuronal Kir2.1 gene expression can safely inhibit neuronal activity with potency exceeding that of LC mediated synaptic inhibition.

描述（由申请人提供）：本提案将继续Boulis博士作为功能神经外科领域的临床医生-科学家的职业发展，重点是神经调节现有策略的替代方案。神经调节，即在解剖学上离散的目标内操纵神经活动，是功能神经外科的主要工具，在运动障碍、疼痛、痉挛、癫痫和精神疾病的治疗中找到应用。它在很大程度上取代了神经组织的破坏作为治疗难治性功能障碍的手段。尽管如此，电流的集中输送不具有药理学特异性，并且需要具有显著并发症率的电子神经假体。病毒基因疗法在治疗功能性神经疾病方面比植入装置有几个优点。神经元基因表达可以通过微创立体定向注射来实现。此外，病毒载体的向性可以通过操纵病毒表面以将载体靶向单个细胞类型以及限制和引导基因表达的传播来工程化。最后，病毒基因表达可以在神经元中以持续的方式实现，而不会破坏它们的架构或突触结构。因此，基因转移可以用来操纵功能神经结构的方式，目前的外科手术不能实现，提供药理学和解剖学特异性的双重优势。下面的建议探讨了载体的发展，以实现突触功能的控制调制，使用最好的可诱导的基因表达系统的梭菌破伤风毒素轻（LC）基因和内向整流钾通道（Kir2.1）基因的调节释放。本发明的目的将测试以下假设：1）AAV介导的LC突触抑制是持久的，并且比腺病毒介导的递送具有更低的免疫原性，并且持久的表达可以通过Tet-on系统调节。2)表达盒修饰，靶向表达到运动神经元和转基因递送到轴突，可以提高基于LC基因的神经抑制的效力和特异性。3)Rheoswitch（r）诱导型表达系统将改善LC的受控递送。4)神经元Kir2.1基因表达可以安全地抑制神经元活动，其效力超过LC介导的突触抑制。