Oscillated Insertion Tool for Minimally Invasive, Low-Damage, Accurate Placement of Delivery Cannula to Improve Efficacy for DREADDS Therapy in Alcohol Addiction Treatment

振荡插入工具可微创、低损伤、准确放置输送插管，以提高酒精成瘾治疗中 DREADDS 疗法的疗效

• 批准号: 10546872
• 负责人: KEVIN A SNOOK
• 金额: $ 38.49万
• 依托单位: ACTUATED MEDICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546872
• 关键词: Achievement; Addictive Behavior; Address; Affect; Age; Air; Alcohol abuse; Alcohol dependence; American; Animals; Award; Behavior; Blood specimen; Brain; Brain region; Cannulas; Cells; Cerebrospinal Fluid; Clinical; Collaborations; Complex; Complication; Coupling; Development; Devices; Drug Receptors; Dura Mater; Effectiveness; Electrodes; Engineering; Enteral Feeding; Foundations; Friction; Goals; Grant; Health Sciences; Infusion procedures; Injections; Lead; Legal patent; Liquid substance; Location; Magnetic Resonance Imaging; Medical; Medical Research; Metals; Methods; Modeling; Motion; National Institute on Alcohol Abuse and Alcoholism; Neurosciences Research; Nucleus Accumbens; Operative Surgical Procedures; Oregon; Patient-Focused Outcomes; Pharmacologic Substance; Phase; Pre-Clinical Model; Primates; Public Health; Relapse; Research; Risk; Rodent; Sales; Small Business Innovation Research Grant; Structure; Syringes; System; Technology; Testing; Therapeutic; Thinness; Tissues; Transducers; United States National Institutes of Health; Universities; Validation; Viral; Viral Vector; Virus; Work; alcohol effect; alcohol pharmacology; alcoholism therapy; behavioral outcome; clinical application; commercialization; delivery vehicle; design; designer receptors exclusively activated by designer drugs; expression vector; flexibility; improved; improved outcome; innovation; migration; minimally invasive; nervous system disorder; neural circuit; neural implant; new technology; nonhuman primate; optogenetics; pre-clinical; pre-clinical research; preclinical study; prevent; psychosocial; receptor expression; success; tool; verification and validation; vibration; Achievement; Addictive Behavior; Address; Affect; Age; Air; Alcohol abuse; Alcohol dependence; American; Animals; Award; Behavior; Blood specimen; Brain; Brain region; Cannulas; Cells; Cerebrospinal Fluid; Clinical; Collaborations; Complex; Complication; Coupling; Development; Devices; Drug Receptors; Dura Mater; Effectiveness; Electrodes; Engineering; Enteral Feeding; Foundations; Friction; Goals; Grant; Health Sciences; Infusion procedures; Injections; Lead; Legal patent; Liquid substance; Location; Magnetic Resonance Imaging; Medical; Medical Research; Metals; Methods; Modeling; Motion; National Institute on Alcohol Abuse and Alcoholism; Neurosciences Research; Nucleus Accumbens; Operative Surgical Procedures; Oregon; Patient-Focused Outcomes; Pharmacologic Substance; Phase; Pre-Clinical Model; Primates; Public Health; Relapse; Research; Risk; Rodent; Sales; Small Business Innovation Research Grant; Structure; Syringes; System; Technology; Testing; Therapeutic; Thinness; Tissues; Transducers; United States National Institutes of Health; Universities; Validation; Viral; Viral Vector; Virus; Work; alcohol effect; alcohol pharmacology; alcoholism therapy; behavioral outcome; clinical application; commercialization; delivery vehicle; design; designer receptors exclusively activated by designer drugs; expression vector; flexibility; improved; improved outcome; innovation; migration; minimally invasive; nervous system disorder; neural circuit; neural implant; new technology; nonhuman primate; optogenetics; pre-clinical; pre-clinical research; preclinical study; prevent; psychosocial; receptor expression; success; tool; verification and validation; vibration

This Phase I SBIR develops and tests an Oscillated Syringe for Intracranial Injections (OSII) of viral constructs for chemogenetic studies of alcohol addiction neurocircuitry in the brain. The project’s long-term goal is to develop and commercialize a surgical tool to enable reliable and safe injections of viral constructs into the brain for preclinical studies, and eventually clinical therapeutic approaches. Actuated Medical, Inc. (AMI) develops innovative motion devices incorporating electronically-controlled actuator technologies to improve patient outcomes and advance medical research. This work is in collaboration with Drs. K. Grant and V. Cuzon Carlson at the Oregon Health and Science University (OHSU). Public Health Problem: Alcohol addiction is estimated to affect 28 million Americans over the age of 12 in 2020 – and is subject to relapse rates of 40-60% despite available pharmaceutical and psychosocial therapies. Chemogenetic tools have significant potential to lead to translational findings in preclinical research that can illuminate mechanisms underlying alcohol pharmacology and addiction. However, the utility of chemogenetics, such as designer receptors exclusively activated by designer drugs (DREADDs), is limited by how well the viral constructs can be targeted to specific brain regions, to maximize and precisely control designer receptor expression. In a recent preclinical study targeting DREADD receptors to the nucleus accumbens, the percent of targeted cells expressing the DREADD receptor ranged from 41-87%. This poor delivery accuracy significantly impacted subsequent behavioral outcomes and prevented conclusive study hypothesis testing. Solution: This project commercializes the OSII to improve targeting and viral expression in preclinical studies, initially examining the neural circuitry underlying alcohol addiction. AMI will leverage its oscillated neural implant insertion technology which enables low-force, low-friction insertion of probes and electrodes into the brain. The goals for the OSII system are 1) reduce insertion force, 2) enable use of smaller and more flexible viral injection syringes, including the potential for blunted tips, 3) reduce tissue damage, 4) reduce risk of virus migration to other tissues along the syringe insertion track, and 5) allow insertion through the dura. Aim 1 Demonstrate accurate placement of 25-36G micro-injection cannulas in simulated deep brain targets using vibration with and without intact dura. Acceptance Criteria: >70% reduction in insertion force compared to non-vibrated insertion, and <1 mm deviation from target path with 5 cm deep insertions using 25-36G polyimide and metal cannulas in models. 100% insertion success through dura with 36G metal cannula. Aim 2 Demonstrate OSII improves viral vector delivery to targets with less off-target spreading and DREADD receptor expression in preclinical model. Acceptance Criteria: Improved mean percentage (>55%) of DREADD receptor expression restricted to the target tissue with viral injection via OSII (as compared to previous study).

这一阶段I SBIR的开发和测试振荡的注射器，以便对病毒构建体进行颅内注射（OSII） 用于对大脑中酒精成瘾神经通路的化学发生研究。该项目的长期目标是 开发和商业化手术工具，以将病毒构建的可靠和安全注射到 用于临床前研究的大脑，最终是临床治疗方法。驱动医疗公司（AMI） 开发融合了电子控制的执行器技术以改进的创新运动设备 患者的结果并提高医学研究。这项工作与Drs合作。 K. Grant和V. Cuzon 俄勒冈州健康与科学大学（OHSU）的卡尔森。 公共卫生问题：估计饮酒会影响12岁以上的2800万美国人 2020年 - 受到40-60％的救济率所需的可用药物和社会心理疗法。 化学发生工具具有巨大的潜力，可以导致临床前研究中的翻译结果 照明药理学和成瘾的基础机制。但是，化学遗传学的效用， 例如设计师药物（Dreadds）专门激活的设计师接收器，受病毒的限制 构造可以针对特定的大脑区域，以最大化和精确控制设计器接收器 表达。在针对伏隔核的最新临床前研究中，百分比 表达Dreadd接收器的目标细胞的范围为41-87％。这种差的交付精度 显着影响了随后的行为结果，并阻止了确定的研究假设检验。 解决方案：该项目将OSII商业化以改善临床前研究中的靶向和病毒表达， 最初检查酒精成瘾的神经元电路。 AMI将利用其振荡的神经元 植入物插入技术，可以使问题和电极的低强度，低摩擦插入到 脑。 OSII系统的目标是1）减少插入力，2）启用较小，更灵活的使用 病毒注射注射器，包括钝尖的潜力，3）减少组织损伤，4）降低病毒的风险 沿注射器插入轨道迁移到其他组织，5）允许通过硬脑膜插入。 AIM 1证明在模拟的深脑目标中准确放置25-36g微注射插管 使用有或没有完整硬脑膜的振动。接受标准：比较插入力降低70％ 进行未振动的插入，<1 mm从目标路径出发，使用25-36g的5 cm深插入 模型中的聚酰亚胺和金属插管。用硬脑膜插入36克金属套管的100％插入成功。目标2 演示OSII改善了病毒矢量的传递到靶向较小的靶标和dreadd接收器的目标 临床前模型中的表达。接受标准：提高Dreadd接收器的平均百分比（> 55％） 通过OSII注射病毒的表达限于目标组织（与先前的研究相比）。