Novel Nanosecond Laser and Ultrasound to Selectively Treat Eye Blood Vessels

摘要/项目摘要 湿性老年性黄斑变性(AMD)是发达国家不可逆性失明的主要原因 世界。抗血管内皮生长因子治疗是目前湿性AMD治疗的金标准。然而，高达50%的 从长期来看，患者对抗血管内皮生长因子治疗的反应不是最好的。一种更好的替代方法 AMD的治疗迫在眉睫。我们最近发明了一种新颖、有效、高度选择性的反- 血管疗法，称为“光介导型超声疗法(PUT)”。PUT是基于微空化的 激光脉冲和超声脉冲协同作用产生的微血管。正如我们的 临床相关动物模型的初步研究，PUT可消除靶血管 不会对周围组织造成不必要的损害，有助于获得最佳的治疗结果 适用于AMD患者。 我们研究的最终目标是开发一种新的非侵入性治疗技术并将其商业化。 目的：安全有效地治疗湿性AMD患者的脉络膜新生血管(CNV)。要实现 最终目标是，该项目简化以实现技术过渡，包括以下里程碑： (1)在兔眼模型上构建并验证第一阶段α-原型；(2)构建并验证第二阶段β- 人类受试者的原型，(3)完成临床研究，以及(4)确定批准路径与 美国食品和药物管理局。在这项第一阶段的研究中，PhotoSonoX LLC通过与凯洛格眼科中心建立了合作 在密歇根大学医学院，将建立一个临床就绪的α原型系统，并全面测试 其安全性和有效性为第二阶段的临床研究铺平了道路。 I期研究的假设是PUT可以精确地去除眼内的病理性微血管。 而不会对周围组织造成短期和长期的损害。为了检验这一假设， 将完成以下具体目标：目标1.开发可用于临床的α原型PUT系统 成本合理，可在临床相关的兔眼和人眼上进行测试 第二阶段。目的2.确定PUT治疗脉络膜微血管的长期安全性 活体内的兔子。目的3.验证PUT治疗病理的近、远期疗效和安全性 AMD兔模型体内脉络膜新生血管的研究。这项研究的结果将证明- PUT有效和安全地移除病理性脉络膜微血管治疗AMD的概念。我们 期待拟议的PUT设备具有巨大的潜力，通过以下方式改变我们对AMD患者的护理 在减轻治疗负担和副作用的同时，促进有针对性和精准的治疗。

ABSTRACT / PROJECT SUMMARY Wet age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Anti-VEGF therapy is currently the gold standard for wet AMD treatment. However, up to 50% of patients in the long term have a suboptimal response to anti-VEGF therapy. A better alternative method for treatment of AMD is urgently needed. We have recently invented a novel, effective, and highly-selective anti- vascular therapy, termed “photo-mediated ultrasound therapy (PUT)”. PUT is based on microcavitations in microvessels produced by synergistically applied laser pulses and ultrasound bursts. As demonstrated by our preliminary studies on clinically relevant animal models, PUT is capable of eliminating the target microvessels in the choroid without causing unwanted damage to the surround tissue, facilitating optimal treatment outcome for patients with AMD. The ultimate goal of our research is to develop and commercialize a new, noninvasive therapeutic technique for safe and efficient treatment of choroidal neovascularization (CNV) in patients with wet AMD. To achieve the ultimate goal, the project streamlines to achieve the technological transition, including the following milestones: (1) to build and verify the Phase I α-prototype on rabbit eye models, (2) to build and verify the Phase II β- prototype for human subjects, (3) to complete clinical studies, and (4) to define the approval pathway with the FDA. In this Phase I research, PhotoSonoX LLC, via an established collaboration with the Kellogg Eye Center at the University of Michigan School of Medicine, will build a clinically ready α-prototype system, and fully test its safety and efficacy to pave the road to clinical studies in Phase II. The hypothesis of the Phase I study is that PUT can precisely remove pathologic microvessels in the eye without causing short-term and long-term damage in the surrounding tissue. To test this hypothesis, the following specific aims will be accomplished: Aim 1. Develop a clinically ready α-prototype PUT system which has a reasonable cost and can be tested on clinically relevant rabbit eyes in Phase I and on human eyes in Phase II. Aim 2. Determine the long-term safety of PUT for treatment of choroidal microvessels on normal rabbits in vivo. Aim 3. Validate the short and long-term efficacy and safety of PUT for treating pathologic choroidal neovascularization in vivo on a rabbit model of AMD. The outcome from this research will be proof- of-concept that the PUT effectively and safely removes pathologic choroidal microvessels to treat AMD. We expect that the proposed PUT device has great potential to transform our care of patients with AMD by facilitating targeted and precise therapy while reducing the treatment burden and side effects.