Targeted Nano-enhanced Optical Delivery of opsin for dry-AMD therapy

 描述（由申请人提供）：干性AMD的特征在于黄斑中的光感受器变性。虽然黄斑只占视网膜的一小部分，但它比周边视网膜对细节更敏感。干性AMD是约1500万65岁以上老年人新发视力丧失的主要原因。此外，随着年龄的增长，视力下降的程度也会增加，这是我们人口结构向老年人口转变的一个主要问题。目前大多数临床治疗主要集中在减缓疾病的进展，因为既没有治愈方法可以阻止退化，也没有治疗方法。我们已经开发了一种环境光可激活的高光敏多特征视蛋白（MCO），以允许刺激光敏视网膜神经节细胞，用于在干性AMD的情况下恢复视力。然而，用于视力恢复的这种疗法（使用光遗传学激活）的临床转化受到缺乏将MCO编码基因递送到变性视网膜的空间靶向区域（即干性AMD中的黄斑）中的方法的限制。我们最近开发了一种基于连续波近红外（NIR）激光的方法，用于将外源性物质（包括MCO质粒）有效地体内递送到组织中。在这 纳米增强光传递（NOD）方法，我们利用金纳米棒的场增强作用瞬时包裹细胞膜，将外源分子传递到细胞中。通过在目标区域（例如AMD视网膜中的地图状萎缩）中照射低功率连续波（cw）激光束来实现空间靶向原位递送。我们的初步结果表明，使用近红外（NIR）连续波激光束可以将不可渗透的分子（包括视蛋白质粒）输送到靶细胞中。由于金纳米棒具有非常低的细胞毒性，并且已被广泛用于各种临床试验，因此它是临床NOD的理想纳米材料。与脉冲激光器相比，连续近红外（二极管）激光器结构紧凑，易于使用，因此具有显著的平移潜力。该I期SBIR项目的总体目标是证明使用cw NIR激光束以安全的方式将MCO靶向体内光学递送至AMD小鼠模型的退化视网膜区域。为了这个目标，我们有以下目的：（i）优化NOD以用多特征视蛋白（MCO）敏化RGC;和（ii）使用电生理学评估AMD小鼠模型中的长期存活力/保持力和视力恢复。该提案是NanoScope Technologies与德克萨斯大学Mohanty博士和Kim博士的实验室之间的合作努力。这一提议的成功将导致一种新的临床方法，用于通过玻璃体内注射gol纳米棒和MCO治疗干性AMD患者，然后对目标黄斑区域进行NIR激光照射，从而使那些退化区域对环境日光光敏化。在完成I期后，我们设想II期SBIR的目标是（i）优化最终产品设计和方法，（ii）识别AMD治疗人群，（iii）向FDA提交孤儿药/器械许可申请，以及（iv）为产品和方法的商业化提供核心营销材料。

 DESCRIPTION (provided by applicant): Dry-AMD is characterized by degeneration of photoreceptors in the macula. Though macula makes up only a small part of the retina, it is much more sensitive to detail than peripheral retina. Dry AMD is the leading cause of new vision loss in ~15 million persons older than 65 years of age. Further, the degree of visual loss increases with ageing and this is a major concern for our demographic changes towards elderly population. Most of the current clinical treatments are primarily focused on slowing down the progression of the disease, as there is neither a cure that can stop the degeneration nor a therapy. We have developed an ambient-light activatable highly-photosensitive multi-characteristics opsin (MCO) to allow stimulation of photosensitized retinal ganglion cells for restoring vision in case of dry-AMD. However, clinical translation of such therapy (using optogenetic activation) for vision restoration is limited by the lack of approach for delivery of MCO- encoding genes into spatially-targeted regions of degenerated-retina (i.e. macula in dry-AMD). We have recently developed a continuous wave near-infrared (NIR) laser based method for efficient in-vivo delivery of exogenous material (including MCO-plasmids) into tissues. In this Nano-enhanced Optical Delivery (NOD) method, we are utilizing the field enhancement by gold nanorods to transiently perforate cell membrane to deliver exogenous molecules to cells. Spatially-targeted in-situ delivery is achieved by shining the low-power continuous wave (cw) laser beam in targeted areas (e.g. geographic atrophy in AMD retina). Our preliminary results using NOD method show that impermeable molecules (including opsin-plasmids) could be delivered into targeted cells using near-IR (NIR) continuous wave laser beam. Since the gold nanorods have very low cytotoxicity and have been widely used in various clinical trials, it is an ideal nanomaterial for clinical NOD. Compared with pulsed lasers, cw NIR (diode) lasers are compact, easy-to-use and therefore, have significant translational potential. The overall objective of this Phase I SBIR project is to demonstrate targeted in-vivo optical delivery of MCO to degenerated retinal regions in mice models of AMD using cw NIR laser beam in a safe manner. Towards this goal we have following aims: Towards this goal we have following aims: (i) Optimization of NOD for sensitizing RGCs with multi-characteristics opsin (MCO); and (ii) Assessment of long- term viability/retention and vision restoration in AMD mice model using electrophysiology. This proposal is a collaborative effort between NanoScope Technologies, and Drs. Mohanty and Kim's laboratories at University of Texas. Success of this proposal will lead to a new clinical approach for treating patients with dry AMD by intravitreal injection of gol nanorods and MCO, followed by NIR laser irradiation of targeted macular regions, thus photosensitizing those degenerated regions toward ambient day-light. Upon completion of the Phase I we envision a Phase II SBIR targeted at (i) optimizing the final product design and method, (ii) identifying AMD- population for treatment, (iii) submission of orphan drug/device license application to FDA, and (iv) providing core marketing material for commercializing the product and method.