Engineered multi-therapeutic agents delivery system towards retinal ganglion cell axon regeneration

项目摘要 在美国，大约有220万人患有视神经病变，占世界人口的9 - 12%。 所有的失明病例。其中，10%接受适当治疗的患者继续经历 视力丧失，这显然需要一种替代治疗策略。 目前的治疗方法之一是利用神经营养因子（NTFs）增加视网膜神经节细胞（RGC） 生存，负责视觉功能。虽然通过玻璃体内注射直接施用NTF具有一定的优势， 虽然已经取得了一些成功，但这些NTFs对变性的敏感性限制了其临床成功。另外， 由于视神经病变伴随神经变性， 是由神经毒素循环引起的 为了解决这些问题，我们设计了模拟带负电荷的聚合物纳米颗粒， 天然肝素中的磺化基团并递送多种治疗剂以持续供应NTF， 抑制神经毒性。我们的策略的优点包括：1）在靶点持续递送NTFs， 模拟连续的NTF转运，2）包封在系统中的NTF的延长的生物活性和3） 持续递送抗神经毒性剂，在治疗期间持续抑制神经变性， 视神经病变的进展。 我们根据两个具体目标构建了此应用程序：（1）确定适当的 用于多种治疗剂的共递送的纳米颗粒制剂和（2）评估RGC轴突 大鼠视神经损伤模型的再生。

PROJECT SUMMARY In the U.S., approximately 2.2 million people suffer from optic neuropathies, accounting for 9 to 12% of all cases of blindness. Of them, 10% of patients that receive proper medical treatment continue to experience vision loss, which obviously needs an alternative treatment strategy. One of current treatments utilizes neurotrophic factors (NTFs) to increase retinal ganglion cell (RGC) survival, responsible for the visual function. While direct administration of NTFs via intravitreal injection has had some success, a susceptibility to denaturation of these NTFs limits its clinical success. Also, the delivery of NTFs alone may result in limited treatment success since optic neuropathies accompany neurodegeneration, caused by the neurotoxic cycles. To resolve these problems, we have engineered polymeric nanoparticles that mimic negatively charged sulfonate groups in natural heparin and deliver multiple therapeutic agents to continuously supply NTFs and inhibit the neurotoxicity. The advantages of our strategy include: 1) sustained delivery of NTFs at target site, mimicking continuous NTF transport, 2) prolonged bioactivity of NTFs encapsulated in the system and 3) sustained delivery of an anti-neurotoxic agent, continuously inhibiting neurodegeneration during the progression of optic neuropathies. We have constructed this application under two specific aims: (1) determine an appropriate nanoparticle formulation for the co-delivery of the multiple therapeutic agents and (2) evaluate RGC axon regeneration in rat optic nerve crush model.