Neurotrophic growth factors co-crystals for disease modifying therapy of Parkinson's disease

用于帕金森病疾病修饰治疗的神经营养生长因子共晶

• 批准号: 105102
• 金额: $ 26.6万
• 依托单位: CELL GUIDANCE SYSTEMS LIMITED
• 依托单位国家: 英国
• 项目类别: Feasibility Studies
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=105102
• 关键词: Neurotrophic; growth; factors; co; crystals

"Parkinson's disease (PD) is a neurodegenerative disorder that affects around 1% of individuals over the age of 55\. The disease is associated with loss of a relatively small number of cells, called dopaminergic neurons (DNs), which are located deep in the centre of the brain. PD is a progressively debilitating disease with patients currently treated using drugs and therapies to reduce the severity of the symptoms. However, none of the available therapies impact the overall progression of the disease. Therefore, there is an urgent, unmet clinical need to develop a therapy which is able to slow-down or, ideally, reverse the progression of PD.Strong evidence from animal models shows that regenerating DNs can arrest PD progression. The most effective way to promote DN survival is by treatment with neurotrophic growth factors (nGFs) (naturally occurring signalling proteins which are vital for the development and the maintenance of the healthy nervous tissue). nGFs are highly potent molecules which, if deployed systemically (i.e. intravenous), have marked potential for toxicity, causing damage to healthy non-target cells. Consequently, nGFs need to be precisely administered by surgery. nGFs are fragile proteins with very short half-lives, typically of _minutes to several hours_. However, any nGF drug needs to be active for _weeks to months_ in order to have a measurable effect on DNs. Since repeated surgery is impractical, a great focus of research has been the development of technologies and devices to stabilize, and/or provide sustained release of nGFs from a depot which can be surgically delivered to the required location, deep in the brain.We are developing PODS (POlyhedrin Delivery System), a recently developed sustained-release protein technology based on a natural system that evolved in an insect virus lifecycle. By engineering this system, PODS is able to neatly package and protect perfectly formed nGFs inside protein crystals. These protein crystals are highly stable but start to loosen and release their valuable cargo in contact with proteases from living cells. The rate of cargo protein release can be controlled over time, and release over several months has been achieved. We have demonstrated the utility of PODS using rat models of disease. PODS has the unparalleled potential to deliver on the promise of nGFs to provide vital disease-modifying therapy to treat PD. In this project, we plan to evaluate this potential in various PODS crystal formulations containing nGFs in cell-based and small animal models of PD."

“帕金森病 (PD) 是一种神经退行性疾病，影响约 1% 的 55 岁以上个体。该疾病与相对少量的细胞（称为多巴胺能神经元 (DN)）的丢失有关，这些细胞位于大脑深处。帕金森病是一种逐渐使人衰弱的疾病，目前正在使用药物和疗法来减轻症状的严重程度。然而，目前还没有任何可用的治疗方法。 治疗影响疾病的整体进展。因此，临床迫切需要开发一种能够减缓或理想情况下逆转 PD 进展的疗法。来自动物模型的有力证据表明，再生 DN 可以阻止 PD 进展。促进 DN 存活的最有效方法是使用神经营养生长因子 (nGF)（天然存在的信号蛋白，对于糖尿病肾病的发育和发育至关重要）进行治疗。 维持健康的神经组织）。 nGF 是一种高效分子，如果全身使用（即静脉注射），则具有显着的潜在毒性，对健康的非靶细胞造成损害。因此，nGF 需要通过手术精确施用。 nGF 是脆弱的蛋白质，半衰期非常短，通常为_分钟到几个小时_。然而，任何 nGF 药物 需要活跃_几周到几个月_才能对 DN 产生可衡量的影响。由于重复手术不切实际，研究的一大重点是开发稳定和/或持续释放 nGF 的技术和设备，这些技术和设备可以通过手术将 nGF 递送到大脑深处的所需位置。我们正在开发 PODS（多角体蛋白递送系统），这是一种最近开发的缓释蛋白 基于在昆虫病毒生命周期中进化的自然系统的技术。通过设计这个系统，PODS 能够整齐地包装和保护蛋白质晶体内完美形成的 nGF。这些蛋白质晶体高度稳定，但在与活细胞的蛋白酶接触时开始松散并释放其有价值的货物。货物蛋白的释放速率可以随着时间的推移进行控制，并且已经实现了几个月的释放。我们已经展示了 PODS 的实用性 使用大鼠疾病模型。 PODS 具有无与伦比的潜力，可以兑现 nGF 的承诺，为 PD 提供重要的疾病缓解疗法。在这个项目中，我们计划在基于细胞和小动物的 PD 模型中评估各种含有 nGF 的 PODS 晶体制剂的这种潜力。”