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

“帕金森病（PD）是一种神经退行性疾病，影响约1%的55岁以上的人。这种疾病与相对少量的细胞损失有关，称为多巴胺能神经元（DN），位于大脑中心深处。PD是一种进行性衰弱性疾病，患者目前使用药物和疗法治疗，以减轻症状的严重程度。然而，现有的治疗方法都不会影响疾病的总体进展。因此，有一个迫切的，未满足的临床需要，以开发一种治疗，这是能够减缓或，理想情况下，逆转PD的进展。来自动物模型的有力证据表明，再生DN可以阻止PD的进展。促进DN存活的最有效方法是用神经营养生长因子（nGF）（天然存在的信号蛋白，对健康神经组织的发育和维持至关重要）治疗。nGF是高度有效的分子，如果全身（即静脉内）部署，则具有明显的毒性潜力，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是具有非常短的半衰期的脆弱蛋白质，通常为几分钟至几小时。然而，任何nGF药物都需要持续数周至数月才能对DN产生可测量的影响。由于重复手术是不切实际的，因此研究的重点一直是开发技术和设备，以稳定和/或提供持续释放的nGFs从一个仓库，可以通过手术输送到所需的位置，在大脑深处。我们正在开发PODS（多角体蛋白输送系统），这是最近开发的持续释放蛋白质技术，基于自然系统，在昆虫病毒的生命周期中进化。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。这些蛋白质晶体是高度稳定的，但在与活细胞中的蛋白酶接触时开始松动并释放其有价值的货物。货物蛋白释放的速率可以随时间控制，并且已经实现了几个月的释放。我们已经使用大鼠疾病模型证明了PODS的实用性。PODS具有无与伦比的潜力，可以兑现nGF的承诺，提供治疗PD的重要疾病修饰疗法。在这个项目中，我们计划在PD的细胞和小动物模型中评估含有nGF的各种PODS晶体制剂的这种潜力。"

"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."