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，约有1%的55岁以上的人受到影响。这种疾病与相对少量的称为多巴胺能神经元（DNs）的细胞的丧失有关，这些细胞位于大脑中心深处。PD是一种逐渐衰弱的疾病，患者目前使用药物和疗法来减轻症状的严重程度。然而，没有一种可用的治疗方法影响疾病的整体进展。因此，迫切需要开发一种能够减缓或理想情况下逆转PD进展的治疗方法。来自动物模型的有力证据表明，再生的DNs可以阻止PD的进展。促进DN存活的最有效方法是使用神经营养生长因子（nGFs）治疗（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）。nGFs是强效分子，如果全身（即静脉注射）使用，具有明显的潜在毒性，对健康的非靶细胞造成损害。因此，需要通过手术精确地给药。nGFs是易碎的蛋白质，半衰期很短，通常为几分钟到几个小时。然而，任何nGF药物都需要持续几周到几个月才能对dn产生可测量的影响。由于反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/或提供从储存库持续释放的ngf，这些ngf可以通过手术输送到大脑深处所需的位置。我们正在开发pod (POlyhedrin Delivery System)，这是最近开发的一种基于昆虫病毒生命周期中进化的自然系统的缓释蛋白质技术。通过设计这个系统，PODS能够在蛋白质晶体中整齐地包装和保护完美形成的nGFs。这些蛋白质晶体非常稳定，但在与活细胞中的蛋白酶接触时，它们开始松动并释放出宝贵的货物。货物蛋白的释放速度可以随时间控制，几个月的释放已经实现。我们已经用疾病的大鼠模型证明了pod的效用。PODS具有无与伦比的潜力，可以实现nGFs的承诺，为PD治疗提供重要的疾病改善疗法。在这个项目中，我们计划在基于细胞和小动物的PD模型中评估含有nGFs的各种pod晶体配方的潜力。”

"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."