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

"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."