Hydrogels for combined delivery of novel growth factor mimetics and small molecule ligands for treatment of CNS damage

Lead Research Organisation: University College London
Department Name: School of Pharmacy

Abstract

Central nervous system (CNS) damage and disease is a leading cause of disability, resulting in symptoms such as cognitive impairment, loss of sensory function, paralysis, chronic pain and severely impaired quality of life. CNS damage has a variety of possible causes, including traumatic injury to the brain or spinal cord, ischaemia or hypoxia resulting from vascular disorders or stroke, and a wide range of congenital or degenerative diseases. Despite intensive research into understanding both acute and chronic CNS damage, limited treatment options are available for most conditions. There are major challenges around the formulation and delivery of medicines for application in the CNS which can be addressed through the development of new pharmaceutical technology.
It is known that CNS damage and neurodegeneration can be positively modulated by a variety of small molecule ligands and growth factors. For example, growth factors such as glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been shown to promote neuronal regeneration in models of Parkinson's and Alzheimer's disease with some promise in early clinical tests.1 At present, the delivery of growth factors to the CNS relies on either direct infusion of the protein, or production of the protein via gene or cell therapies. Cell therapies are the method of choice for delivery of growth factors to the brain over long periods, however immunosuppression is required to prevent activation of the immune response and the cost and complexity of this approach is prohibitive. There remains a critical need for new treatments for CNS damage which are safe and effective, suitable for scalable manufacture, and do not cause adverse host immune and inflammatory responses.
Direct delivery of growth factors themselves eliminates the need for cell and gene therapies and immunosuppression in treatment, but there are inherent difficulties in delivering these proteins to the CNS. Further, if the domain of the growth factor responsible for receptor activation is known, these could be synthesised and used as therapies themselves. The viability of this approach has previously been demonstrated with peptide mimetics of BDNF and NGF.2,3 Decreasing the size of the active agent also has the advantage that delivery formulations can be loaded with higher doses, meaning that longer-term treatments become possible without cell or gene therapies or frequently repeated dosing. One drawback of this approach is that the dose of growth factor available in the CNS after administration is limited by low blood-brain-barrier permeability and poor in vivo half-life of the proteins.
This project aims to address this issue by developing a hydrogel local delivery formulation for small molecule ligands and growth factor mimetics which will promote neural regeneration and restoration of CNS function. Hydrogels are 3D polymeric networks which are hydrophilic and biocompatible, and can be loaded with cargoes which are released slowly over time as the polymer biodegrades. Steady release of cargo over time is essential for this project, because growth factor receptors can become desensitised when exposed to continually high levels of growth factor. Additionally, hydrogels mimic the architecture and mechanical properties of the nervous system which minimises adverse host tissue responses, making them ideal delivery systems for CNS therapies. Ligands and growth factor mimetics with implications in neuroregeneration will be synthesised and incorporated into hydrogel formulations to ensure long-term local release of the active agents and prevent premature degradation. The developed formulations will be characterised and tested using in vitro cellular models of CNS damage.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023054/1 01/10/2019 31/03/2028
2425891 Studentship EP/S023054/1 28/09/2020 27/09/2024 Emily Anne Atkinson