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

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.

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.