The development of innovative techniques for controlled drug delivery to the central nervous system
Lead Research Organisation:
North Bristol Nhs Trust
Department Name: Directorate of Neurosciences
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The blood-brain barrier represents a considerable hurdle to the delivery of drugs to the nervous
system. We propose to develop innovative techniques to bypass this barrier that could
revolutionise the management of numerous neurological diseases.
Convection-enhanced delivery (CED) utilises extremely fine intracranial catheters and low infusion rates to impart drugs directly into the brain extracellular space. In contrast to direct
intraparenchymal injection, encapsulated cells and biodegradeable polymers, CED does not
depend on diffusion. The use of a carefully designed cannula with a precisely controlled infusion
rate leads to the development of a pressure gradient, along which drug passes directly into the
extracellular space. Consequently, unlike diffusion, it is possible to achieve controlled,
homogeneous drug distribution, regardless of drug molecular size, over large volumes of the
brain.
The principal limitation of CED is that the distribution of drugs through the extracellular space can
be unpredictable. The key factors affecting drug distribution by CED are catheter design and site
of placement, infusion flow-rate, drug charge and non-specific drug binding. At present, although
there are a number of clinical trials attempting to administer drugs using this technique, there are
no commercially available catheters that have been designed to tackle these issues, and indeed
the available evidence suggests that the catheters in use are incompatible with successful CED.
We propose to develop a versatile, stereotactically inserted drug delivery system, with associated software, that is capable of delivering neurotrophic proteins, as well as liposomal and viral vectormediated gene therapy and RNA interference in a controlled and predictable manner. The use of synthetic brain models and post-mortem brain specimens would allow evaluation of novel catheter designs, insertion techniques, coinfusion agents and infusion parameters and discourage the use of primates in the modelling of CED.
Aside from the optimisation of CED we propose to evaluate entirely novel concepts that may
dramatically improve drug delivery. We intend to utilise available knowledge on safe current
application to the brain, derived from the technique of deep brain stimulation (DBS), to improve
drug delivery. As proteins, liposomes and viruses typically possess an intrinsic charge, it should
be possible to achieve “steerable” drug movement through the brain, in a comparable approach
to transdermal iontophoresis. This would be particularly relevant in the safe delivery of gene
therapy or RNA interference in which gene expression or repression is required in tightly
controlled anatomical structures.
This research represents innovative, but high-risk research. We will be working closely with a
number of researchers to optimise the delivery of novel therapeutic agents, including
neurotrophic factors for Parkinson’s disease, RNA interference for Huntington’s disease and
hereditary ataxias, as well as oncolytic viruses for brain tumours. The development of an efficient drug delivery system capable of precisely controlled delivery of these agents has the potential to revolutionise the management of these conditions and is ideal for Milstein funding.
system. We propose to develop innovative techniques to bypass this barrier that could
revolutionise the management of numerous neurological diseases.
Convection-enhanced delivery (CED) utilises extremely fine intracranial catheters and low infusion rates to impart drugs directly into the brain extracellular space. In contrast to direct
intraparenchymal injection, encapsulated cells and biodegradeable polymers, CED does not
depend on diffusion. The use of a carefully designed cannula with a precisely controlled infusion
rate leads to the development of a pressure gradient, along which drug passes directly into the
extracellular space. Consequently, unlike diffusion, it is possible to achieve controlled,
homogeneous drug distribution, regardless of drug molecular size, over large volumes of the
brain.
The principal limitation of CED is that the distribution of drugs through the extracellular space can
be unpredictable. The key factors affecting drug distribution by CED are catheter design and site
of placement, infusion flow-rate, drug charge and non-specific drug binding. At present, although
there are a number of clinical trials attempting to administer drugs using this technique, there are
no commercially available catheters that have been designed to tackle these issues, and indeed
the available evidence suggests that the catheters in use are incompatible with successful CED.
We propose to develop a versatile, stereotactically inserted drug delivery system, with associated software, that is capable of delivering neurotrophic proteins, as well as liposomal and viral vectormediated gene therapy and RNA interference in a controlled and predictable manner. The use of synthetic brain models and post-mortem brain specimens would allow evaluation of novel catheter designs, insertion techniques, coinfusion agents and infusion parameters and discourage the use of primates in the modelling of CED.
Aside from the optimisation of CED we propose to evaluate entirely novel concepts that may
dramatically improve drug delivery. We intend to utilise available knowledge on safe current
application to the brain, derived from the technique of deep brain stimulation (DBS), to improve
drug delivery. As proteins, liposomes and viruses typically possess an intrinsic charge, it should
be possible to achieve “steerable” drug movement through the brain, in a comparable approach
to transdermal iontophoresis. This would be particularly relevant in the safe delivery of gene
therapy or RNA interference in which gene expression or repression is required in tightly
controlled anatomical structures.
This research represents innovative, but high-risk research. We will be working closely with a
number of researchers to optimise the delivery of novel therapeutic agents, including
neurotrophic factors for Parkinson’s disease, RNA interference for Huntington’s disease and
hereditary ataxias, as well as oncolytic viruses for brain tumours. The development of an efficient drug delivery system capable of precisely controlled delivery of these agents has the potential to revolutionise the management of these conditions and is ideal for Milstein funding.
Organisations
- North Bristol Nhs Trust, United Kingdom (Lead Research Organisation)
- University College London, United Kingdom (Collaboration)
- Amgen Inc (Collaboration)
- University of Cambridge (Collaboration)
- Oxford BioMedica UK Ltd (Collaboration)
- University of Bristol, United Kingdom (Collaboration)
- Renishaw Plc, United Kingdom (Collaboration)
- Hermo Pharma (Collaboration)
People |
ORCID iD |
Steven Gill (Principal Investigator) |
Publications


Bienemann A
(2012)
The development of an implantable catheter system for chronic or intermittent convection-enhanced delivery.
in Journal of neuroscience methods

Kenny GD
(2013)
Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain.
in Biomaterials

Killick-Cole CL
(2017)
Repurposing the anti-epileptic drug sodium valproate as an adjuvant treatment for diffuse intrinsic pontine glioma.
in PloS one

Singleton WG
(2017)
Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model.
in International journal of nanomedicine

Tsujiuchi T
(2014)
Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains.
in American journal of translational research

White E
(2011)
A robust MRI-compatible system to facilitate highly accurate stereotactic administration of therapeutic agents to targets within the brain of a large animal model.
in Journal of neuroscience methods

White E
(2011)
An evaluation of site-specific immune responses directed against first-generation adenoviral vectors administered by convection-enhanced delivery.
in The journal of gene medicine


White E
(2012)
A phase I trial of carboplatin administered by convection-enhanced delivery to patients with recurrent/progressive glioblastoma multiforme.
in Contemporary clinical trials
Description | EPSRC Nanotechnology for Healthcare EP/G061831/1 Nanoparticles for the Targeted Delivery of Therapeutic Agents to the Brain for the Treatment of Dementias |
Amount | £21,195 (GBP) |
Funding ID | EP/G061831/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2009 |
End | 03/2012 |
Description | MRC MR/J005134/1. Convection-enhanced delivery of encapsulated nanosperes for controlled delivery of chemotherapy to the brain |
Amount | £800,000 (GBP) |
Funding ID | MR/J005134/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2011 |
End | 11/2013 |
Title | ICP-MS |
Description | Inductively coupled plasma mass spectrometry (ICP-MS) is a type of mass spectrometry which is capable of detecting metals and several non-metals at concentrations as low as one part in 1012 (part per trillion). Used .for ongoing projects in collaboration with Sheffield university |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | Excellent quantitative results obtained. |
Description | AAV |
Organisation | University of Cambridge |
Department | Department of Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have evaluated and optimised the administration of recombinant adeno-associated viral vectors by convection-enhanced delivery in both small and large animal models. |
Collaborator Contribution | Provision of viral vectors for testing in animal models. |
Impact | Plans to conduct a gene therapy trial for Tay-Sachs disease in 2012. |
Start Year | 2007 |
Description | Diffusion imaging |
Organisation | University College London |
Department | Department of Computer Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We initiated a project and provided the raw data to undertake studies attempting to use diffusion imaging to predict drug distribution in the brain. |
Collaborator Contribution | This collaboration has allowed us to optimise the MR imaging performed in our preclinical studies. |
Impact | Mathematical models have been developed in an attempt to visualise the brain extracellular space. These are currently being tested. Tractography atlases of rat and pig brain have also been developed. |
Start Year | 2008 |
Description | EIAV |
Organisation | Oxford BioMedica UK Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have evaluated and optimised the administration of lentiviral vectors by convection-enhanced delivery in both small and large animal models. |
Collaborator Contribution | Provision of lentiviral vectors for testing in animal models. |
Impact | Publication due for submission Jan, 2010. |
Start Year | 2007 |
Description | HSV |
Organisation | Amgen Inc |
Department | Biovex |
Country | United States |
Sector | Private |
PI Contribution | We have evaluated and optimised the administration of HSV-1-based viral vectors by convection-enhanced delivery in both small and large animal models. |
Collaborator Contribution | Provision of herpes simplex-1 based viral vectors for testing in vivo. |
Impact | Publication due for submission Jan, 2010. |
Start Year | 2007 |
Description | Mathematical Modelling |
Organisation | University of Bristol |
Department | School of Mathematics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We initiated this project and supplied raw data for our collaborators to develop mathematical models of drug distribution through the brain. |
Impact | This collaboration has led to the development of a mathematical model of drug distribution by convection-enhanced delivery. We are in the process of testing this model in vivo. |
Start Year | 2008 |
Description | Nanoparticle Project |
Organisation | University College London |
Department | Institute of Child Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We evaluated the ability of these nanoparticles to transduce cells in vivo. In addition we examined the immune responses directed against these nanoparticles when infused into the brain. |
Collaborator Contribution | Provision of receptor-targeted, MRI-visible nanoparticles for testing in animal models. |
Impact | Publication due for submission December 2009. |
Start Year | 2007 |
Description | Pre-clinical CDNF Distrubution Studies |
Organisation | Hermo Pharma |
Country | Finland |
Sector | Private |
PI Contribution | Research partners |
Collaborator Contribution | The purpose of this study is assess the distribution infused CDNF in order for clinical studies to occur in the future |
Impact | Knowledge to aid Large preclinical and clinical trials. |
Start Year | 2011 |
Description | Surgical Equipment |
Organisation | Renishaw PLC |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have evaluated their drug delivery equipment in large animal models. |
Collaborator Contribution | Renishaw have provided stereotactic surgical equipment that have allowed us to undertake experiments in large animals. |
Impact | Collaboration with medical engineering company to develop drug delivery equipment for use in humans. |
Start Year | 2006 |
Description | 3rd International Symposium on Convention Enhanced Delivery to the Brain |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Health professionals |
Results and Impact | 3rd International Symposium on Convention Enhanced Delivery to the Brain I gave a talk with regard to our experiences with techniques of direct intracranial drug delivery. |
Year(s) Of Engagement Activity | 2007 |
Description | Blood-Brain Barrier Consortium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Health professionals |
Results and Impact | Gave a talk to a consortium of health care professionals involved in caring for patients with lysosomal storage diseases. This talk led to discussions regarding future treatment strategies that could be employed to treat the neurological complications of lysosomal storage diseases. These discussions may lead to clinical trials being initiated. |
Year(s) Of Engagement Activity | 2007 |
Description | British Paediatric Neurology Association 2006 Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Health professionals |
Results and Impact | I gave a talk on the future surgical therapies for paediatric movement disorders to paediatric neurologists nationally. Nil. |
Year(s) Of Engagement Activity | 2006 |
Description | Conference (2015) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Surgical Modification of Neurodegenerative Disorders Dementia-HIT Research Showcase, University of Bristol Knowledge sharing of CED to other researchers |
Year(s) Of Engagement Activity | 2015 |
Description | Conference (Liverpool) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | he 17th International Symposium on Pediatric Neuro-Oncology will be held June 12 - 16, 2016 in the vibrant city of Liverpool. The meeting will follow the successful format of previous ISPNO meetings with a full program of plenary and poster sessions covering all the main aspects of paediatric neuro-oncology. In addition, the organizers plan to host an education day and a neuro-oncology nurses meeting. Congress will include keynote lectures from world leading speakers and a number of lively debates on key areas of this speciality. In addition to the scientific aspects of the congress, ISPNO 2016 will offer a rich network and social environment that is considered a key aspect of a major international congress. We had a poster and an oral presentation show casing our work. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.soc-neuro-onc.org/events/160/ |
Description | Conference (2015) Ireland |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Nov 2015 Robot-assisted Deep Brain Stimulation for Pain Neuromodulation Society of the UK and Ireland, London, UK |
Year(s) Of Engagement Activity | 2015 |
Description | Dutch Childhood Oncology Group and Adult Drug Delivery Symposium 15th May 2017 |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Dutch Childhood Oncology Group and Adult Drug Delivery Symposium 15th May |
Year(s) Of Engagement Activity | 2017 |
Description | First Hammer Out Patient/Carer Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Participants in your research and patient groups |
Results and Impact | I gave a talk to patients and carers of patients with primary brain tumours regarding our research into new techniques and treatments for brain tumours. Nil. |
Year(s) Of Engagement Activity | 2008,2012 |
Description | Friends of Bristol Haematology and Oncology Centre |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Participants in your research and patient groups |
Results and Impact | I gave a talk to patients with cancer and members of the public with regard to the development of techniques to administer drugs to the brain. This meeting led to a significant donation to support our research. |
Year(s) Of Engagement Activity | 2006 |
Description | GDNF Phase II Study Planning Meeting |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | A number of company, health professionals and researcher involved in the collaboration Engagement in the role of all interested parties |
Year(s) Of Engagement Activity | 2012 |
Description | Mini-Symposium on Drug Delivery to the Brain - FDA - Washington 19th December |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Mini-Symposium on Drug Delivery to the Brain |
Year(s) Of Engagement Activity | 2017 |
Description | Minneapolis |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I gave a talk on the surgical management of movement disorders to health care professionals and members of the medical devices industry. Nil. |
Year(s) Of Engagement Activity | 2006 |
Description | NCRI - Brain Tumour Technology Subgroup Committee |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Health professionals |
Results and Impact | I presented evidence to the NRCI Brain Tumour Technology Subgroup Committee regarding techniques of drug delivery to patients with brain tumours. I specifically discussed the technique of convection-enhanced delivery. This committee is now seeking to develop and support a phase I/II study of convection-enhanced delivery of conventional chemotherapeutic agents in the management of patients with high-grade gliomas. |
Year(s) Of Engagement Activity | 2008 |
Description | Neurological Society of Australasia, Auckland |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Health professionals |
Results and Impact | I gave a talk to health care professionals regarding the development of novel therapies for Parkinson's disease, based on direct intracranial delivery of neurotrophic agents. Nil. |
Year(s) Of Engagement Activity | 2008 |
Description | Neuromodulation Symposium (Budapest) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | I gave a talk to health care professionals, members of the medical device industry and the public on the subject of techniques of drug delivery to the brain for the treatment of movement disorders. Nil. |
Year(s) Of Engagement Activity | 2009 |
Description | Royal Society of Medicine |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Health professionals |
Results and Impact | I gave a talk to health care professionals regarding the development of novel therapies for Parkinson's disease, based on direct intracranial delivery of neurotrophic agents. Nil. |
Year(s) Of Engagement Activity | 2006 |
Description | Society for CNS Interstitial Delivery of Therapeutics (SCIDOT) Meeting San Francisco 15th/16th November |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The Society for Neuro-Oncology (SNO) and the Society for CNS Interstitial Delivery of Therapeutics (SCIDOT) invite you to attend the 2017 SNO-SCIDOT Joint Conference on Therapeutic Delivery to the CNS which will be held on November 15-16, 2017 at the Marriott Marquis Hotel in San Francisco, California (in conjunction with the SNO Annual Meeting). The conference organizers will include abstract presentations of original research on the interstitial delivery of therapeutics to the CNS selected from the following categories: BBB Physiology and Barriers to CNS drug distribution Pharmacokinetics and pharmacodynamics of CNS therapeutics Methods for evaluating drug delivery to the CNS Devices that directly treat CNS pathology Pharmacologic approaches to overcoming the BBB Devices for delivery of therapeutics to the CNS Nanoparticles and liposomes for drug delivery Gene therapy for CNS pathology Clinical trials using convection enhanced delivery Regulatory considerations for delivery of therapeutics directly into the CNS Mathematical and computational modeling of transport in the CNS |
Year(s) Of Engagement Activity | 2017 |
Description | Society for Neuro-Oncology Meeting - New York 15th/16th June |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Society for Neuro-Oncology Meeting - New York 15th/16th June |
Year(s) Of Engagement Activity | 2017 |
Description | South-West Oncology Study Day |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Health professionals |
Results and Impact | Talks were given to health care professionals involved in the care of patients with brain tumours, with regard to experimental treatment strategies to manage these patients. This talk led to financial donations being given to further this project. |
Year(s) Of Engagement Activity | 2007 |
Description | The Bristol Medico-Chirurgical Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Health professionals |
Results and Impact | I gave a talk on techniques of drug delivery to the brain for the treatment of a range of neurological diseases. Nil. |
Year(s) Of Engagement Activity | 2008 |
Description | The DIPG Collaborative Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | DIPG Collaborative Symposium 2017 |
Year(s) Of Engagement Activity | 2017 |
Description | World Society for Stereotactic and Functional Neurosurgery |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | I gave a talk to health care professionals regarding the development of methods of drug delivery to the brain for the treatment for a range of neurological diseases. Nil. |
Year(s) Of Engagement Activity | 2009 |