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.

Publications

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publication icon
Writer MJ (2012) Lipid peptide nanocomplexes for gene delivery and magnetic resonance imaging in the brain. in Journal of controlled release : official journal of the Controlled Release Society

 
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 04/2009 
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 05/2011 
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