The development of innovative techniques for controlled drug delivery to the central nervous system

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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.