Technologies for the Treatment of Brain Diseases

Lead Research Organisation: School of Pharmacy
Department Name: Pharmaceutics

Abstract

The Grand Challenge is the treatment of brain diseases. Brain diseases span pain, sleep disorders, schizophrenia, mood disorders and neurodegenerative conditions. At any time 450 million persons worldwide are living with mental, neurological or behavioural illnesses and 24 million people worldwide suffer from dementias. The treatment of brain diseases is hampered by the blood brain barrier (BBB), a barrier between the blood and the brain which does not permit the passage of most drug molecules, due to the tightness of the intercellular capillary junctions, low uptake activity of capillary cells and the activity of efflux transporters. Previous attempts to target drugs to the brain and cross the BBB have involved the use of targeting ligands, e.g. mouse monoclonal antibodies for carrier mediated uptake or the inhibition of the above mentioned efflux transporters. However all of the particulate-based strategies (including the use of mouse monoclonal antibodies) that have been investigated over the last two decades have yet to yield any clinical products and the inhibition of the high capacity efflux transporters, which incidentally are not merely confined to the BBB, is not a viable clinical option. Our multidisciplinary consortium drawn from academia and industry (GSK) propose a new nanoscience based strategy founded on two recent significant findings: a) chitosan amphiphile based nanoparticles significantly increase the central activity of hydrophobic and peptides drugs via the intravenous and crucially oral routes, b) apolipoprotein E targeted nanoparticles bypass the brain capillary efflux transporters and cross the BBB, increasing drug delivery to the brain. The project aims to use these data to create an optimised nanotechnology brain delivery platform for peptides and low molecular weight drugs with low brain permeability. These drug classes represent the bulk of the compounds which are trapped in the drug development bottleneck due to: a) their poor brain exposure and b) the absence of suitable brain targeting strategies. Candidate drugs to be used are potential treatments for schizophrenia, pain and sleep disorders. These compounds and their potential indications are particularly relevant to the call (targeting psychiatric diseases) and a specific output of the project is a candidate medicine for the treatment of psychiatric or neurological disorders. The project will involve a significant level of particle engineering, where particle matrix chemistry, surface chemistry (including the discovery and evaluation of other BBB targeting peptides) and particle size will be systematically varied and the impact of these variations tested using in vitro and animal models. The resulting pharmacokinetic, pharmacodynamic and mechanistic data will inform the optimisation of the platform which is the ultimate goal of the project. Fundamentally the mechanism of brain permeation of the drug cargoes will be studied and elucidated en route to the optimised nanosystem and this will also fulfil a requirement of regulators and health providers, who desire an underlying mechanistic basis for new health technologies. Stage 2 of the project (GSK fully supported) will focus on the development of a clinical medicine based on the nanotechnology platform.Public engagement activities will occur via our nanomedicines.org website and also via public communication of science events. The key beneficiaries of the project will be patients, carers and the pharmaceutical industry as the platform will pave the way for novel therapeutic targets to be exploited. The engagement of scientists, with a past history of collaboration and a strong track record in nanoscience innovation, therapeutic target discovery, lead identification, drug targeting, translating scientific concepts to clinical products and basic brain physiology makes the consortium ideally suited to deliver the nanoscience based drug targeting goals of the Grand Challenge.

Publications

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Cassano R (2013) Dextran-pegylated microparticles for enhanced cellular uptake of hydrophobic drugs. in European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

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Fisusi FA (2018) Nanomedicines in the treatment of brain tumors. in Nanomedicine (London, England)

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Gewin Virginia (2018) It takes more than a vow in NATURE

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Godfrey L (2018) Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia. in Journal of controlled release : official journal of the Controlled Release Society

 
Description The project resulted in the development of oral to brain peptide delivery pharmaceutical nanotechnology and the discovery that peptide nanofibres could be used to deliver peptides to the brain. The project also uncovered mechanistic insights into these two technologies.
Exploitation Route Nanomerics aims to become a multimillion pound company with its own pharmaceutical products based on its Molecular Envelope Technology and also aims to form partnerships with drug discovery companies in order to enable difficult molecules to transition into the clinic.


Founded Nanomerics Ltd (Company Number = 073730430) in September 2010.



Attracted a TSB grant (101163) into Nanomerics for the development of METDoloron, an oral neuropeptide medicine for the treatment of chronic neuropathic pain.



Has signed deals with partner pharmaceutical companies for paid for feasibility work and an option to licence.
Sectors Healthcare

URL http://www.nanomerics.com
 
Description The findings support the use of innovative polymer for drug development by Nanomerics Ltd.
First Year Of Impact 2013
Sector Healthcare
Impact Types Economic

 
Description Technology Strategy Board
Amount £1,550,000 (GBP)
Funding ID 16939-124181 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 08/2012 
End 07/2014
 
Title Delivering hydrophilic drugs to the brain. 
Description A method of delivering hydrophilic drugs to the brain is disclosed. 
IP Reference WO2015063510 
Protection Patent application published
Year Protection Granted
Licensed No
Impact This discovery will enable the delivery of peptides to the brain.
 
Title Delivery of hydrophilic peptides 
Description A patent application protecting the use of peptide self assemblies to deliver peptides to the brain. 
IP Reference WO2012004610 
Protection Patent granted
Year Protection Granted
Licensed Yes
Impact This intellectual property has been licensed to Nanomerics Ltd.
 
Title Polymeric micellar clusters 
Description A composition of matter is disclosed for delivering drugs. 
IP Reference US8470371 
Protection Patent granted
Year Protection Granted
Licensed Yes
Impact This technology underpins the UCL spin out company Nanomerics Ltd.
 
Company Name Nanomerics 
Description Nanomerics Ltd (Company Number: 07373043) was founded in September 2010 to develop METDoloron - a leucine5-enkephalin based therapeutic for the treatment of neuropathic pain. The Wellcome Trust funded work on the delivery system - quaternary ammonium palmitoyl glycol chitosan - that also derisked the company's intellectual property portfolio. A grant of £650,000 was received in 2007. 
Year Established 2010 
Impact The company is now attracting revenues and will turn over £0.5 M in 2013.