Technologies for the Treatment of Brain Diseases

Lead Research Organisation: University of Exeter
Department Name: Physics

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.
 
Description The poor bioavailability of peptides, nature's own 'drugs', limits their therapeutic application. Molecular envelope technology (MET) delivery allows their use as nanoenabled medicines, with an up to 18-fold increase in brain levels. The multi-disciplinary 'Peptide Pill' consortium aimed to develop the pain peptide pill METDoloron. 20% of European adults suffer from chronic pain often inadequately controlled by opioids, which often have life threatening side effects. METDoloron avoids these problems by targeting a different receptor and using an endogenous peptide and is therefore expected to have a significant impact on the large (US$ 50 bn), fragmented, and growing pain market for pain.



This project was part of a larger consortium lead by The London School of Pharmacy (UCL), to confirm the pharmacology, transport mechanisms, established scale-up and manufacturing processes, and confirm product safety of METDoloron. In achieving this the project created new know-how in biophotonics, pain therapy, flow reactor design and nanoparticle processing techniques.

Exeter's specific contribution to the project was to provide novel information on mechanisms by which the nanoparticles enhance the delivery of the drugs from both oral and IV routes to the brain. Exeter have leading expertise in the application of non-linear optical microscopy for imaging the interaction of nanomaterials in biological tissues and in a long-standing collaboration with the London School of Pharmacy have developed label-free optical imaging techniques to provide mechanistic data regarding the uptake of polymeric nanomedicines. The label-free nature of these developmental techniques proved essential since they remove the reliance on fluorescent markers which are know to perturb the transport kinetics of drugs.



This project made the following key contributions to the development of METDoloron:

1. Using Coherent Raman Scattering (CRS) microscopy we detected deuterated polymeric nanoparticles within mice and rats following a range of dosing routes. We have confirmed that after oral dosing in mice, the particles cross the epithelium of the intestine, from whence they travel to the liver, kidneys and lungs. We have identified several cell types (hepatocytes, white blood cells etc.) inside which the particles are found in discrete volumes of 1 - 6 microns, co-localised with strong CH signal, which suggest potential clearing mechanisms of the particles from the body. The discovery of particles within the liver hepatocytes and bile canaliculi provides further evidence for the recirculation pathway of these particles from the Gi tract to the liver and then back into the gut via the release of bile from the gall bladder.

2. We have demonstrated the adherence of particles to the endothelium of blood vessels within the brains of mice after IV dosing. However, there was no evidence for adherence of these particles to peripheral vasculature, which suggests that the particles preferentially adhere to blood vessels within the brain.

3. Nasal dosing of rats has also shown to be an effective technique for transferring particles into the brain. We have shown that the particles are found in the olfactory bulb at 2 and 5 minutes after nasal dosing, and within the basal ganglia at 1 hour after nasal dosing.
Exploitation Route To fully exploit the potential impacts of METDoloron, Nanomerics has entered into a mutually beneficial alliance with Depomed in order to progress METDoloron to clinical development (please see accompanying GANNT chart). Depomed has product launch experience, having recently launched a neuropathic pain product - Gralise, and have a marketing resource and a contracted sales force. To fully exploit the MET platform and generate partnering opportunities, Nanomerics will aggressively market its capability once each of the key validation steps has been reached, e.g. on achieving dosage form scale up, on filing an investigational new drug application and particularly once METDoloron has been validated in humans. The main output from this research is a set of protocols, data and materials that will lead to the first in human trials of molecular envelope technology for the delivery of peptides (MET Doloron). The launch of METDoloron, a new pain therapeutic with a better safety profile, should contribute to the UK's economic competitiveness, as royalties will flow to Nanomerics.

With respect to quality of life improvements METDoloron is expected to provide improved pain therapy, with fewer deleterious side effects for some of the 80% of the world's population that have inadequate access to pain relief.

The project also has indirect effects on UK R&D because of its strategic importance for the partnering companies. The project brought together the capabilities of two innovative technologies, Nanomerics' MET platform technology and AMT's Coflore system. Both enabling technologies with clear USPs and product profiles that make them attractive for their target markets. Nevertheless, significant market entry barriers existed for both novel technologies, in particular in the pharmaceutical industry. This project demonstrated the effectiveness of both technologies for this industry thus dramatically reducing market barriers and allowing the partner companies to attract further UK R&D investment for additional projects.
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Findings from this award have been used to leaver funding to develop a novel nano medicine that will be taken to clinical trials.
First Year Of Impact 2015
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description University of Exeter
Amount £95,034 (GBP)
Funding ID TS/J004820/1 
Organisation University of Exeter 
Sector Academic/University
Country United Kingdom
Start 08/2012 
End 08/2014