Evaluation of optimised heparins as novel therapeutics for Alzheimers Disease

Lead Research Organisation: University of Liverpool
Department Name: Sch of Biological Sciences

Abstract

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Technical Summary

The key step in the generation of toxic Abeta peptides that cause Alzheimer's disease (AD) is the action of an enzyme known as BACE1. We have recently discovered that a naturally occurring complex sugar called heparan sulphate (HS) is a regulator of BACE1 activity. The anti-coagulant drug heparin is a member of the HS family of molecules and we have generated a semi-synthetic modified heparin as a lead compound which is a powerful BACE1 inhibitor, has very low anticoagulant activity, and is not toxic in mice. Optimised heparins thus have potential as a new class of anti-AD drugs. In this proposal we will test a novel modified heparin in a validated mouse model of AD, and make initial assessments of the bioavailability of the compound and its ability to cross the blood/brain barrier. An assessment of the potential market for a novel heparin-based Alzheimer's drug will also be made. The overall goal of this project will be to establish proof-of-concept in an animal model of the use of an optimised heparin as a novel treatment for Alzheimer's Disease. This will enhance the opportunities for commercial exploitation through either a licening deal or development of a spin out company.

Publications

10 25 50
 
Description Developed candidate compounds as inhibitors of BACE1 for treatment of AD
Exploitation Route Further translational research
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Further preclinical development of candidate compounds as inhibitors of BACE1 for treatment of AD
First Year Of Impact 2010
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Title Engineered heparins 
Description Libraries of selectively chemically modified heparins for applications in heparin-based drug discovery. 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Exploited for a number of publications and to develop drug leads for AD, malaria, ant-cancer therapeutics and spinal repair therapies. 
 
Title Heparan sulphate saccharide libraries 
Description Development of technologies for and production of complex libraries of HS saccharides 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Novel discoveries of structure-activity relationships for complex HS saccharides of relevance to biological and disease processes 
 
Title Novel brain slice assays for ex vivo screening in transgenic mouse models 
Description Developed a brain tissue slice ex vivo culture assay which allows screening of the effects of exogenous compounds on brain tissue biochemistry. This is particularly useful for obtaining data on the activity of for example BACE1 inhibitors on Abeta levels, using transgenic mouse models. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Publication in preparation for submission. 
 
Description Animal testing of AD secretase inhibitors 
Organisation University of Leicester
Department Department of Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution Develeopment of novel compounds as inhibitors for the Alzheimers beta-secretase
Collaborator Contribution Provision of transgenic mouse models of AD
Impact IP and patenting + publications
 
Description Animal testing of AD secretase inhibitors 
Organisation University of Oslo
Department Department of Medical Biochemistry
Country Norway 
Sector Academic/University 
PI Contribution Develeopment of novel compounds as inhibitors for the Alzheimers beta-secretase
Collaborator Contribution Provision of transgenic mouse models of AD
Impact IP and patenting + publications
 
Description Animal testing of AD secretase inhibitors 
Organisation Uppsala University
Department Department of Medical Biochemistry and Microbiology
Country Sweden 
Sector Academic/University 
PI Contribution Develeopment of novel compounds as inhibitors for the Alzheimers beta-secretase
Collaborator Contribution Provision of transgenic mouse models of AD
Impact IP and patenting + publications
 
Description Development of AD therapeutics 
Organisation Callaghan Innovation
Department Carbohydrate Chemistry
Country New Zealand 
Sector Private 
PI Contribution Providing target structures and bioassays
Collaborator Contribution Developing synthetic chemistry for BACE inhibitors and providing compounds and radiolabelled compounds
Impact Chem Eur J publication, further manuscripts in preparation, joint funding and IP patent submissions
Start Year 2008
 
Description Development of AD therapeutics 
Organisation Victoria University of Wellington
Department Ferrier Research Institute
Country New Zealand 
Sector Academic/University 
PI Contribution Providing target structures and bioassays
Collaborator Contribution Developing synthetic chemistry for BACE inhibitors and providing compounds and radiolabelled compounds
Impact Chem Eur J publication, further manuscripts in preparation, joint funding and IP patent submissions
Start Year 2008
 
Description Synthetic chemistry for HS analogues 
Organisation Callaghan Innovation
Department Carbohydrate Chemistry
Country New Zealand 
Sector Private 
PI Contribution Design of target molecules for synthesis and provision of bioassays for screening
Collaborator Contribution Development of advanced synthetic chemistry to produce heparan sulphate saccharides Major contribution in kind through New Zealand government grants to fund their chemistry development
Impact Publication in JACS and Chem Euro Journal and ongoing collaborations
 
Description Synthetic chemistry for HS analogues 
Organisation Industrial Research Ltd
Department Glycochemistry Division
Country New Zealand 
Sector Private 
PI Contribution Design of target molecules for synthesis and provision of bioassays for screening
Collaborator Contribution Development of advanced synthetic chemistry to produce heparan sulphate saccharides Major contribution in kind through New Zealand government grants to fund their chemistry development
Impact Publication in JACS and Chem Euro Journal and ongoing collaborations
 
Description Synthetic chemistry for HS analogues 
Organisation University of Georgia
Country United States 
Sector Academic/University 
PI Contribution Design of target molecules for synthesis and provision of bioassays for screening
Collaborator Contribution Development of advanced synthetic chemistry to produce heparan sulphate saccharides Major contribution in kind through New Zealand government grants to fund their chemistry development
Impact Publication in JACS and Chem Euro Journal and ongoing collaborations
 
Description Synthetic chemistry for HS analogues 
Organisation Victoria University of Wellington
Department Ferrier Research Institute
Country New Zealand 
Sector Academic/University 
PI Contribution Design of target molecules for synthesis and provision of bioassays for screening
Collaborator Contribution Development of advanced synthetic chemistry to produce heparan sulphate saccharides Major contribution in kind through New Zealand government grants to fund their chemistry development
Impact Publication in JACS and Chem Euro Journal and ongoing collaborations
 
Description Synthetic chemistry for heparan sulfate analogues 
Organisation Callaghan Innovation
Country New Zealand 
Sector Public 
PI Contribution International collaboration to develop synthetic chemistry for heparin/HS glycans
Start Year 2008
 
Title Beta-secretase inhibitors for Alzheimers disease 
Description Novel class of beta-secretase inhibitors based on natural heparin glycans, with potential as first in class disease-modifying treatment for AD 
IP Reference WO2007138263 
Protection Patent application published
Year Protection Granted 2007
Licensed Yes
Impact IP licensed to University of Liverpool spinout IntelliHep and currently in further development
 
Title Engineered heparins 
Description Platform technology for generating selectively chemivcally modified heparins for drug discovery and biotechnology applications 
IP Reference US2006240473 
Protection Patent granted
Year Protection Granted 2006
Licensed Yes
Impact Licences to University of Liverpool spin out IntelliHep Ltd for exploitation.
 
Title Novel saccharide dendrimers 
Description Novel glycodendrimers with potent bioactivities, including inhibition of BACE1. 
IP Reference PCT/NZ2012/000035 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact Still in early stage of development
 
Title Saccharide inhibitors of beta-secretase 
Description Patent submitted on novel saccharide inhibitors of beta-secretase as potential therapeutics for Alzheimers disease 
IP Reference WO2007/138263 
Protection Patent granted
Year Protection Granted 2013
Licensed Yes
Impact Licenced to IntelliHep Ltd, and ongoing patent costs will be paid by IntelliHep.
 
Title Synthetic beta-secretase inhibitors 
Description Novel fully synthetic beta-secretase inhibitors with potential as disease-modifying treatment for AD 
IP Reference WO2012121617 
Protection Patent application published
Year Protection Granted 2011
Licensed No
Impact Further development being undertaken in collaboration with University of Liverpool, and spinout IntelliHep.
 
Company Name IntelliHep Ltd 
Description Spin-out company from University of Liverpool aiming to exploit engineered heparins in drug discovery and biotechnology applications. Company has a number of collaborative projects with external partners, and is also developing an internal pipeline of projects. Company is pre-investment and established a lab in 2010 and seeking further grant and investment income.; http://www.intellihep.com/ 
Year Established 2006 
Impact Early stage development of hit compounds as beta-secretase inhibitors for treating the underlying cause of Alzheimers disease. Option to licence IP from Liverpool University on an anticancer metastatic drug. Employment of research staff and regular funded projects sub-contracted into University labs. Collaborating with China partners on commercial applications of heparin by-products.
Website http://www.intellihep.com/
 
Description Hosting visit to Liverpool University by local ARUK funding supporters 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Contact was invaluable in informing supporters directly about research activities supported in Liverpool by their fund raising efforts

Funding supporters were able to gain insights into new potential treatments for AD, and how their funding is used for research.
Year(s) Of Engagement Activity 2013
 
Description Media releases on research findings 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact University press releases on the novel Alzheimer drug hits we discovered, along with developments in synthetic chemistry of our sugars, and applications in nerve repair and cancer therapeutics

International press coverage, radio interviews (Radio City Liverpool), and TV news (BBC NW Tonight).
Year(s) Of Engagement Activity 2006,2007,2008,2012,2013
 
Description Outreach to Business Community 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact Article in magazine Research Intelligence by UoL Business Gateway,(see website link "Sweet Smell of Success" http://www.liv.ac.uk/researchintelligence/issue30/alzheimers.html)

Dissemination of information to business community
Year(s) Of Engagement Activity 2007
URL http://www.liv.ac.uk/researchintelligence/issue30/alzheimers.html
 
Description Public Lecture to Garston Rotary Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Lecture to Garston Rotary Club

Contributing the Public Understanding of Science
Year(s) Of Engagement Activity 2008
 
Description Public lecture to Liverpool Soroptimists Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk sparked many questions and discussion of AD and potential new drugs and diagnostics

Contribution to Public Understanding of Science
Year(s) Of Engagement Activity 2014
 
Description RCUK/BBSRC event: Lifelong Health: Bioscience of Ageing (at Westminster) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Poster highlighting discovery of new class of drugs for AD at the RCUK/BBSRC event: 2007 Lifelong Health: Bioscience of Ageing (at Westminster)

Dissemination of information on research success to MPs and policymakers
Year(s) Of Engagement Activity 2007
 
Description Supporting ARUK fund raising publicity with major London donor 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Supporters
Results and Impact Supporters engaged directly with researcher undertaking research activity.

As above
Year(s) Of Engagement Activity 2013