Evaluation of optimised heparins as novel therapeutics for Alzheimers Disease
Lead Research Organisation:
University of Liverpool
Department Name: Sch of Biological Sciences
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 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.
Organisations
- University of Liverpool (Lead Research Organisation)
- Industrial Research Ltd (Collaboration)
- UNIVERSITY OF LEICESTER (Collaboration)
- Callaghan Innovation (Collaboration)
- University of Oslo (Collaboration)
- Uppsala University (Collaboration)
- Victoria University of Wellington (Collaboration)
- University of Georgia (Collaboration)
Publications
Arungundram S
(2009)
Modular synthesis of heparan sulfate oligosaccharides for structure-activity relationship studies.
in Journal of the American Chemical Society
Guimond SE
(2006)
Engineered bio-active polysaccharides from heparin.
in Macromolecular bioscience
Guimond, SE
Novel ex vivo transgenic mouse brain tissue assay for screening BACE1 inhibitors
in Nature Methods
Patey S
(2007)
Oligosaccharide agents for treating Neurodegeneration
in Patent WO2007/138263
Patey SJ
(2006)
Heparin derivatives as inhibitors of BACE-1, the Alzheimer's beta-secretase, with reduced activity against factor Xa and other proteases.
in Journal of medicinal chemistry
Patey SJ
(2008)
Engineered heparins: novel beta-secretase inhibitors as potential Alzheimer's disease therapeutics.
in Neuro-degenerative diseases
Schwörer R
(2013)
Synthesis of a targeted library of heparan sulfate hexa- to dodecasaccharides as inhibitors of ß-secretase: potential therapeutics for Alzheimer's disease.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Turnbull, JE
Identification of Orally Available Synthetic Heparinoids with Potent BACE1 Inhibitory Properties
in Nature Biotechnology
Zubkova, O
Heparan sulphate glycodendrimers with potent bioactivities: tools for chemical biology and therapeutic development.
in Angewandte Chemie
| 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 | Private |
| PI Contribution | International collaboration to develop synthetic chemistry for heparin/HS glycans |
| Start Year | 2008 |
| Title | OLIGOSACCHARIDE COMPOUNDS |
| Description | The invention relates generally to oligosaccharide compounds and the use of these compounds as pharmaceuticals for treating diseases or conditions in which it is desirable to inhibit ß-secretase. |
| IP Reference | WO2012121617 |
| Protection | Patent application published |
| Year Protection Granted | 2012 |
| Licensed | No |
| Impact | Still in early stage of development |
| Title | PREVENTION AND/OR TREATMENT OF NEURODEGENERATIVE DISORDERS |
| Description | A pharmaceutical composition for use in the prevention and/or treatment of a neurodegenerative disorder comprising a compound comprised of one or more disaccharide units, the or each disaccharide unit comprising a uronate moiety linked to a glucosamine moiety, wherein the 2-O atom of the uronate moiety is substituted with a hydrogen atom, the 6-O atom of the glucosamine moiety is substituted with a sulphate group and the 2-N atom of the glucosamine moiety is substituted with an atom or group other than a sulphate group. The composition is particularly preferred for use in the prevention and/or treatment of Alzheimer's disease. |
| 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 | PREVENTION AND/OR TREATMENT OF NEURODEGENERATIVE DISORDERS |
| Description | A pharmaceutical composition for use in the prevention and/or treatment of a neurodegenerative disorder comprising a compound comprised of one or more disaccharide units, the or each disaccharide unit comprising a uronate moiety linked to a glucosamine moiety, wherein the 2-O atom of the uronate moiety is substituted with a hydrogen atom, the 6-O atom of the glucosamine moiety is substituted with a sulphate group and the 2-N atom of the glucosamine moiety is substituted with an atom or group other than a sulphate group. The composition is particularly preferred for use in the prevention and/or treatment of Alzheimer's disease. |
| IP Reference | WO2007138263 |
| Protection | Patent granted |
| Year Protection Granted | 2007 |
| Licensed | Yes |
| Impact | Licenced to IntelliHep Ltd, and ongoing patent costs will be paid by IntelliHep. |
| Title | Saccharide libraries |
| Description | Novel methodologies for producing saccharide libraries are provided as well as the libraries themselves. |
| IP Reference | US2006240473 |
| Protection | Patent granted |
| Year Protection Granted | 2006 |
| Licensed | Yes |
| Impact | Licences to University of Liverpool spin out IntelliHep Ltd for exploitation. |
| Company Name | IntelliHep |
| Description | IntelliHep develops a precision therapeutics for diseases such as Alzheimers and cancers. |
| Year Established | 2002 |
| 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 | 2006,2007,2008,2012,2013,2014 |
| 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 |