Integrins as a therapeutic tool for CNS repair

Lead Research Organisation: University of Cambridge
Department Name: Clinical Neurosciences

Abstract

Repair of the damaged spinal cord and brain is a major unmet need in the treatment of neurological diseases, with no treatments currently licensed. After spinal injury the nerve fibres that connect the brain to the spinal cord are cut, leading to paralysis and loss of sensation in the body below the area of damage. In order for patients to regain function the nerve fibres must be made to regenerate so as to reconnect the brain to the body via the spinal cord.

Several laboratories are working to develop treatments to enhance axon regeneration after spinal cord injury and various candidates have emerged. However these first-generation treatments are only partially effective. The programme will develop a new strategy for inducing nerve fibre regeneration. Regrowing nerve fibres have to penetrate the extracellular matrix that lies between cells. In order to gain traction on this material the nerve fibres must have adhesion molecules known as integrins that adhere to molecules in the matrix. Axons in the brain and spinal cord lack the integrin that is needed to interact with the spinal cord and brain extracellular matrix. We have found an integrin that solves this problem. In order to make it possible for this integrin to stimulate nerve fibre regeneration we have to use genetic engineering to place the molecule in nerve cells, then we have to ensure that the integrins can be transported into nerve fibres. In addition, inhibitory molecules in the damaged nervous system can turn off integrins, and we will develop methods to turn them back on. Together these interventions have the promise of stimulating robust regrowth of damaged spinal cord nerve fibres.

Technical Summary

The aims of the application are to use integrin engineering to promote axon regeneration after spinal cord injury. In order to regenerate in the damaged CNS axons must grow through the extracellular matrix, for which they need an integrin that recognises the CNS matrix glycoprotein tenascin However CNS axons lack a tenascin-binding integrin. By expressing an integrin that recognises tenascin we were able to promote exuberant growth on inhibitory environments. However this approach is only partially successful in vivo because the inhibitory molecules in the environment inactivate integrins and because integrin transport into mature CNS axons but not PNS axons is blocked at the axon initial segment. The programme will: 1) indentify the trafficking mechanism for integrins in PNS axons, 2) Investigate regulation of integrin trafficking by arf6, 3) find why transport of integrins and other molecles into axons is blocked at the axon initial segment of CNS axons and how to overcome it, 4)investigate the use of talins and kindlins to promote integrin activation in axons, 5)investigate the use of constitutively active integrins to promote axon regeneration in inhibitory environments, 6) investigate the use of integrin activating antibodies to promote regeneration. The successful strategies will be tested in a spinal injury model.

Publications

10 25 50
 
Description ABBVIE advisory
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact ABBVIE decided on the basis of the meeting to proceed to clinical trials
 
Description BIRAX
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description Bristol review
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Vertex advisory board
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Design of clinical trial protocol leading to phase 2/3 trial
 
Description ARUK fellowship for Sujeong Yang
Amount £205,000 (GBP)
Funding ID ARUK-RF2016A-1 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2016 
End 10/2019
 
Description Centre of Reconstructive Neuroscience
Amount 152,574,847 Kč (CZK)
Organisation Academy of Sciences of the Czech Republic 
Sector Learned Society
Country Czech Republic
Start 01/2017 
End 01/2023
 
Description Christopher and Dana Reeve Foundation Consortium
Amount $600,000 (USD)
Organisation Christopher and Dana Reeve Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2013 
End 01/2016
 
Description ERANET
Amount € 1,104,603 (EUR)
Funding ID RG88983 
Organisation European Union 
Sector Public
Country European Union (EU)
Start 02/2017 
End 03/2020
 
Description MS Society Research Grants
Amount £242,367 (GBP)
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 12/2020
 
Description Project grant
Amount SFr. 150,000 (CHF)
Organisation International Foundation for Research in Paraplegia (IRP) 
Sector Charity/Non Profit
Country Switzerland
Start 09/2017 
End 09/2019
 
Title New model for measuring intrinsic axon regeneration ability 
Description A new method for culturing mature neurons and measuring regeneration following laser axotomy 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact Used in other labs 
 
Description Pavla Jendelova 
Organisation Institute of Experimental Medicine AS CR
Country Czech Republic 
Sector Academic/University 
PI Contribution Axon regeneration through integrin engineering
Collaborator Contribution Spinal injury model
Impact Grant awarded
Start Year 2016
 
Description Schwab 
Organisation University of Zurich
Department Department of Ophthalmology
Country Switzerland 
Sector Academic/University 
PI Contribution Combination treatments for spinal cord injury. We provide extracellular matrix expertise
Collaborator Contribution Expertise in NogoA
Impact Four collaborative papers, three in J.Neurosci, one in EJNeurosci
Start Year 2009
 
Description Simone di Giovanni 
Organisation Imperial College London
Department Imperial College Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Axon growth and signalling
Collaborator Contribution Growth cone signalling with PI3Kinase
Impact ERA-NET application
Start Year 2016
 
Description Verhaagen 
Organisation Royal Netherlands Academy of Arts and Sciences
Country Netherlands 
Sector Learned Society 
PI Contribution Investigation into role of Semaphorin 3A in plasticity Integrin engineering for regeneration
Collaborator Contribution Production of AAV vectors Semaphorin staining
Impact Papers on axon regeneration, semaphorin in perineuronal nets
Start Year 2007
 
Description American spinal injuries 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Keynote to American spinal injury assn on future treatments

many discussions on health policy
Year(s) Of Engagement Activity 2012
 
Description Cheltenham science festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact session on spinal injuries at cheltenham festival. Around 300

contacts with vets on bladder control after spinal injury
Year(s) Of Engagement Activity 2012
 
Description Chrisopher Reeve symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Symposium for patients, carers, donors, researchers
Year(s) Of Engagement Activity 2018
 
Description International spinal cord society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Informing clinicians about future treatments

Communications from several participants
Year(s) Of Engagement Activity 2014
 
Description Japan spinal injury society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Discussions on future policy for Japanese spinal injury patients

Various enquiries from clinicians, researchers, patients
Year(s) Of Engagement Activity 2014
 
Description Japanese spinal injury foundation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation to Japanese spinal injury foundation
Year(s) Of Engagement Activity 2015
 
Description Toledo spinal injury centre 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussions with health care professionals and researchers

Talk about future treatments
Year(s) Of Engagement Activity 2014