Spinal cord repair: releasing the neuron-intrinsic brake on axon regeneration
Lead Research Organisation:
University of Cambridge
Department Name: Cambridge Centre for Brain Repair
Abstract
After Spinal Cord Injury, the connections between nerve cells in the brain and in the spinal cord are lost and fail to grow back. In patients with SCI this results in permanent disability, including paralysis below the level of the injury, and loss of sensory, bladder and sexual function.
There are two major obstacles to the regeneration of nerve fibers (referred to as axons) of central nervous system (CNS) neurons. First, CNS nerve cells do not switch on the necessary machinery for vigorous regrowth of axons. Second, a nerve cell has to deliver the necessary components for growth to the tip of the nerve fibre, which may be quite far as the axon can extend a long way from the cell body. Many CNS nerve cells fail to transport growth proteins into their axons after injury. These proteins are essential for nerve fiber regeneration through the hostile terrain of a spinal lesion. In AxonRepair we aim to promote axon regeneration in the spinal cord by 1. Activating the gene program required for nerve fiber extension, and by 2. Overcoming the transport block of growth-promoting proteins into injured axons.
To achieve aim 1 our approach takes advantage of know-how collected by our consortium on the powerful regenerative abilities of peripheral nerve cells. Peripheral nerve cells do regenerate successfully because they have a kind of 'switch' which turns on a robust regenerative machinery, and because they do not exclude growth-related molecules from their axons. We have identified key molecular components of this switch and aim to use these to activate the regeneration program in neurons after a spinal cord lesion. Previous attempts to do this have focused on individual molecules, which can be considered individual parts of the switch. In AxonRepair we are attempting a novel strategy where we target multiple collaborating elements of the switch at the same time.
Many mature CNS neurons have a specialized structure at the transition zone between their cell body and their axon that acts as a molecular barrier for transport of pro-regenerative proteins. It has recently been recognized that this molecular barrier plays a major role in the failure of axon regeneration: following an injury certain proteins (e.g. integrins) required for axon regeneration are excluded from the nerve fibers. Aim 2 of AxonRepair is therefore to "dissolve" the transport barrier allowing transport of essential pro-regenerative proteins into injured axons.
At the completion of AxonRepair we expect to have developed an intervention strategy to promote robust axon regeneration and functional recovery after injury to long spinal cord axon tracts. The results obtained in the context of AxonRepair will provide the basis for a potential therapeutic strategy for SCI.
There are two major obstacles to the regeneration of nerve fibers (referred to as axons) of central nervous system (CNS) neurons. First, CNS nerve cells do not switch on the necessary machinery for vigorous regrowth of axons. Second, a nerve cell has to deliver the necessary components for growth to the tip of the nerve fibre, which may be quite far as the axon can extend a long way from the cell body. Many CNS nerve cells fail to transport growth proteins into their axons after injury. These proteins are essential for nerve fiber regeneration through the hostile terrain of a spinal lesion. In AxonRepair we aim to promote axon regeneration in the spinal cord by 1. Activating the gene program required for nerve fiber extension, and by 2. Overcoming the transport block of growth-promoting proteins into injured axons.
To achieve aim 1 our approach takes advantage of know-how collected by our consortium on the powerful regenerative abilities of peripheral nerve cells. Peripheral nerve cells do regenerate successfully because they have a kind of 'switch' which turns on a robust regenerative machinery, and because they do not exclude growth-related molecules from their axons. We have identified key molecular components of this switch and aim to use these to activate the regeneration program in neurons after a spinal cord lesion. Previous attempts to do this have focused on individual molecules, which can be considered individual parts of the switch. In AxonRepair we are attempting a novel strategy where we target multiple collaborating elements of the switch at the same time.
Many mature CNS neurons have a specialized structure at the transition zone between their cell body and their axon that acts as a molecular barrier for transport of pro-regenerative proteins. It has recently been recognized that this molecular barrier plays a major role in the failure of axon regeneration: following an injury certain proteins (e.g. integrins) required for axon regeneration are excluded from the nerve fibers. Aim 2 of AxonRepair is therefore to "dissolve" the transport barrier allowing transport of essential pro-regenerative proteins into injured axons.
At the completion of AxonRepair we expect to have developed an intervention strategy to promote robust axon regeneration and functional recovery after injury to long spinal cord axon tracts. The results obtained in the context of AxonRepair will provide the basis for a potential therapeutic strategy for SCI.
Technical Summary
Problem: Spinal cord injury (SCI) leads to permanent disability and is a significant clinical problem with 130.000 new cases/year worldwide. Following SCI long axon tracts fail to regenerate. This is the primary reason for the sustained loss of bodily functions.
Objective and added value: AxonRepair aims to develop a strategy to promote long-distance axon regeneration and functional recovery after SCI by reprogramming neurons into a regenerative state and by overcoming the axon transport block that is a barrier to axon regeneration. The added value of AxonRepair is that we bring together world-class experts on the transcriptional control of axon regeneration, axon transport and therapeutic gene delivery. Individually, we have identified factors that promote CNS axon regeneration and modest sensorimotor recovery in animal models of SCI. Collectively, we now seek to combine these factors to deliver greater axon regeneration and clinically significant functional recovery. We will use clinically translatable adeno-associated vector-based gene delivery, novel techniques to quantify axon trajectories in cleared spinal tissue and innovative, automated methods for assessing dexterity in rats.
Workplan: Work package (WP) 1 aims to reprogram neurons into a regenerative state by testing the effect of combinatorial delivery of key transcription factors identified in our collective's discovery pipelines. WP 2 aims to restore axonal transport of growth-related receptors (integrins) to injured spinal axons. WP 3 aims to provide novel mechanistic insight into how interventions at the transcriptional and axon transport level work and whether these interventions act synergistically in rat models of SCI. WP4 defines the management structure, including a data management and sharing plan. A research steering group will direct, coordinate and monitor progress of AxonRepair.
Objective and added value: AxonRepair aims to develop a strategy to promote long-distance axon regeneration and functional recovery after SCI by reprogramming neurons into a regenerative state and by overcoming the axon transport block that is a barrier to axon regeneration. The added value of AxonRepair is that we bring together world-class experts on the transcriptional control of axon regeneration, axon transport and therapeutic gene delivery. Individually, we have identified factors that promote CNS axon regeneration and modest sensorimotor recovery in animal models of SCI. Collectively, we now seek to combine these factors to deliver greater axon regeneration and clinically significant functional recovery. We will use clinically translatable adeno-associated vector-based gene delivery, novel techniques to quantify axon trajectories in cleared spinal tissue and innovative, automated methods for assessing dexterity in rats.
Workplan: Work package (WP) 1 aims to reprogram neurons into a regenerative state by testing the effect of combinatorial delivery of key transcription factors identified in our collective's discovery pipelines. WP 2 aims to restore axonal transport of growth-related receptors (integrins) to injured spinal axons. WP 3 aims to provide novel mechanistic insight into how interventions at the transcriptional and axon transport level work and whether these interventions act synergistically in rat models of SCI. WP4 defines the management structure, including a data management and sharing plan. A research steering group will direct, coordinate and monitor progress of AxonRepair.
Planned Impact
AxonRepair will advance knowledge relating to axon regeneration following spinal cord injury. This is relevant from a clinical standpoint because the interruption of axonal pathways and their failure to grow back is the reason for paralysis in patients that suffer from a spinal cord injury. There is no therapy that restores function following spinal cord injury. A new treatment would therefore have a huge impact on the health of patients and society. Our ultimate goal is to contribute to the development of a therapy that would promote axon regeneration and functional recovery in patients. The research performed in AxonRepair is preclinical, however, the participation of the world-leading gene therapy company UniQure in an advisory role ensures that know-how generated by us can be rapidly exploited by entering in a co-development agreement and/or intellectual property strategy. UniQure has clinical programs for major CNS-diseases, including AAV-based gene therapy for Parkinson's disease, and conducts early-stage discovery and preclinical research with a R&D focus on gene therapy for CNS-diseases. In this context UniQure has a keen interest in preclinical AAV-based gene therapy for spinal cord injury as developed by AxonRepair.
Publications
Blight A
(2019)
The challenge of recruitment for neurotherapeutic clinical trials in spinal cord injury
in Spinal Cord
Boggio EM
(2019)
Inhibition of Semaphorin3A Promotes Ocular Dominance Plasticity in the Adult Rat Visual Cortex.
in Molecular neurobiology
Cheah M
(2017)
Assessment of Thermal Pain Sensation in Rats and Mice Using the Hargreaves Test.
in Bio-protocol
Cheah M
(2023)
Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Cheah M
(2017)
Dorsal Root Ganglion Injection and Dorsal Root Crush Injury as a Model for Sensory Axon Regeneration.
in Journal of visualized experiments : JoVE
Title | Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS |
Description | In this study, we describe the use of a scaffolding protein, Protrudin to boost axon regeneration and neuroprotection in the adult central nervous system. Our work reveals a novel mechanism of axon regeneration where Protrudin-induced axon regeneration is dependent on its interaction with the endoplasmic reticulum and other axon transport molecules. This data opens up new avenues to explore novel therapeutic targets for conditions of the central nervous system such as glaucoma, spinal cord injury and brain injury. |
Type Of Art | Image |
Year Produced | 2020 |
URL | https://axonrepair2020.figshare.com/articles/poster/Protrudin_functions_from_the_endoplasmic_reticul... |
Title | Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS |
Description | In this study, we describe the use of a scaffolding protein, Protrudin to boost axon regeneration and neuroprotection in the adult central nervous system. Our work reveals a novel mechanism of axon regeneration where Protrudin-induced axon regeneration is dependent on its interaction with the endoplasmic reticulum and other axon transport molecules. This data opens up new avenues to explore novel therapeutic targets for conditions of the central nervous system such as glaucoma, spinal cord injury and brain injury. |
Type Of Art | Image |
Year Produced | 2020 |
URL | https://axonrepair2020.figshare.com/articles/poster/Protrudin_functions_from_the_endoplasmic_reticul... |
Title | Simple RGC: ImageJ plugins for counting retinal ganglion cells and determining the transduction efficiency of viral vectors in retinal wholemounts |
Description | 'Simple RGC' consists of a collection of ImageJ plugins to assist researchers investigating retinal ganglion cell (RGC) injury models in addition to helping assess the effectiveness of treatments. The first plugin named 'RGC Counter' accurately calculates the total number of RGCs from retinal wholemount images. The second plugin named 'RGC Transduction' measures the co-localisation between two channels making it possible to determine the transduction efficiencies of viral vectors and transgene expression levels. The third plugin named 'RGC Batch' is a batch image processor to deliver fast analysis of large groups of microscope images. These ImageJ plugins make analysis of RGCs in retinal wholemounts easy, quick, consistent, and less prone to unconscious bias by the investigator. The plugins are freely available from the ImageJ update site https://sites.imagej.net/Sonjoonho/. |
Type Of Art | Film/Video/Animation |
Year Produced | 2020 |
URL | https://axonrepair2020.figshare.com/articles/poster/Simple_RGC_ImageJ_plugins_for_counting_retinal_g... |
Title | Simple RGC: ImageJ plugins for counting retinal ganglion cells and determining the transduction efficiency of viral vectors in retinal wholemounts |
Description | 'Simple RGC' consists of a collection of ImageJ plugins to assist researchers investigating retinal ganglion cell (RGC) injury models in addition to helping assess the effectiveness of treatments. The first plugin named 'RGC Counter' accurately calculates the total number of RGCs from retinal wholemount images. The second plugin named 'RGC Transduction' measures the co-localisation between two channels making it possible to determine the transduction efficiencies of viral vectors and transgene expression levels. The third plugin named 'RGC Batch' is a batch image processor to deliver fast analysis of large groups of microscope images. These ImageJ plugins make analysis of RGCs in retinal wholemounts easy, quick, consistent, and less prone to unconscious bias by the investigator. The plugins are freely available from the ImageJ update site https://sites.imagej.net/Sonjoonho/. |
Type Of Art | Film/Video/Animation |
Year Produced | 2020 |
URL | https://axonrepair2020.figshare.com/articles/poster/Simple_RGC_ImageJ_plugins_for_counting_retinal_g... |
Description | ABBVIE advisory |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | ABBVIE decided on the basis of the meeting to proceed to clinical trials |
Description | Vertex advisory board |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Design of clinical trial protocol leading to phase 2/3 trial |
Description | Project grant |
Amount | SFr. 150,000 (CHF) |
Organisation | International Foundation for Research in Paraplegia (IRP) |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 08/2017 |
End | 09/2019 |
Description | Repair of the corticospinal tract |
Amount | £638,866 (GBP) |
Funding ID | MR/R004463/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2018 |
End | 12/2020 |
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 | Chet Moritz |
Organisation | University of Washington |
Country | United States |
Sector | Academic/University |
PI Contribution | Model of bladder stimulation and recording |
Collaborator Contribution | Electophysiology methods |
Impact | Grant from GSK |
Start Year | 2016 |
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 | 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 | Public |
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 | 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 | Home Office Inspectors meeting |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Updating Home Office inspectors on new developments |
Year(s) Of Engagement Activity | 2016 |
Description | Ittingen future of spinal cord research |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Ittingen meeting to plan translation of spinal cord treatments |
Year(s) Of Engagement Activity | 2016 |
Description | New York State Spinal Injury symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | New York meeting for patients, carers, medical staff, researchers |
Year(s) Of Engagement Activity | 2018 |
Description | Utrecht Mind the Brain |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Utrecht outreach meeting |
Year(s) Of Engagement Activity | 2016 |