Regenerative Neuroscience2018-05-30T09:57:41+00:00

Regenerative Neuroscience

Research Strategy

Background

The overall aim of this theme is to promote the development of regenerative and neuroprotective treatments of neurological diseases. Depending on the disease, regenerative strategies include replacing neurons, inducing plasticity and connectivity, stimulating remyelination, and regenerating the astrocytic compartment.

The main strategies for regenerative therapies are either the administration of cell-based products or pharmacological treatments aiming at promoting endogenous repair processes. With respect to the latter, inflammation, cell metabolism, cell signalling, epigenetics, and physical interaction of cells with their environment emerge as fundamentally important aspects of biology, which may be targeted in order to stimulate regeneration.

chemical formulae and scan image

Aims and specific short (1 year), medium (2-3 years) and long (4-5 years) objectives

Short term (1 year):

  • Development of mechanical stress models(Terentjev)
  • Initiation of RECEDE Myelopathy(Kotter)
  • Development of Mobile App outcome measure prototype (RobertHarle)
  • Human CNS cell models (Elpis BioMed Ltd., Axol Biosciences,Vallier)
  • PPI: Registration of Myelopathy.org as charity

Medium term (2-3 years):

  • Development of 3D/microfluidics CNS model (Huang)
  • Review of cell transplantation therapy strategies for SCI (Barnett, Choi)
  • PET initiative: imaging synapses, myelin, and descending spinal cord tracts (Franklin)
  • Validation of mobile App as outcome measure in clinical sample remote study tool (Robert Harle)
  • Online Delphi methodology for PPI consensus processes (Myelopathy.org)

Long term (4-5 years):

  • Electrophysiology on a chip models of Autism (Baron-Cohen, Inventya Ltd., Elpis BioMed Ltd) and application to drug discovery
  • In vitro modelling of human neuromuscular junctions, including Duchenne’s disease (Elpis BioMed Ltd.)
  • Human Leukodystrophy models and application to drug discovery (Rowitch)
  • Valididation of App outcome measures in clinical practice (Kotter)
  • PET initiative: synaptic imaging, myelination, neural connectivity (Aigbirhio)
  • Qualitative research tools for PPI data (Myelopathy.org)

SUBTHEME 1: External insults to the CNS

In the field of regenerative neuroscience, damage to the CNS caused by external insults represent a particularly important problem with often devastating life-long impact and significant unmet clinical needs. Apart from traumatic injuries to the brain and spinal cord, persistent mechanical pressure can also induce increasing neurological deficits, such as occur in cervical spondylotic myelopathy (CSM).
CSM is the most common spinal cord disease of adulthood, affecting up to 6% of individuals above 50 years of age. It has devastating impact on quality of life. However, the consequences of CSM as well as the underlying pathophysiology remain poorly understood.
As part of the PPI priorities, the NIHR HTC has supported the development of Myelopathy.org as the first organisation dedicated specifically to CSM.
Within six months Myelopathy.org has grown its membership to more than 530 individuals. This reflects the large unmet clinical needs of CSM patients whose only hope after surgery are future regenerative treatments.
Neuroprotective or regenerative treatment do not exist for conditions of this subtheme. Unlike other disorders, the primary cause of injury in these conditions can be removed, and therefore will no longer influence the regenerative processes.This provides a unique opportunity for identifying and developing regenerative treatments. Regenerative medicine in the neurosciences is still in its infancy. A focus will therefore be the development of human cell based assays for early stage drug development.

Development of in vitro models of mechanical stress for early stage drug discovery

Apart from stretch models, mechanical stresses, including shear, compression, and displacement (e.g. bending of axons) stress forces have not yet been modelled in in vitro assays. Moreover, none of the existing stretch models utilise human cells, further limiting their potential for translation. A priority therefore is to stimulate the development of adequate models, which can serve as a platform for drug discovery (Prof. Terentjev, Dr. Huang).

Markers for disease stratification

Disease stratification and selection of appropriate patient cohorts is fundamental to the development of regenerative treatments. Apart from characterising the underlying pathology (e.g. neuronal loss versus demyelination), genetic factors influence the vulnerability of the CNS to mechanical injury and also the response to treatment. We will collaborate and intersect with the functional imaging and neurodegeneration themes to support the development and implementation of molecular imaging and quantitative MRI markers for prognosis and as surrogate marker of regeneration in the CNS. The degree of mechanical impact on the CNS often does not correlate well with the extent of injury. This is particularly true in the context of CSM: ca. 30% of individuals above 50 of age show evidence of spinal cord compression on MRI, but only ca. 20% will develop myelopathy. Moreover, the rate of disease progression is highly variable. Increasing evidence points to a genetic vulnerability of the spinal cord. Similarly, it is well recognised that in TBI APOE ?4 is associated with poor outcome[1]. The underlying genetic network influencing disease prognosis is very likely to also influence the response to neuroprotective and regenerative treatments. A long-term aim will therefore be to elucidate the genetic basis of the vulnerability of the spinal cord in CSM patients. Quantitative trait analyses require access to large patient cohorts, for which Myelopathy.org will serve as a valuable partner.

Quantitative tools for measuring regenerative treatmentresponses

Present outcome measures for assessing TBI, SCI and CSM severity do not provide accurate quantitative data and are restricted to data collection at discrete points in time (e.g. outpatient clinic visits). Novel, mobile sensor based outcome tools promise to overcome these limitations. Led by Dr. Robert Harle, a newly developed outcome measure tool at proof of principle stage enables quantification of manual dexterity (typing speed and accuracy) and gait parameters using sensor technology that is commonly present in mobile phones. Designed to run in the background of mobile phones, such Apps can prompt patients to fill in questionnaires. The quantitative longitudinal data derived from such technology has the potential to increase sensitivity and reduce sample size required for clinical trials. The MIC will also support a collaboration with Google, who wants to extend their use of SmartWatch sensors to clinical application.

Clinical translation of novel therapeutic approaches

Where an existing drug can be re-purposed, translation can be rapidly achieved. The REgeneration in CErvical DEgenerative Myelopathy trial, which is based on findings made in the Filbin and Kotter laboratories in 2004 and 2013 respectively, serves as an example. Funded by the NIHR TCC, RECEDE Myelopathy is the first trial to test a regenerative therapy in CSM. The trial will also provide a unique infrastructure and serve as a platform for validation of biological markers for regenerative treatments in the spinal cord as well as the development of relevant clinical outcomemeasures.

SUBTHEME 2: Development of human cell models for neurodevelopmental and neurodegenerative disorders

Generation of human cell models.

Neurodevelopmental brain disorders represent a unique challenge and are often caused by particular gene defects requiring distinct (bespoke) treatment strategies. Potential treatment strategies include modulating metabolic processes and inflammation, gene correction or replacement (gene therapies), and cell transplantation. Other polygenetic or sporadic conditions such as Autism are poorly understood. A specific aim will be to generate culture model systems relevant to neurodevelopmental and neurodegenerative diseases that are applicable for early stage drug discovery.

Generation of highly mature and pure human cell types for disease modelling.

A well-recognised unmet need is the absence of human cell based models