Regulating neuroplasticity to restore upper limb and hand function after spinal cord injury

A spinal cord injury (SCI) can have devastating consequences, often resulting in a lifetime of disability and dependence. Most human SCIs occur in the neck (cervical) region and cause disability in the upper limbs and hands. Losing the ability to reach, grip, hold and pick up objects can severely limit independence, quality of life, participation in society and sense of self. There is currently no cure for SCI and no adequate therapies, therefore new regenerative therapies are urgently needed, particularly those that enable recovery of hand function.

The enzyme therapy chondroitinase is a promising experimental treatment that enables new growth and connectivity (termed "neuroplasticity") by breaking down growth-blocking molecules in SCI scar tissue. There is now overwhelming pre-clinical evidence that treatment with chondroitinase enables recovery of lost function after SCI, demonstrated by numerous laboratories and in multiple species, including mouse, rat, cat, canine and primate. Chondroitinase is therefore a leading candidate for clinical development. The Bradbury lab and their collaborators have made many advances in optimizing and evaluating this therapy as a potential treatment option for SCI, recently developing an advanced gene therapy approach where a single injection of a viral vector containing a humanized version of the chondroitinase gene enables cells of the spinal cord to produce the enzyme directly into the injured tissue. In a further advance, the gene therapy has been engineered to contain an on/off switch which can be controlled by antibiotic administration (taking the antibiotic orally switches the gene on, and withdrawal switches the gene off), adding an important safety element plus a tool to examine when, and for how long, to turn the gene on to maximise the potential for recovery. With this approach we recently demonstrated recovery of reach and grasp ability in rats with cervical level contusion injuries when they were treated for 8 weeks with the gene continuously on. This exciting data, plus a recent study from our collaborator showing improved hand dexterity with chondroitinase gene therapy in hemi-contused monkeys, provides compelling evidence for testing this therapy in humans, and we are preparing for a first in man study.

However, in order to improve the chances of clinical success, we first need to answer critical questions that remain: is recovery maintained after gene switch off? What are the long-term effects of gene therapy? How can we optimally apply this therapy with rehabilitative training to maximise the potential for recovery? Can we enable neuroplasticity and recover hand function in long term (chronic) SCI? What motor pathways are responsible for the recovery and are the targets for chondroitinase the same in rats and higher species?

To address these, we will use rat cervical contusion injuries to mimic the most common type of human SCI; we will focus on recovery of hand function since this is the highest rated patient priority for improving independence and quality of life; we will apply targeted training to maximise the potential for recovery and for clinical relevance, since any new therapy for SCI will be applied alongside rehabilitative training in the clinic; we will apply this treatment to chronic SCI, to evaluate its potential application for the majority of patients who are living with long-established injuries. Finally, we will use gene silencing to determine the motor pathways that mediate recovery of hand function and we will carry out a cross-species tissue analysis comparison (rat, primate, human) to determine the optimal pattern of treatment for application in man.

This project will provide essential information required to translate a promising regenerative therapy into a clinical treatment for restoring hand function in man and has the potential to improve the lives of millions of patients living with lifelong disability as a result of SCI.

Spinal cord injury (SCI) results in profound disability, and there are no regenerative therapies. Most SCIs occur in the cervical region and recovering hand function is the highest rated patient priority for improving quality of life.

Chondroitinase ABC (ChABC) is a potent neuroplasticity-promoting agent that breaks down inhibitory components of the extracellular matrix, enabling new connectivity and functional recovery after SCI. The proven pre-clinical benefits of ChABC have been demonstrated by multiple labs worldwide, making it a leading candidate for clinical development.

In recent work we have applied a novel, regulatable gene therapy approach, which enables temporal control of ChABC transgene expression and the ability to switch the gene on and off multiple times in vivo, effectively opening "windows of neuroplasticity". We demonstrated recovery of skilled hand function in cervical contused adult rats when treated for 2 months with the gene continuously on.

Here, we will use inducible ChABC vectors to evoke neuroplasticity and address critical steps that remain before this therapy can be translated to the clinic:

Aim 1: We will explore the potential for "training neuroplasticity" by varying the gene induction regime alongside high-intensity reach and grasp training to determine the optimal regimen for recovery.

Aim 2: We will determine whether late-stage neuroplasticity can enable recovery in chronic SCI, and examine patterns of gene expression and biodistribution with acute and chronic delivery.

Aim 3: We will use chemogenetic silencing to determine the motor pathways that mediate recovery, and utilise human and primate SCI tissue to determine key targets of ChABC and whether their spatio-temporal distribution is conserved across species.

This work will provide crucial translational and mechanistic data needed for advancing a candidate regenerative gene therapy into a clinical treatment to enable recovery of hand function after SCI.

Potential beneficiaries of this research might be as follows:

1. The SCI community; this includes patients, their families, carers, supporters, charitable foundations, donors and SCI advocacy groups.

2. Scientists, clinicians, neurosurgeons, patients, carers and therapists who are interested in research into how the tissue microenvironment of the injured central nervous system can be manipulated to enable new connectivity and functional repair and which may lead to future regenerative therapies for SCI.

3. Scientists and clinicians interested in rehabilitation, training and improving upper limb and hand function, and understanding how to best combine a neuroplasticity-promoting treatment with targeted training to maximise functional recovery.

4. Industry and academic partners as well as clinicians, who are interested in forming networks and consortia for dissemination of findings relating to potential regenerative therapies for SCI.

5. Wider groups of researchers and clinicians interested in regenerative/neuroplasticity therapies for improving functional outcome in many different neurological disorders, particularly disorders which affect mobility and where neuroplasticity is a potential route to restoring function (e.g. stroke, ALS, multiple sclerosis and some neurodegenerative disorders).

6. Researchers and clinicians interested in gene therapies for neurological disorders.

Thus, the wider field of regenerative medicine will benefit from new knowledge, new approaches and new therapies for improving neuroplasticity, functional connectivity and meaningful recovery of motor function in the injured or diseased CNS.

How they may benefit from this research is detailed below:

This research will benefit the many stakeholders with an interest in regenerative research for SCI (including academic researchers, SCI patients and their families, carers, supporters, charitable foundations, donors, SCI advocacy groups, clinicians, neurosurgeons, physical therapists, industry and the government) by revealing new methods for enabling functional neuroplasticity of motor pathways, of maximising these with targeted training, and enabling recovery of high priority patient functions.

Since there are currently no disease-modifying or regenerative therapies available for SCI, new therapies that enable neuroplasticity and improve functional outcome after SCI would have significant social and economic impact. For example, recovering the ability to reach, grip, hold and pick up an object would enable autonomy (e.g. being able to wash, dress and feed independently), greater ability to participate in society, an improved sense of self worth and consequently an improved quality of life for patients, their families and carers.

As well as benefits to quality of life and health this would also have a significant economic impact, since the costs of SCI are among the highest of any medical condition (estimated lifetime costs to U.K. economy are £1.87 million per individual with tetraplegia) and small improvements in function and ability could significantly reduce the economic costs of high dependence care.

Developing regenerative therapies for SCI is a top priority for medical research and success of this project would significantly impact health, quality of life and economics. Therefore, it directly addresses one of the MRCs Priority challenges of "Regenerative Medicine for accelerating the discovery and development of treatments for many currently untreatable diseases".