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

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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.