“Blocking the blockers – can this help recovery from spinal cord injury?”

Release date: 16-Apr-2010

Organisation: University of British Columbia

A systematic review of directly applied biologic therapies for acute spinal cord injury by Kwon et al, Journal of Neurotrauma / Jan, 2010

What prevents/ inhibits repair? 

In contrast to tissues such as bone or skin, the spinal cord demonstrates a limited capacity for spontaneous repair after injury. This is due to a number of factors including the presence of inhibitory molecules, or “blockers”, acting on spinal nerve pathways. During normal development these inhibitory molecules exert an important control on growing nerve fibres, preventing the formation of abnormal connections. Blockers are important, also, as a means to control promiscuous regrowth in spinal nerve pathways after damage. A failure to inhibit abnormal nerve growth, for example, may contribute to susceptibility for chronic pain, or dsyregulated blood pressure control. However, these inhibitory molecules also block regenerative processes and regrowth of axons so interventions that can “block the blockers” are an important target for drug development. There are several classes of inhibitory molecules, which has led to the development of classes of drugs that block these inhibitors. One class is associated with myelin, a fatty insulating material found in the spinal cord. The best known myelin inhibitor is the aptly named protein Nogo, also known for its role as a drug for pulmonary hypertension, the implication being that it has effects on blood pressure. It is a potent blocker of axon growth as well as affecting cell migration and survival. Given this, blocking its effect by antibodies to Nogo or to its receptor (known as anti-Nogo’s), is seen as a promising way to promote nerve regeneration.  

This review by Kwon and collaborators only considers factors which have been directly applied to the spinal cord or its coverings by injection or implants; and only studies using animal models of traumatic cord injuries such as compression or bruising are included. Moreover this review only discusses blockers of inhibition and excludes other directly applied therapies, such as neuroprotective drugs that enhance cell survival. This review poses the question: “how ready is this particular therapy for clinical translation?”This question is important because, first, these ways to overcome inhibition may have untoward side effects; and secondly, the method of delivery (how much and for how long), known as pharmacokinetics, affects their biological activities. For example, it is as yet unknown if the ability to block inhibitory molecules in spinal nerve pathways differs in rodents and humans. Kwon and colleagues discuss three classes of blockers of inhibitory molecules: 1. Chondroitinase ABC (24 papers); 2. Anti-Nogo approaches (24 papers); and 3. Rho antagonists (9 papers). Chrondroitinase acts by breaking up the dense inhibitory ‘matrix’ which develops around injured cells and axons, whereas Rho is part of a molecular pathway within the neurons which shuts down their growth.

Results of the Review

To date, no blocker of inhibition has been approved for clinical use. However, of the three classes of blockers chosen for study, an anti-Nogo monoclonal antibody, developed by Schwabb et al, was translated to clinical trial in 2007, and a fusion protein known as CethrinR that enhances the blockers of the Rho pathway, has advanced to a Phase 2 trial. The major findings of this review are that, despite extensive animal studies, a number of issues about readiness for translation remain to be addressed. The key issues for translation are:

  • whether the research is robust, and has been replicated in different labs.

  • the physiological relevance for human spinal cord injury of the different animal/injury models that are used, and of the doses/pharmacokinetics and bio-distribution of blockers.   This involves the extent to which the blockers may penetrate the outer covering of the cord, or diffuse within the cerebrospinal fluid which bathes the cord, before reaching the injury site. Distances are generally much further in human cord than in commonly used animal models such as rodents. This concern also relates closely to dosing, the implication being that dosing and related to that, drug toxicity, has not been fully established.

  • the optimal time window for intervention. For convenience, blockers have generally been given at the time of spine surgery, although this may not necessarily correspond with the optimal period at which blockers act on regenerating spinal nerve pathways. Therefore, it is as yet unknown if this window of opportunity is biologically appropriate, or if it will yield the best outcome.

Because extensive animal work has not yielded answers to these questions, it is possible that further refinement of the animal models and pharmacokinetics of blockers will lead to better results. Be that as it may, a majority of studies in the review found that blockers of inhibition “created a situation that was conducive” to spinal nerve regeneration and few reported untoward effects.   In contrast, several NIH funded replication studies found that some, but not all studies, were robust and reproducible.

The big picture

Concepts of critical reviews of a large number of studies have evolved in recent years, with the realisation of the need to capture all of the evidence required for clinical decision-making. Kwon and colleagues ask questions about “how ready is this particular therapy for clinical translation?” Because a systematic review, such as this, has no formal analysis it may be criticised on a number of grounds, and the question arises of whether this is the best approach for assessing this field.   What can the reader gain from this?   Indeed, on a personal note, I think a major reform of editorial policy would be necessary for systematic reviews, or meta-analyses, to yield meaningful insights.  

What then is the take home message? Our understanding of recovery after spinal cord injury has largely revolved around neuronal mechanisms. However, the immune system and immune cells which are present in the brain and spinal cord recently have been recognised as powerful modulators of neuronal functions. Blocking the blockers of spinal nerve regeneration is just one approach to a chain of biological events that begins with spinal cord injury. We need more studies of drug kinetics, drug-drug interactions and importantly, immunogenetics before we can say that blocking the blockers will help recovery from spinal cord injury.

Link to abstract www.ncbi.nlm.nih.gov/pubmed/20082560

Dr Jillian Clark
Research Development Committee
Post Doctoral Research Fellow
Hampstead Rehabilitation Centre, SA

April 2010

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