PLASTICISE April 2012 Press Release
Neurodegenerative diseases are the major causes of chronic disability in European communities. The overall concept behind the Plasticise project is that restoration of the function in neurodegeneration can be achieved through the promotion of plasticity in the central nervous system (CNS). These plasticity events include the formation of new functional nerve cell connections, the withdrawal of inappropriate connections, or the modulation of synaptic strength. The concept behind the research programme of the Plasticise teams is that plasticity enables the nervous system to bypass damage, enabling recovery from many conditions. The Plasticise teams are therefore able to use treatments that induce plasticity to target diseases as diverse as Alzheimer’s disease, Stroke, Traumatic Brain Injury and Spinal Cord Injury. Since 2011, several discoveries that will have significant impact on the treatment of neurodegenerative diseases have been made. The consortium has developed several plasticity-activating treatments based on proteins of the extracellular matrix and the anti-NogoA antibody. TARGETING THE EXTRACELLULAR MATRIX Several teams have focused their investigations on perineuronal nets (PNNs) which are cartilage like structures of the extracellular matrix responsible for restricting plasticity in the adult brain & spinal cord. PNNs are largely composed of chondroitin sulfate proteoglycans, which play a key role in plasticity mechanisms in the adult CNS. Plasticise teams have demonstrated that removing PNNs reactivates plasticity in various brain structures and is therefore a potential novel treatment with general efficacy on axon regeneration/sprouting. The treatment is also able to restore memory in animal models of Alzheimer’s disease. This evidence constitutes the conceptual starting point for the use of PNN-related treatments to hinder cognitive and motor deterioration in neurodegenerative disease. In addition, the inhibition of matrix metalloproteinases (MMPs), enzymes that break down proteins of the extracellular matrix, promotes plasticity in the visual system - as studied by Prof. Tommaso Pizzorusso in Pisa (IT)- and protects neurons from degeneration and cell death - as demonstrated by Prof. Leszek Kaczmarek from Warsaw (PL). GREATER EFFICACY OF COMBINED PLASTICITY-ENHANCING TREATMENTS The teams of Prof. Martin Schwab (Zürich, CH) and Prof. James Fawcett (Cambridge, UK) have demonstrated that the combination of plasticity-enhancing treatments (such as anti-NogoA antibody followed by ChondroitinaseABC treatment) produces a better recovery of function after spinal cord injury in rats than either treatment alone. This novel combination treatment represents a promising approach for functional repair after spinal cord injury. Furthermore, the combination of pharmacological application of neuroprotective/ neurite outgrowth-boosting drugs with neuro-rehabilitation after stroke or spinal cord injury is of great interest from a clinical point of view. Plasticise teams have established the general principle that rehabilitation can be much more effective on a background of enhanced plasticity. In order to develop optimal rehabilitation schedules, the Plasticise teams have studied whether regeneration / plasticity-enhancing treatments should precede rehabilitation training or vice versa or whether they should be given simultaneously. It has been shown that the time window for anti-NogoA antibody treatment leading to good functional recovery is one week post injury in the rat after spinal cord injury and stroke. This result was translated and used in the ongoing NogoA clinical trial (coordinated by the Plasticise partner Novartis, CH): freshly injured para- and tetraplegic patients are treated with humanized anti-Nogo antibodies for 4 weeks starting within the first month after the spinal cord insult. In both animal models of stroke and spinal cord injury, Plasticise researchers have recently demonstrated that, to be more efficient, rehabilitation training should take place after the drug treatments. It is expected that some of these promising results will now lead to breakthroughs in several areas of plasticity, and will have a significant resonance in clinical research. DEVELOPMENT OF NEW INNOVATIVE TECHNIQUES AND TOOLS Several teams have developed innovative tools to assess the efficacy of plasticity-enhancing treatments. Several new methods and paradigms have been established to study plasticity at the microscopic level, both in vitro and in vivo. The team of Prof. Fritjof Helmchen (Zürich, CH) is now able to study cortical sensory map dynamics using genetically encoded calcium indicators in chronically-implanted animals. They are currently developing cortical imaging in awake and behaving animals. The teams of Prof. Anthony Holtmaat (Geneva, CH) and Prof. Martin Schwab have successfully developed a new focal stroke model in the cortex induced by photothrombosis. Combined with chronic two-photon laser imaging as developed by the team of Prof. Fritjof Helmchen, they can now study functional plasticity at the synapse level. Alzheimer-like focal lesions have been produced by team of Dr. Bernard Schneider (Lausanne, CH) using viral vectors expressing mutant forms of APP and tau. Profound memory deficits have been found. These novel animal models are currently used to assess the efficacy of the regenerative treatments developed by the consortium. TESTING PLASTICITY-MODULATING TREATMENTS IN PATIENTS AND PRIMATES Major advances have been made in clinical use and assessment of plasticity. New imaging methods have been developed by the team of Prof. Nick Ward (London, UK) for evaluating plasticity in human patients. A clinical trial of stroke patients with combined rehabilitation and plasticity-inducing Transcranial Magnetic Stimulation (TMS) has been conducted by the team of Prof. John Rothwell (London, UK). The results of these clinical studies will be known soon.
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