University of Zurich
Martin Schwab
Our group is investigating the molecular mechanisms responsible for the decreased capacity of the adult central nervous system (CNS) to regenerate after an injury such as spinal cord injury, brain trauma or stroke. After spinal cord injury, nerve fibers of the spinal cord are typically disrupted and new outgrowth is very limited.
The search for cellular and molecular differences between the peripheral nervous system (PNS), which allows for regeneration, and the CNS has lead to the characterization of a protein inhibiting nerve outgrowth which we called “Nogo-A”.
In the meantime we could show that Nogo-A is mainly located in oligodendrocytes, thereby enhancing the conductance of nerve signals. In addition, Nogo-A has an important function as a ‘stop signal’ for outgrowing adult CNS nerve fibers. Further investigation of the molecular mechanisms involved in these processes is ongoing.
To show that Nogo-A has a significant function in vivo, we use different animal models to study regeneration. For example, hand tame rats which are partially lesioned in the spinal cord or with a stroke injury are treated with an antibody against Nogo-A or with a control antibody for two weeks starting immediately after the injury. The recovery of the animals is observed over weeks with behavioral tests such as walking on beams and ladders or the swimming test.
Anatomical analysis of the spinal cord of these animals reveals that different regeneration processes take place: Regenerative sprouting caudal to the lesion site (white area), fiber outgrowth over tissue bridges, and sprouting of intact fibers.
Translation of basic research to a clinical application
The long range goal of this research is to contribute to the development of a treatment of CNS injuries such as spinal cord injury.
In collaboration with research and clinical groups at Novartis, Basel, we are currently conducting a clinical trial with human anti-human antibodies against Nogo-A in acutely injured paraplegic patients. A European and a North American clinical network were founded with the financial help of private foundations in close collaboration with Prof. Volker Dietz and Prof. Armin Curt (Paraplegic Centre, Balgrist, Zurich). Following a large toxicology study in rodents and monkeys conducted by Novartis with us, a Phase I safety study of the anti-Nogo-A antibody trial started in summer 2006. We are currently concluding Phase I. The placebo controlled Phase 2 “proof of concept study” is planned to start in the second half of 2009.
Martin E. Schwab Professor Regeneration and plasticity after CNS injury
Dr. Anita Buchli PhD Scientific coordinator Project management
Björn Tews, PhD Postdoc Signalling mechanisms in plasticity and repair
Vincent Pernet, PhD Postdoc Regeneration in the visual system
Roman Gonzenbach PhD student Surgery, behaviour, tracing techniques
Tien Chau Technician Molecular biology, cell culture
Regula Schneider Technician Tissue preparation, Immunhistochemistry
Selection of important publications
Maier et al. (2009) Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury. Brain. 2009. [Epub ahead of print]
Montani L., Gerrits B., Gehrig P., Dimou L., Wollscheid B., Schwab M.E. (2009) Neuronal Nogo-A modulates growth cone motility via RhoGTP/LIMK1/cofilin in the unlesioned adult nervous system. J Biol Chem. 284: 10793-807.
Maier I.C., Baumann K., Thallmair M., Weinmann O., Scholl J., Schwab M.E. (2008) Constraint-induced movement therapy in the adult rat after unilateral corticospinal tract injury. J Neurosci 28:9386-9403, 2008.
Pernet V., Joly S., Christ F., Schwab M.E. (2008) Nogo-A and mag differently regulate oligodendrocyte maturation and meyelin formation. J Neurosci 28:7435-7444, 2008.
Freund, P., Schmidlin, E., Wannier, T., Bloch, J., Mir, A., Schwab, M.E. and Rouiller, E.: Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nature Med. 12: 790-792, 2006.
Weinmann, O., Schnell, L., Ghosh, A., Montani, L., Wiessner, C., Wannier,T., Rouiller, E., Mir, A. and Schwab, M.E.: Intrathecally infused antibodies against Nog-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A. Mol. Cell. Neurosci. 32: 161-173, 2006.
Liebscher, T., Schnell, L., Schnell, D., Scholl, J., Schneider, R., Gullo, M., Fouad, K., Mir, A., Rausch, M., Kindler, D., Hamers, F.P.T. and Schwab, M.E.: Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann. Neurol. 58: 706-719, 2005.
Dodd, D.A., Niederoest, B., Bloechlinger, S., Dupuis, L., Loeffler, J.-P. and Schwab, M.E.: Nogo-A., -B and –C are found on the cell surface and interact together in many different cell types. J. Biol.Chem. 280: 12494-12502, 2005.
Bareyre, F.M., Kerschensteiner, M., Raineteau, O., Mettenleiter, T.C., Weinmann, O. and Schwab, M.E.: The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nature Neurosci. 7: 269-277, 2004.
Thallmair, M., Metz, G.A.S., Z’Graggen, W.J., Raineteau, O., Kartje, W.L. and Schwab, M.E.: Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nature Neurosci. 1: 124-131, 1998.
Schnell, L., Schneider, R., Kolbeck, R., Barde, Y.-A. and Schwab, M.E.: Neurotrophin 3 (NT-3) enhances regenerative sprouting of the lesioned adult corticospinal tract. Nature 367: 170-173, 1994.
