Erythropoietin to enhance nerve repair in preclinical models of GBS
by Kazim A. Sheikh, MD, Department of Neurology, Johns Hopkins Medical Institutions
The following article is a progress report from one of the Foundation's grantees at the completion of his one-year grant cycle

Guillain-Barre syndrome (GBS) is an autoimmune disease that affects peripheral nerves. Antibodies and T cells (a type of white blood cell) directed against the nerves are involved in nerve injury. Two therapies, intravenous immunoglobulins (IVIg) and plasma exchange (PE) have proven beneficial for the treatment of GBS. The principle underlying these therapies is that modulation or neutralization of autoimmune responses causing nerve injury will limit neural damage and allow natural repair processes to restore nerve structure and function. A significant proportion of patients with GBS are left with residual neurological deficits and incomplete recovery despite the availability of Mg and PE. Poor or incomplete recovery after GBS is partly due to failure of nerve regeneration and reconnection with target organs such as muscles and skin. We have experimental evidence indicating that autoimmune antibodies found in some patients with GBS inhibit repair of injured nerves in a preclinical animal model (1).

Treatments that enhance nerve repair in the recovery period of GBS can decrease the incidence of residual neurological deficits and incomplete recovery. Recombinant human erythropoietin (EPO) is an FDA-approved drug used for the treatment of certain varieties of anemia. EPO is one of the earliest recombinant proteins in clinical use as a drug originally identified for it role in erythropoiesis. This drug also has remarkable tissue-protective activity in preclinical models of neuronal, retinal, cardiac, and renal ischemic injury. Notably, EPO has been shown to be neuroprotective in animal models of stroke, spinal cord, and nerve injury. EPO readily penetrates the blood-brain barrier and a recent phase II study showed that peripherally administered EPO is beneficial in stroke patients. Extensive past experience with dosing and side effects make it a valuable candidate to develop further as a neuroprotective therapy in GBS. Therefore, we examined the efficacy of EPO in overcoming autoimmune antibody-mediated inhibition of nerve repair in preclinical cell culture and animal models. Our studies indicate that EPO can promote nerve repair in sensory and motor neuron cultures and in an animal model of nerve injury produced with antibodies that are relevant to patients with GBS. Notably, the animal studies also indicate that EPO improves nerve repair. The results of these GBS/CIDP Foundation sponsored studies were recently presented at Peripheral Nerve Society meeting in Utah (2). Now, we are in the process of examining the effects of different doses of EPO in these antibody-mediated experimental models.

Besides antibodies, T-cells are also involved in the pathogenesis of GBS. Experimental allergic neuritis (EAN) is a prototypic T-cell-mediated model of GBS. We now want to extend neuroprotective studies with EPO to EAN. GBS Foundation has funded this project this year. Demonstration of EPO-mediated neuroprotection in both antibody- and T cell-mediated preclinical models of immune nerve injury would be extremely relevant to GBS, because both humoral and cellular autoimmunity is invoked in the pathogenesis GBS. Overall, these preclinical studies would provide a rationale for a clinical trial with EPO in patients with GBS. Since GBS is a monophasic disease, EPO can be administered for a limited/short period of time, thus decreasing the probability of projected thromboembolism with chronic use of EPO.

Acknowledgements: Sponsors GBS/CIDP Foundation International and NINDS. 1) Lehmann HC, Lopez PHH, Zhang G, Ngyuen T, Zhang JY, Kieseier BC et al. Passive immunization with anti-ganglioside antibodies directly inhibits axon regeneration in an animal model. J Neurosci 2007; 27(1):27-34. 2) Zhang G, Lehmann HC, Sheikh KA. Anti-GD 1 a antibody-mediated inhibition of neu rite outgrowth and its reversal with erythropoietin. JPNS 2007; 12 (Suppl): 96