Arisla | The research

Active project: EPOSS

EPOSS
ErythroPOietin in ALS: a Study of dose-finding and Safety

Erythropoietin (EPO) is one of the most interesting neuroprotective molecules. It is a multifunctional trophic factor mainly produced by kidney, liver, and nervous system. EPO and its receptor (EPOr) are located in neurons, astrocytes, and Schwann cells and their expression increases during hypoxia. Preclinical studies showed that administration of recombinant human EPO (rhEPO) is effective in preventing neuron apoptosis and axonal degeneration. Apoptosis is inhibited by Bcl-xL upregulation through activation of transcription factor NFkB and JAK2 phosphorylation. Axonal neuroprotection is mediated by EPOr upregulation and production of endogenous EPO by Schwann cells, induced by nitric oxide (NO). These events can be exploited by the administration of rhEPO. In brain, EPO can stimulate angiogenesis and oxygen delivery by proliferation and migration of endothelial progenitor cell (EPC) and regulation of VEGF and NO production. These mechanisms are likely involved in neuronal protection. Preclinical and clinical studies indicated a potential neuroprotective role of rhEPO in ALS. Our recent pilot trial in 23 patients suggested that rhEPO could slow the course of the disease. The dose of 40.000 U i.v. we gave fortnightly was chosen for safety reasons. However, higher doses likely give stronger neuroprotection in patients, as preclinical studies suggested. No data on safety for rhEPO given at higher doses in non-anaemic subjects are available.
Our first aim is to assess safety and tolerability of rhEPO given at 40.000, 80.000, or 120.000 U by either s.c. or i.v. route for 16 weeks in 50 patients with ALS. Safety will be analyzed as to the events related to the rhEPO erythropoietic activity. Doses will be reduced according to the values of hematocrit and hemoglobin. Course of the disease and quality of life will be monitored by ALSFRS-R and McGill questionnaire.
Our second aim is to investigate if rhEPO can modulate EPC, VEGF, and NO levels. Changes in these potential biomarkers of rhEPO neuroprotective activity can give information on its biological efficacy and optimal dosage.
The third aim is to assess the quote of rhEPO crossing the blood brain barrier (BBB) in ALS patients. Its neuroprotective efficacy depends on the bioavailability and rhEPO is known to cross the intact BBB through selective chaperons. However, it is unknown to what extent it occurs. The results of the project will provide useful information for phase III clinical trial.

Research Team:

Principal Investigator:

Giuseppe Lauria