2012 PH/TBIRP Investigator Vignette

Title: Neuroprotective Small-Molecule Erythropoietin Mimetics for the Treatment of Traumatic Brain Injury

Investigator: Juha Punnonen, MD, PhD; STATegics, Inc.

Our grant is focused on discovery and development of small molecules targeting erythropoietin, EPO, receptor. We?ve shown that these small molecules have potent neuro-protective effects, and therefore we believe they have significant potential in the treatment of traumatic brain injury. These compounds are, in fact, mimetics of erythropoietin, EPO. EPO is, in fact, perhaps one of the most successful biotech drugs in the history of biotechnology. Its role in erythropoiesis has been known for more than 50 years.

It is more recent knowledge that EPO also has potent neuro-protective effects and beneficial effects in the brain in general. The truly unique part of our program is the fact that our compounds mimic the neuronal effects of erythropoietin, without the erythropoietic functions. In other words, they bind to the neuronal receptor while not binding to the hematopoietic EPO receptor.

We believe this is a major competitive advantage compared to any other program that we are aware of, in that we will be able to trigger the neuronal receptor, using a small molecule that penetrates into the brain, and triggers the beneficial neuronal effects, without the erythropoietic function which has been associated with adverse effects, such as thrombosis, and also immunogenicity associated with recombinant EPO proteins.

We have prepared about 150 new compounds that we screened for neuro-protection, and the data has been quite exciting in that we were able to show that our compounds provide consistent, significant, and dose-dependent enhancement and survival of neuronal cell lines. And, as shown here, the protection and the enhancement in cell survival has been at least comparable, or perhaps even better, than that of recombinant EPO.

What is truly exciting to us is the fact that we have been able to demonstrate more than 200-fold improved ability of the compounds to penetrate the blood brain barrier, as compared to recombinant EPO. Given that we have also demonstrated direct activation of the neuronal EPO receptor with our compounds, and given the better ability to penetrate into the brain, we believe these results in combination truly support the conclusion that these compounds have significant potential in the treatment of traumatic brain injury. And, we are now testing that also in the animal model of traumatic brain injury. And, hopefully someday, we'll take these compounds into clinical studies to test them in the real settings.