Stroke Treatment by Chemically-induced Hypothermia - ABSTRACT
While acute stroke is a leading cause of human death and disability in the United States, unfortunately,
clinical therapies for stroke are limited and unsatisfactory. The overwhelming failures of stroke treatments in
clinical trials strongly indicate that, to battle this multifaceted brain disorder, novel strategies that target multiple
cell types and afford different mechanisms of protection are needed to achieve positive therapeutic effects.
One strategy, mechanical induction of mild hypothermia (defined as a 1-5oC decrease in body temperature),
has shown remarkable neuroprotective effects against brain ischemia in both animal and human studies. At
this time, however, available physical cooling techniques are ineffectual and usually impractical. A more recent
focus has been to identify pharmacological compounds that can be used to induce hypothermia. In theory,
pharmacologically induced hypothermia (PIH) can be initiated much earlier after the stroke event and in the
absence of mechanical cooling. Even a small (1-2oC) decrease in body temperature during early hours after
stroke prevents detrimental post-stroke hyperthermia, while mild hypothermia (2-5oC reduction) decreases the
extent of ischemic injury. In our Phase I and Phase II investigations, we demonstrated that rapid and
reproducible hypothermia is induced by several novel neurotensin receptor 1 (NTR1) agonists, resulting in
significant neuroprotection against brain damage induced by ischemic stroke, hemorrhage stroke, or traumatic
brain injury (TBI) in rodent models. The key breakthrough is that the NTR1 agonists do not induce shivering in
the subject animals, the major problem associated with other agents that mechanically or pharmacologically
induce hypothermia. The NTR1 compounds also act synergistically with tissue plasminogen activator (tPA), the
only FDA-approved thrombolytic treatment at this time. During Phases I and II, we also demonstrated
hypothermia induction by our leads in non-human primates, and completed a number of IND-enabling tasks
with satisfactory outcomes. For this Phase IIb study, in Specific Aim 1, we will continue to study the
hypothermic effect of our compounds in monkeys, with the overall opportunity of providing a clear bridge
between rodent, non-human primates, and human clinical studies. In particular, we will demonstrate the stroke
protection synergism between tPA and our NTR1 agonists, as was previously demonstrated in rodents. In
Specific Aim 2, required IND-enabling preclinical evaluations will be completed, while in Specific Aim 3, we
will commission 28-day toxicity studies in two species (rat and dog), which also are necessary for IND
preparation. Finally, in Specific Aim 4, we will prepare and submit the IND. When these four Specific Aims
are completed satisfactorily, our lead will be ready to enter human clinical trials, which will serve as a
major value influx point for seeking further funding to support the program.