• Neuralstem’s new branch

After 14 years spent working on neural stem cell therapies for neurological disorders, Neuralstem Inc. thinks it has found a second way to monetize its research investment. This quarter, the company plans to begin a Phase I trial of its first small molecule therapeutic discovered using the company’s CNS stem cell lines.

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Neuralstem was founded in 1996 to develop human CNS stem cell lines to treat neurological disorders such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI). The company’s lead product, NSI-566RSC, is a human spinal cord-derived stem cell line in Phase I testing to treat ALS.

In 2000, the U.S. Department of Defense’s Defense Advanced Research Projects Agency (DARPA) awarded Neuralstem a contract to use the company’s human neural stem cell lines to screen for an orally available small molecule with activity in the hippocampus. The objective was to identify compounds that could trigger growth of hippocampal neurons to counteract the stress-induced hippocampal atrophy that is believed to cause impaired cognition and memory in soldiers.

While those screens did turn up a few small molecules that triggered neurogenesis in cultured human hippocampal neural stem cells, DARPA discontinued funding of the research following a change in priorities in the wake of the 9-11 terrorist attacks. Neuralstem set the small molecules aside and returned to moving its stem cell therapy pipeline forward.

Over time, multiple lines of evidence from animal models and patients have suggested a link between impaired growth of hippocampal neural stem cells and neuropsychiatric diseases. In particular, chronic depression has been associated with atrophy and shrinkage of the hippocampus.

Those findings, combined with the receipt of a U.S. patent covering the composition of matter and use of the small molecules to promote neurogenesis to treat CNS diseases, led Neuralstem to revisit the small molecule strategy in 2009.

Neuralstem scientists hypothesized that their small molecules might be able to stimulate growth of new neurons in the hippocampus to treat depression. To test that idea, the company chose NSI-189, the best of four small molecule nicotinamide derivatives at stimulating neurogenesis in cell culture and mice.

NSI-189 is now set to begin a two-part Phase I trial. If the safety endpoints are met in healthy volunteers, the second part will enroll depressed patients for a dose-escalation study. The entire trial is expected to last about one year, CSO and cofounder Karl Johe told BioCentury.

Meanwhile, the company will work on identifying the molecular target of NSI-189.

“Our screens are set up to identify compounds that enhance the complex cellular process of neurogenesis, which involves a variety of different neural pathways that include many different potential targets. Thus, based solely on those screens, we cannot say what the molecular target of NSI-189 is,” Johe said.

He hypothesized NSI-189 might reverse the disease process in depression by “triggering structural changes in the hippocampus, including formation of new synapses and increased hippocampal volume.”

If that proves true, Johe said, the improvements achieved with NSI-189 would probably be longer-lasting than those achieved by marketed drugs such as selective serotonin reuptake inhibitors (SSRIs), which transiently alter serotonin levels.

Johe said the small molecule approach is complementary to the company’s cell therapies.

“The small molecules would be ideal for triggering growth of endogenous stem cells to treat neuropsychiatric disorders, whereas the stem cell therapies are probably more geared toward indications like spinal cord injury,” he said. “Looking very far ahead, we might speculate that the two approaches could be used together to treat some disorders — stroke, for example.”

“Because the marketed antidepressants are orally active compounds, the invasive surgical procedures necessary for neural stem cell transplant may seem impractical to doctors and regulatory agencies for most forms of depression,” noted CEO Richard Garr.

Garr also thinks NSI-189 could be useful in Alzheimer’s disease, as enhancing neurogenesis could lead to improvements in cognition and memory. “Depending on how the depression trial goes, we hope to be able to begin a clinical trial in AD sometime in 2011,” he said.

NSI-189 is exclusively licensed from an undisclosed chemistry company that supplied some of the compound libraries originally screened under the DARPA project.

Garr said Neuralstem hopes to partner out the other small molecule nicotinamide derivatives identified by its screen, as the company’s resources are sufficient to move only NSI-189 into the clinic.

“We are also interested in partnering out our stem cell discovery platform to identify whole new classes and families of compounds that could treat CNS disorders,” he said.

According to Johe, “One area of interest might be multiple sclerosis (MS). Using our stem cell screen, it might be possible to identify compounds that promote differentiation of oligodendrocytes and myelination.”

Neuralstem plans to continue to develop and commercialize its stem cell therapy pipeline on its own, Garr said.

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