• U-M stem cell trial to enter crucial phase

The first clinical trial using stem cells in Lou Gehrig's disease patients soon will begin testing the safety of the procedure in an area of the spine that eventually could be life-saving.

The landmark trial aims to slow progression of the fatal disease, also known as amyotrophic lateral sclerosis, or ALS, by injecting millions of stem cells into patients.

• 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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• Health Watch: Stem Cell Trial

myfoxatlanta by Beth Galvin, October 18, 2010
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A Georgia man battling Lou Gehrig's Disease or ALS, is gearing up for an experimental, risky surgery this week. On Wednesday, John Conley will become the seventh person in the U.S. to undergo a stem cell transplant for ALS.

When Conley was diagnosed with ALS in September of 2009, he said it was terrifying.

A few months later, Conley said he heard about research at Emory University where doctors were taking fetal stem cells derived from a fetus and directly injecting them into the spinal cord for the first time.

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Conley said he signed up for because the procedure offered him hope.

If it's possible to be blessed, and cursed at the same time, Conley says that about sums up the last 13 months of his life.

At 58, Conley has a wife, two sons, and an incurable disease, known as ALS. The disease will gradually take away Conley's ability to walk and move his body.

Conley intends to allow Emory University surgeons to transplant hundreds of thousands of neural stem cells, derived from a fetus and grown in a lab, directly into his spinal cord. The procedure is high risk, and no promises.

Emory neurologist Dr. Jonathan Glass, who's heading up the stem cell study says the ultimate goal is to see if stem cells can actually slow down or stop the progression of ALS. First, researchers have to find out if the surgery and the stem cells are safe.

Conley, who gets massages to help him deal with the pain and spasms in his arms and legs, says in just the last month his leg muscles have markedly weakened.

"As ALS patients we only have hope, a renewed sense of hope," said Conley.

Conley says he knows the procedure may not help him win his battle, but, he hopes it will help others who follow in his footsteps.

Conley's surgery will take about four and half hours.

Dr. Glass says he knows this surgery is controversial because it involves the use of fetal stem cells. Controversy aside, the team feels there is tremendous potential to treat the fatal disease.

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• Human Neural Stem Cells Reverse Rat Stroke Brain Damage

Neuralstem has released a new report detailing positive results for stem cell treatments. Initial findings show that not only do implanted human spinal cord-derived stem cells survive, but also differentiate into neurons in rats brains affected by strokes. This finding could potentially provide new therapies for treating strokes.

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Neuralstem stem cells survive and differentiate into neurons in rats with stroke

Neuralstem, Inc. announced that its spinal cord stem cells survived in rat brains affected by stroke and differentiated predominantly into neurons. The transplanted animals showed significant improvement in some motor skill and strength measurements. The study entitled, “Intracerebral Implantation of Adherent Human Neural Stem Cells To Reverse Motor Deficits in Chronic Stroke Rats,” was presented earlier today by senior study author, Dr. Shinn-Zong Lin, M.D., Ph.D., at the Stem Cells USA & Regenerative Medicine Conference, in Philadelphia, PA. Dr. Lin is a Professor of Neurosurgery and Vice Superintendent at China Medical University Hospital of Taiwan.

“This animal study shows the potential promise of this cell line in treating post-stroke symptoms,” Dr. Lin commented. “Four weeks after transplantation, the rats treated with Neuralstem’s cells showed significantly decreased asymmetric body swing, increased vertical movements and increased grip strength, compared with the control group.”

“Dr. Lin’s findings represent a significant milestone for Neuralstem. They are the first to show how our human spinal cord-derived stem cell product, NSI-566RSC, currently in a clinical trial for ALS, and which we expect to be in another clinical trial for spinal cord injury, also works in the stroke brain,” said Dr. Karl Johe, Ph.D., Neuralstem’s Chief Scientific Officer and Chairman of the Board of Directors. “Our proposed treatment for paralysis due to stroke will involve transplantation near the motor tracts close to the stroke lesion in the brain in order to promote regeneration and repair. While the trial protocol for ALS and chronic spinal cord injury involves transplantation into the spinal cord, and that for stroke will involve transplantation into the brain, we are nevertheless targeting the circuitry that controls motor function in each indication. We are developing clinical programs for stroke in both the U.S. and Taiwan, and hope to start our first trial in 2011.”

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• Neuralstem Files Spinal Cord IND Amid Stem Cell Hubbub

Neuralstem Inc.'s news that it filed an investigational new drug application for the first stem cell trial in chronic spinal cord injury came only two days after a federal judge's ruling overturned President Obama's stem cell policy, but that was merely "coincidence," said the firm's president and CEO Richard Garr.

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“We’ve been working around the clock, and this just happened to be when we got it done,” he told BioWorld Today.

So it’s hard to say whether the 6.7 percent stock bump Wednesday was spurred by the latest IND filing or by the fact that Neuralstem, which works on fetal-derived neural stem cells rather than the more controversial human embryonic stem cells, isn’t likely to be at all affected by the late Monday ruling that claimed Obama’s March 2009 executive order to expand federal funding for hESC research was illegal. (See BioWorld Today, Aug. 25, 2010.)

Shares of Rockville, Md.-based Neuralstem (AMEX:CUR) gained 12 cents to close at $1.92.

While he doesn’t expect that ruling to stand, Garr also does not anticipate any political fallout to impede the agency’s review of Neuralstem’s IND. It shouldn’t have “any impact at all at the FDA on the ground level,” he said.

Besides, he pointed out, Neuralstem has “gone through [the IND process] once before.”

The firm gained clearance last year for a Phase I trial testing its spinal cord stem cells in amyotrophic lateral sclerosis patients, but was only allowed to move forward after a roughly nine-month clinical hold.

Other investigational stem cell treatments also have been hit with clinical holds, most notably Geron Corp., which waited several months for FDA clearance after filing an IND in 2008.

The agency lifted the hold in January (only a few days after Obama took the oath of offi ce), but Geron’s Phase I was stalled by another hold due to safety issues. The Menlo Park, Calif.-based fi rm was permitted earlier this month to resume the study of hESC therapy GRNOPC1 in subacute thoracic spinal cord injuries. (See BioWorld Today, Jan. 26, 2009, and Aug. 2, 2010.)

The FDA’s caution isn’t unusual for new therapeutic approaches, Garr said, but the good news is that the firm’s ALS trial is proceeding as planned.

To date, six patients have been transplanted with cells via direct injection into the gray matter of their spinal cords. Five of those have been reviewed by the study’s safety monitoring board and “are all doing well,” he added.

The proposed 16-patient Phase I trial in chronic spinal cord injuries – defined as patients with complete injuries for one to two years – will involve the same cells and same injection as in the ALS trial.

The plan is to start with eight patients who have thoracic injuries and, if data show the firm’s spinal stem cells are safe, to move on to patients with the riskier cervical spinal cord injuries, Garr said.

As in the ALS trial, safety is the primary endpoint, though Neuralstem hopes to measure some functional recovery as a secondary endpoint.

The company’s stem cells are not embryonic, but neither are they really adult stem cells. Its technology is designed to isolate CNS stem cells derived from fetal tissues and then expand each cell up to 60 doublings, or a billion billionfold, Garr said. “So one donated tissue can transplant over a million patients,” he explained.

But the cells are not immortal, so there’s less risk of expanding beyond the treatment area compared to hESCs. “And they have the best part of adult cells, in that we know what they will turn into,” he added.

Though there are no predictive animal models of chronic human spinal cord injury, transplantation of Neuralstem’s neural stem cells in a rat model of ischemiainduced spinal cord injury resulted in signifi cant motor recovery. Data from that study, published in the June 29, 2007, issue of Neuroscience, also indicated robust graft survival, extensive neuronal differentiation and integration of grafted cells into the host circuitry.

Pending smooth FDA clearance, Neuralstem hopes to start the spinal cord trial before the end of this year.

The company is funding its clinical programs on its own. As of June 30, it had cash, equivalents and marketable securities totaling $14 million, which included $9.3 million in proceeds from a June offering.

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