Human Stem Cells Help Acute SCI Rats; Chronic Trial Update

http://www.spinalcordinjury-paralysis.org/research/2013/05/31/human-stem-cells-help-acute-sci-rats-chronic-trial

Human Stem Cells Help Acute SCI Rats; Chronic Trial Update

Posted by Sam Maddox
Friday, May 31, 2013

A study was published this week showing that rats improved function after receiving transplants of Neuralstem, Inc.’s human neural stem cells three days after a spinal cord contusion injury (at L3). The study, “Amelioration of Motor/Sensory Dysfunction and Spasticity in a Rat Model of Acute Lumbar Spinal Cord Injury by Human Neural Stem Cell Transplantation,” was led by Martin Marsala, M.D., of the University of California, San Diego (UCSD) School of Medicine.

The human cells in this experiment — they call them NSI-566 cells — are derived from a single, legally aborted fetus; these are the same ones used by Neuralstem in 15 patients in an ALS safety trial. They are also the same ones set for clinical trial in chronic SCI, which we will get to in a minute.

In all cases, the cells are injected into the exposed spinal cord in several locations; so far, they appear to be safe. For the ALS trial, the company reported earlier this month that the procedure “was found to be safe, well-tolerated, and promising for other spinal cord conditions.”

The company also notes that some of the patients benefited from the cell transplants. A 39-year-old man with ALS, Ted Herada, got two sets of stem cell transplants. After the first, in 2011, he was recovered a meaningful degree of function, then declined. A year later, he got more cells. Neuralstem reports that Ted recently completed 2.5 -mile fundraising ALS walk in Atlanta, “still going strong past finish line.”  He is “Living a normal life: walking, climbing stairs, hands stronger again, increased dexterity.”

Says Principal Investigator Eva L. Feldman, M.D., University of Michigan, from a release, “Although this phase of the trial was not powered to demonstrate efficacy, we appear to have interrupted the progression of the disease in one subgroup of patients. We are anxious to move to future trial phases to examine therapeutic efficacy.”

Indeed, a Phase II trial with much larger cell dosage has been approved. From the company:

The Phase II trial is designed to treat up to 15 ambulatory ALS patients, in five different dosing cohorts, advancing up to a maximum of 40 direct injections and 400,000 cells per injection, based on safety. This compares to a maximum of 15 injections of 100,000 cells each, directly into the gray matter of the spinal cord, in the completed Phase I trial. The first 12 Phase II patients will receive injections in the cervical region of the spinal cord only, where the stem cells could help preserve breathing function; the final three patients will receive both cervical and lumbar injections.


And yes, as we reported in January a clinical trial is being prepped for chronic spinal cord injury – for those one to two years post. It is expected to begin enrolling patients this summer as centers and institutional approvals are lined up. The company hasn’t released any information about the trial but a look at the trial detail at clinicaltrial.gov shows that several centers have been identified:

• Crawford Research Institute at the Shepard Center in Atlanta. Former Reeve Foundation International Research Consortium on Spinal Cord Injury Associate Keith Tansey, M.D., Ph.D. is listed as principal investigator for the study. (keith_tansey@shepard.org).
• University of Miami
• Thomas Jefferson University Hospital, Philadelphia
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• Karl Johe, the chairman and chief medical officer of Neuralstem, announced this week that UCSD Medical School would also be one of the trial centers. For more about this site, contact Adrienne Rebollo, arebollo@ucsd.edu.


I spoke with Johe: “The dogma has been that human cell transplants to the spinal cord were not feasible. First, the environment is too hostile, due to necrosis and inflammation. Second, there is no way to overcome this. We have shown here [in the acute rats], however, that our human cells integrate into the animals. Most of the stem cells die. Some survive and they proliferate in the injured area; they continue to divide until they fill the cavity. At that point they begin to differentiate into neural tissue.”

According to Marsala, the 556 cells appear to be doing two things: stimulating host neuron regeneration and partially replacing the function of lost neurons. “Grafted spinal stem cells are a rich source of different growth factors which can have a neuroprotective effect and can promote sprouting of nerve fibers of the host neurons. We have also demonstrated that grafted neurons can develop contacts with the host neurons and, to some extent, restore the connectivity between centers, above and below the injury, which are involved in motor and sensory processing.”



Johe said his 566 cells appear to reduce the size of injury. Our studies with MRI show that the surface area of scar is much, much less. The stem cells also appear to stabilize the injury – the cells restore the integrity of the tissue. The fact the animals showed reduced spasticity is a sign of reduced  secondary damage,” said Johe.

“Rats often recover spontaneously,” said Johe, “so it is difficult to demonstrate a functional benefit; but the animals in our study have more accurate foot placement and better coordination of limb movement.”

Chronic SCI Trial

Johe wasn’t able to predict when this trial would commence – this summer, he hopes. He acknowledged that there has been great interest – the word chronic is extremely rare in SCI trials.

Johe thinks his stem cells are versatile and robust enough to make a difference in both acute and chronic SCI, stroke, even brain cancer. Stem cells, he said, are not like drugs, which might target a specific process or action. “Stem cells are more like a shotgun – they offer many possible actions and mechanisms. A plethora of effects will be required for a reconstructive treatment in the spinal cord.”

Here’s a summary of the chronic trial, from a release

This open-label, multi-site study will enroll up to eight patients with thoracic spinal cord injuries (T2-T12) who have an American Spinal Injury Association AIS-A level of impairment, between one and two years post injury. These patients exhibit no motor or sensory function in the relevant segments at and below the injury, and are considered to be in complete paralysis. Study patients will receive six injections in, or around, the injury site: the first four patients will receive 100,000 cells per injection; the second four patients, 200,000 cells per injection. All NSI-566 SCI patients will receive post-surgery physical therapy, as well as immunosuppressive therapy, which will be for three months, as tolerated. The trial study period will end six months post-surgery for each patient. The primary objective of the study is to determine the safety and toxicity of NSI-566 for the treatment of paralysis and related symptoms due to SCI. The secondary objectives are to evaluate graft survival in the transplant site by MRI, as well as the effectiveness of transient immunosuppression.

It is anticipated that each individual medical center will handle its own recruitment. We’ll pass along more information as it is available.

Ted Harada: His ALS miracle continues to amaze

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Ted Harada: His ALS miracle continues to amaze

Stem-cell protesters are blind to the big picture

After stem cell injections, Ted Harada no longer needs his canes

You can understand Ted Harada being more than a little cheesed off when knee-jerk protesters start whining about embryonic stem cells and how it’s against God’s wishes and all that is moral and right to use them in the name of science.

But Harada is too busy still reveling in the seemingly miraculous improvement in his symptoms of ALS to be mad at anyone. Nothing is going to wipe that smile off his face.

Here’s the deal:

Harada, 40, is a former manager at FedEx who first noticed symptoms of ALS in 2009 while playing Marco Polo with his kids in the family swimming pool.

On March 9, 2011, he got an injection of 500,000 stem cells — the cells were derived by Rockville, Md.-based Neuralstem Inc. after a patient donated her fetus’ spinal-cord tissue in 2002 — as part of an 18-operation, 15-patient trial that last 2 1/2 years.

Harada doesn’t know if the tissue was from an embryo that was aborted or one that was miscarried or one that died as a result of an accident. The stem cells he got weren’t from that embryo, they were from cells that begat cells that begat cells that begat cells during 11 years and many generations of cells.

The operations were conducted by Emory University Hospital physician Dr. Nicholas Boulis. The trial was designed, in part, by Dr. Eva Feldman, director of the A. Alfred Taubman Medical Research Institute at UM and director of the ALS clinic at the UM Health System. Boulis is a former colleague of hers at UM.

Harada was one of three patients who got two rounds of injections, the second last August. Researchers monitored all patients for side effects, the trials proved to be safe and last month, the U.S. Food and Drug Administration gave its blessing for Phase 2 trials, to begin later this year in Ann Arbor and at Emory.

Signs of Harada’s ALS diminished noticeably after his first injection, and the improvement after his second injection was even more noticeable.

He hasn’t used his canes in months, his strong grip has returned, he easily walks upstairs to kiss his kids goodnight. On Oct. 20, he was even able to do a 2.5-mile fundraising walk in Atlanta to fight ALS.

“If the walk had been in July, I wouldn’t have attempted it,” he said. “After a third of a mile I would have been done. I would have sat down and said, `Someone come pick me up in a car.’ ”

Harada still has ALS. He still knows the likely prognosis is death. But there’s hope the prognosis of death won’t always accompany the diagnosis, now that there’s clearly some mechanism for improvement that researchers need to understand and refine.

“We’ve got to turn Lou Gehrig’s disease into Lou Gehrig’s chronic illness,” he told me last summer.

Today, Harada told me nearly all the improvement that happened after his last injection is still evident. Wednesday, he underwent his usual round of post-injection testing at Emory. “I’ve been doing great and feeling great. Just now, the left leg showed a little bit of weakness returning, but I’m still so much better than I was before the surgeries. It’s the first time, since August, they’ve noticed any slight weakness.

“It’s clear from the data that the injections reversed my symptoms and slowed down the progression of the disease. I’ve received a blessing. I almost forget I have ALS. I don’t have the constant reminder of having to use the canes. Now, I don’t think about ALS every day. Every couple of days something happens and I think, `Oh, yeah, I have ALS.’ ”

When Feldman told me the good news in April that the FDA had given its blessing for Phase 2 trials, she said Harada would be welcome to apply for another round of injections.

And Boulis briefly told him the same thing in Atlanta. But he and Feldman had overlooked an important detail: The trial protocol calls for patients who have been diagnosed within a certain window of time. Harada had been recently diagnosed when he got his first injection, and the thought, based on how well he did, is that those more recently diagnosed will show more dramatic results.

Alas, the irony is that based on his success, the change in test criteria now excludes him from further participation.

“I’d be intellectually dishonest if I said I wasn’t disappointed, but I’m still the biggest cheerleader for the trials,” he said. “If they can get good results and get to market, I might still be able to take advantage.”

The day after UM and Feldman happily announced Phase 2 trials would commence, loud and strident protesters showed up at UM to bloviate against the use of embryonic stem cells.

They were on TV, they were on the radio. Never mind that the embryo they were concerned about died 11 years ago and that this is a line of cells gathered legally in a process that obeyed all state and federal rules and is finally giving hope to people who no longer are sure their disease is a death sentence.

“I don’t think the protestors understand,” said Harada. “An embryo dying is a one-time tragedy, I know that. But this is a way to turn it into a gift. And it’s a gift that’s done so much good. That’s proved to be life extending.”

Drug might treat depression, brain damage in athletes

Gazette.Net

Gazette.NetDrug might treat depression, brain damage in athletes

Friday, May 03, 2013

by Elizabeth Waibel Staff writer

http://www.gazette.net/article/20130503/NEWS/130509458/0/gazette&template=gazette

A Rockville company is conducting clinical trials on a drug it hopes could treat both depression and traumatic brain injuries in athletes.

The drug, developed by Neuralstem Inc., appears to rebuild a region of the brain that seems to atrophy in patients with major depression, according to a news release from the company.

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“These injuries can result in long-term and serious loss of cognitive function, depression, a shorter life span and, sadly, death by suicide in some cases,” Richard Garr, president and CEO of Neuralstem, said in a statement.

During the past few years, the suicides of several ex-NFL players have drawn attention to depression as a possible symptom of traumatic brain injuries. A year ago, former NFL linebacker Junior Seau was found dead in his home of an apparent suicide.

After his death, scientists determined that he suffered from chronic brain damage. His family sued the NFL, The Washington Post reported, saying that he committed suicide because of brain disease caused by violent hits during football games.

Some research suggests that a region of the brain called the hippocampus might shrink in patients suffering from depression and in people with traumatic brain injuries, according to the news release. Based on tests in mice, researchers think the drug, named NSI-189, works by regrowing neurons and rebuilding the hippocampus.

Neuralstem researchers also think the drug might be able to help treat Alzheimer’s disease and post-traumatic stress disorder, but they have not yet done any trials to test that theory.