First Patient Randomized for ACTIsSIMA Trial for Chronic Stroke


SanBio, a regenerative medicine company in Mountain View, California, has announced the randomization of the first enrolled patient in the ACTIsSIMA Phase 2B clinical trial. This trial will examine the efficacy of SanBio’s proprietary SB623 product in patients who suffer from chronic motor deficits as a result of strokes. SB623 consists of modified adult bone-marrow-derived stem cells. A secondary purpose of this trial is to evaluate the safety of SB623 in these patients.

Ischemic strokes account for about 87 percent of all strokes in the United States. Ischemic strokes occur when there is an obstruction in one or more of the blood vessels that provide blood and oxygen to the brain. On the order of 800,000 cases of ischemic stroke occur in the United States every year, and it is the leading cause of acquired disability in the United States. Present drug treatments for stroke either try to prevent strokes or address patients who have recently suffered a stroke. Unfortunately, there are no medical treatments currently available for people who live with the effects of stroke, months or even years after suffering a stroke.

SB623 cells are derived from bone marrow mesenchymal stem cells extracted from healthy donors. These cells are designed to promote recovery from injury by triggering the brain’s natural regenerative ability. SB623 cells have been genetically engineered to express a modified version of the Notch gene (NICD) that conveys upon the cells the ability to promote the formation of new blood vessels and the survival of endothelial cells that form these new blood vessels (see J Transl Med. 2013, 11:81. doi: 10.1186/1479-5876-11-81).

SB623 was tested in a Phase 1/2A clinical trial in which SB623 was implanted into stroke patients and produced some improved motor function.

This follow-up trial, ACTIsSIMA, will treat stroke patients with SB623 cells in order to examine the safety and efficacy of SB623 cells. All patients in this trial have suffered from a stroke anywhere from six months to five years. Also, all patients must exhibit chronic motor impairments.

Damien Bates, M.D., Chief Medical Officer & Head of Research at SanBio, said, “Our previous trial suggested there was potential for SB623 to improve outcomes for patients with lasting motor deficits following an ischemic stroke. Randomization of the first subject marks an exciting step toward further evaluating this treatment as a promising new option for patients.”

For this trial, SanBio is collaborating with Sunovion Pharmaceuticals, Inc. Sunovion is a wholly owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd., and SanBio and Sumitomo Dainippon Pharma have entered into a joint development and license agreement for exclusive marketing rights in North America for SB623 for chronic stroke.

The ACTIsSIMA trial will include approximately 60 clinical trial sites throughout the United States, and total enrollment is expected to reach 156 patients.

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Athersys’ MultiStem® Cell Therapy Provides Benefit in Neonatal Stroke Patients


In an article published in the Journal of Neuroinflammation (2015 12(1):241), Dr. Reint Jellema, in collaboration with scientists from Maastricht University, Maastricht University Medical Center and Máxima Medical Center Veldhoven in the Netherlands, and Athersys scientists described the results of experiments designed to evaluate the potential for Multipotent Adult Progenitor Cells (MAPCs) to stroke patients.

In the series of experiments described in this publication, Jellema and others examined pre-term sheep that suffered strokes while still in the womb. Such injuries in human babies are one of the main causes of cerebral palsy. In the case of these pre-term sheep, the intravenous administration of MAPCs reduced both the number and duration of seizures compared to placebo-treated animals.

Seizures commonly follow strokes in new born babies and these strokes usually cause several detrimental neurodevelopmental outcomes. MAPC treatment significantly reduced inflammation in the injured brain. The implanted cells reduced activation and proliferation of immune cells in the brain. In general the immune response after the onset of the stroke was tamped down.

This paper provides further evidence that multipotent adult progenitor cells (MAPCs) have can provide benefit following strokes. Such injuries are caused by oxygen deprivation to the brain before or during birth and are a leading cause of cerebral palsy.

“This study in a large animal model of pre-term hypoxic-ischemic injury further demonstrates the potential for MultiStem therapy to provide benefit to patients suffering from an acute neurological injury,” said Dr. Robert Mays, Vice President and Head of Neuroscience Research at Athersys. “These results are consistent with those from previous studies testing our cells in rodent models of hypoxic ischemia and ischemic stroke, and confirm our previous findings supporting the biological mechanisms through which MAPC treatment provides benefit following acute neurological injury. The results strengthen the biologic rationale for our ongoing clinical and preclinical research in ischemic stroke and hypoxic-ischemic injury, as well as traumatic brain and spinal cord injury.”

Gene Therapy for Stroke Applied with Eye Drops


Administering growth factors to the brains of patients with neurodegenerative diseases can prevent neurons from dying and maintain the structure of their brains. For example, a recently published clinical trial by Nagahara and others from the Department of Neuroscience and the University of California, San Diego examined 10 Alzheimer’s disease (AD) patients and showed that these patients responded to Nerve Growth Factor gene therapy. When they compared treated and nontreated sides of the brain in 3 patients who underwent gene transfer, expansion of cholinergic neurons was observed on the NGF-treated side. Both neurons exhibiting the typical pathology of AD and neurons free of such pathology expressed NGF, which indicates that degenerating cells can be infected with therapeutic genes. No adverse pathological effects related to NGF were observed. In the words of this study, “These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. [Neuronal s]prouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.” See JAMA Neurol. 2015 Oct 1;72(10):1139-47.

Another study that also shows that the brains of AD patients can respond to growth factors comes from a paper by Ferreira and others from the Journal of Alzheimers Disease. These authors hail from the Karolinska Institutet, Stockholm, Sweden, and they implanted encapsulated NGF-delivery systems into the brains of AD patients. Six AD patients received the treatment during twelve months. These patients were classified as responders and non-responders according to their twelve-month change in the Mini-Mental State Examination (MMSE), which is a standard. In order to set a proper standard of MMSE decline and brain atrophy in AD patients, Ferreira and other examined 131 AD patients for longitudinal changes in MMSE and brain atrophy. When these results provided a baseline, the NGF-treated were then compared with these baseline data. Those patients who did not respond to the implanted NGF showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments than responding patients. The responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Aβ1-42, and less brain shrinkage and better progression in the clinical variables and CSF biomarkers. In particular, two responders showed less brain shrinkage than what was normally experienced in the baseline data. From these experiments, Ferreira and others concluded that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD.

Now new, even simpler treatment strategy has been developed by a research team funded by the National Institute of Biomedical Imaging and Bioengineering for delivering gene therapy to the brains of AD patients. This team invented an eye drop cocktail that can deliver the gene for a growth factor called granulocyte colony stimulating factor (G-CSF) to the brain. They have tested these eye drops on mice with stroke-like injuries.

When treated with these eye drops, the mice experienced a significant reduction in shrinkage of the brain, neurological defects, and death. Ingeniously, this research group also devised a way to use Magnetic Imaging Systems to monitor how well the gene delivery worked. This one-two punch of an inexpensive and noninvasive delivery system combined with a monitoring technique that is equally noninvasive might have the ability to improve gene therapy studies in laboratory animals. Such a strategy might also be transferable to human patients. Imagine that acute brain injury might be treatable in the near future by emergency medical workers by means of eye drops that carry a therapeutic gene.

The growth factor G-CSF (granulocyte-colony stimulating factor) has more than proven itself in several animal studies. In model systems for stroke, AD, and Parkinson’s disease, G-CSF promotes neuronal survival and decreases inflammation (See McCollum M, et al., Mol Neurobiol. 2010 Jun;41(2-3):410-9; Frank T, et al., Brain. 2012 Jun;135(Pt 6):1914-25; Prakash A, Medhi B, Chopra K. Pharmacol Biochem Behav. 2013 Sep;110:46-57; Theoret JK, et al., Eur J Neurosci. 2015 Oct 16. doi: 10.1111/ejn.13105). Unfortunately, when G-CSF was when tested in a human trial in more than 400 stroke patients, it failed to improve neurological outcomes in stroke patients. Therefore, it is fair to say that the excitement this growth factor once generated is not what is used to be. A caveat with this clinical trial, however, is that G-CSF expression in the brains of these patients might have been rather poor in comparison to the expression achieved in mice. To properly establish the efficacy or lack of efficacy of gene therapies in human patients, scientists MUST convincingly determine that the gene is expressed in the target tissue of test subjects. This has been a perennial problem that has dogged many gene therapy trials.

Philip K. Liu, Ph.D., of the Martinos Center for Biomedical Imaging at Harvard Medical School, and his collaborators, H. Prentice and J. Wu of Florida Atlantic University, developed the novel MRI-based techniques for monitoring G-CSF treatment and the eye drop-based delivery system as well. MRI can efficiently confirm successful administration and expression of G-CSF in the brain after gene therapy delivery. This work was published in the July issue of the journal Gene Therapy.

“This new, rapid, non-invasive administration and evaluation of gene therapy has the potential to be successfully translated to humans,” says Richard Conroy, Ph.D., Director of the NIBIB Division of Applied Science and Technology. “The use of MRI to specifically image and verify gene expression, now gives us a clearer picture of how effective the gene therapy is. The dramatic reduction in brain atrophy in mice, if verified in humans, could lead to highly effective emergency treatments for stroke and other diseases that often cause brain damage such as heart attack.”

Liu’s motivation for this project was to develop a gene delivery method that was simple, and could rapidly and effectively deliver the genes to the brain. A simple gene delivery technique would obviate the need for highly trained staff and expensive, sophisticated equipment. They also sought to successfully demonstrate the efficacy of their technology in laboratory animals so that it could be translated to humans.

To test their system, they deprived mice of blood flow to their brains, and then administered a genetically-engineered adenovirus that had the G-CSF gene inserted into its genome. This particular adenovirus is known to be quite safe in humans and can also efficiently infect brain cells. The adenovirus was also safely and effectively administered through eye drops. The simplicity of the eye drops means that it is easy to give multiple gene therapy treatments. By delivering the G-CSF gene at multiple time points after the induced blockage, Liu and others found that the treated mice showed significant reductions in deaths, brain atrophy, and neurological deficits as measured by behavioral testing of these mice.

MRI examinations also confirmed that G-CSF was expressed in treated mouse brains. Liu and his group used an MRI contrast agent tethered to a segment of DNA that targets the G-CSF gene. This inventive strategy enabled MRI imaging of G-CSF gene expression in mouse brains. The brains of mice treated with the recombinant adenovirus showed significant expression of the G-CSF gene. Control mice treated with the same adenovirus carrying the contrast agent bound to a different piece of DNA produced no MRI signal in the brain.

Control mice that did not receive G-CSF in eye drops, MRI scan identified areas of the brain with reduced metabolic activity and shrinkage as a result of the stroke. Mice treated with the G-CSF gene therapy, however, kept their usual levels of metabolic activity and did not have any evidence of brain atrophy. On average, after a stroke, mouse brain striatum size decreased more than 3-fold, from 15 square millimeters in normal mice to less than 5 square millimeters. But in contrast, G-CSF-treated mice retained an average striatum volume of more than 13 square millimeters, which is close to normal brain volume.

“We are very excited about the potential of this system for eventual use in the clinic,” says Liu, “The eye drop administration allows us to do additional treatments with ease when necessary. The MRI allows us to track gene expression and treatment success over time. The fact that both methods are non-invasive increases the ability to develop, and successfully test gene therapy treatments in humans.”

Liu and his collaborators are now jumping through the multitudes of hoops to take this work to a clinical trial. They are trying to secure FDA approval for the use of the G-CSF gene therapy in human patients. Finally, they also need to invite collaborating with physicians to develop their clinical trial protocol.

A New Target for Treating Stroke: The Spleen


If the blood vessels of the brain become plugged as a result of a clot or some other obstructive event, then the brain suffers a trans-ischemic attack (TIA), which is more commonly known as a stroke. The initial stroke starves brain cells of oxygen, which causes cell death by suffocation. However, dying brain cells  often spill enormous amounts of lethal material into the surrounding area, which kills off even more brain cells. Worse still, these dead or dying called can induce inflammation in the brain, which continues to kill off brain cells.

New work, however, from the laboratory of César Borlongan at the University of Southern Florida in Tampa, indicates that the spleen may be a target for treating the stroke-induced chronic inflammation that continues to kill brain cells after the initial stroke.

At the University of Florida Center of Excellence for Aging and Brain Repair, a study found that the intravenous administration of human bone marrow stem cells to post-stroke rats reduced the inflammatory-plagued secondary cell death associated with stroke progression in the brain. The intravenously administered cells preferentially migrated to the spleen where they reduced this post-stroke inflammation.

This study answers some of the perplexing questions surrounding animal experiments that used stem cells to treat stroke. Typically, stem cell administration to animals that suffered an artificially-induced stroke causes some functional recovery, but when their brains are examined for the stem cells that were implanted into them, very few surviving cells are observed.

“Our findings suggest that even if stem cells do not enter the brain or survive there, as long as the transplanted cells survive in the spleen the anti-inflammatory effect they promote may be sufficient enough to therapeutically benefit the stroke brain,” said César Borlongan, principal investigator of this study.

Stroke is the leading cause of death and the number one cause of chronic disability in the United States, yet treatment options are limited.

Stem cell therapy has emerged as a potential treatment for ischemic stroke, but most pre-clinical studies have examined the effects of stem cells transplanted during acute stroke (one hour to three hours aster the onset of the stroke).

In the wake of an acute stroke, an initial brain lesion forms from the lack of blood flow to the brain. The blood-brain barrier is also breached and this allows the infiltration of inflammatory molecules that trigger secondary brain cell death in the weeks and months that follow. This expanded inflammation is the hallmark of chronic stroke.

In this study, Borlongan and his colleagues intravenously administered human bone marrow stem cells 60 days after the onset of a stroke. Thus these animals were well into the chronic stroke stage.

The transplanted stem cells predominantly homes to the spleen. In fact, Borlongan and his crew found 30-times more cells in the spleens of the animals than in the brain.

While in the spleen, the stem cells squelched the production of a protein called tumor necrosis factor, which is a major inflammatory signal that increases in concentration after a stroke. The reduction of the tumor necrosis factor signal prevented the macrophages and other immune cells from leaving the spleen and going to the brain. This reduced systemic inflammation and decreased the size of the lesions in the brain caused by the stroke. There was also a trend toward reduced neuronal death and smaller decreases in learning and memory in the laboratory animals.

Borlongan explained that during the chronic stage of stroke, macrophages seem to fuel inflammation. “If we can find a way to effectively block the fuel with stem cells, then we may prevent the spread of damage in the brain and ameliorate the disabling symptoms many stroke patients live with,” said Borlongan.

Borlongan and his team hope to test whether transplanting human bone marrow stem cells directly into the spleen will lead to behavioral recovery in post-stroke rats.

One drug that has been approved for the emergency treatment of stroke is tPA or tissue plasminogen activating factor, which activates the blood-based protein plasminogen to form the highly active enzyme, plasmin. Plasmin is a powerful dissolved of clots, but tPA must be administered less than 4.5 hours after the onset of ischemic stroke, and benefits only three to four percent of patients.

Even though more work needs to be done, evidence from the USF group and other neurobiology groups indicates that stem fells may provide a more effective treatment for stroke over a wider time frame.

Targeting the spleen with stem cells or the anti-inflammatory molecules they sec rate offers hope for treating chronic neurodegenerative diseases like stroke at later stages.

This study, which was published in the journal Stroke, shows that it is possible to arrest the chronic inflammation that characterizes chronic stroke 60 days after the initial stroke. If such a result can be replicated in human patients, it will indeed be a powerful thing, according the Sandra Acosta, the first author on this paper.

Stem Cell Treatments for Stroke: A Tale of Two Trials


Two different clinical trials that examined the efficacy of stem cell treatments after a stroke have yielded very different results.

“Stroke” refers to a serious medical condition that occurs when the blood supply to the brain is disrupted by blockage of or injury to blood vessels that supply the brain with blood. Strokes cause a loss of, or reduction in, brain function. There are two main types of strokes. Ischemic stroke accounts for about 80% of strokes. Ischemic strokes result from the cessation of blood flow to an area of the brain because of a blood clot. Hemorrhagic stroke occurs if there is a leakage of blood into the brain because a blood vessel has burst. The bleed into the brain increases the pressure on the brain and leads to brain damage.

In the two clinical trials discussed in this post, both treatments were designed to address ischemic strokes, which disrupt the blood supply to the brain and starve brain cells of oxygen, causing them to die. Brain scans of patients who have suffered from an ischemic stroke may reveal large areas of damaged brain tissue. People who have had a stroke may experience difficulties with speech and language, orientation and movement, or memory. Such problems can be permanent or temporary.

Any advances in the treatment of stroke are particularly Currently, the only available treatment is to administer anti-clotting agents to dissolve the clot that has blocked the blood flow to the brain. Unfortunately, this treatment must be provided early and only a small proportion of patients get to hospital in time to be treated in this way.

There are no existing treatments for an ischemic stroke beyond the initial acute phase. However, rehabilitation can alleviate the disabilities caused by a stroke.

The European Stroke Organization released the results of large clinical trials on the treatment of strokes with CTX0E03 human neural stem cells. The PISCES trial, as it is known, is a phase I trial, and such trials usually involve giving a small number of people a new treatment to see if it is safe. Phase I trials are not designed to test if the treatment is effective, so any positive results from a Phase I trial should be treated with some caution.

This study examined the safety and tolerability of a stem cell therapy called ReN001 in the treatment of ischemic stroke.

11 males with long-term disability between 6 and 60 months after a stroke. None of the patients showed any cell-related or immunological adverse events. Patients did show sustained reductions in neurological impairment and spasticity compared to their stable pre-treatment baseline performance.

This clinical trial is a win for ReNeuron, the company that developed, makes and markets, ReN001. A Phase II is being planned.

A second clinical trial examined the efficacy of Athersys, Inc. MultiStem treatment for ischemic stroke. This phase II trial was designed to evaluate the efficacy of the product in stroke patients. 65 patients were treated with MultiStem and 61 were given the placebo. Unfortunately, even though the MultiStem treatment was safe as well tolerated, the cell therapy did not produce any statistically significant differences at 90 days in patients compared with a placebo.

Even though the data was disappointing, a second look at the data showed something interesting. When the 27 stroke patients who had received the MultiStem treatment 24-26 hours after the stroke were compared with all the other patients, it became clear that these patients did the best. Therefore, this trial seems to indicate that the window of treatment for MultiStem after a stroke is 24-36 hours and after 36 hours it works no better than placebo.

“Unfortunately, we just didn’t have the window right for this study,” Athersys Chief Operating Officer William Lehmann Reuters News Service. “We believe investors should see this as a sign that MultiStem works.”

The MultiStem treatment was also associated with lower rates of mortality and life threatening adverse effects, infections and lung-related events. Nine patients who had received the placebo died during the 90 day period (14.8%) while only four who received the MultiStem treatment died (6.2%).

The CEO of Athersys, Gil Van Bokkelen, said: “While the trial did not achieve the primary or component secondary endpoints, we believe the evidence indicating that patients who received MultiStem treatment early appeared to exhibit meaningfully better recovery is important and promising.”

This randomized, double-blind, placebo-controlled Phase 2 study is being conducted at sites in the United States and the United Kingdom.