March 14, 2011 by

StemCells, Inc. Initiates World’s First Neural Stem Cell Trial In Spinal Cord Injury

StemCells Inc Press Release
StemCells Inc announced today they are initiating a clinical trial using their fetal derived neural progenitor cells for the treatment of spinal cord injuries. Previously the company had reported that their stem cells, called HuCNS-SC, are capable of differentiating into various neural lineage cells including neurons, oligodendrocytes, and astrocytes. The fact that HuCNS-SC are derived from fetal sources allows them to possess a lower ability to stimulate immune responses, therefore, the cells can be used as an “off the shelf” product.
According to the company “The Company’s preclinical research has shown that HuCNS-SC cells can be directly transplanted in the central nervous system (CNS) with no sign of tumor formation or adverse effects. Because the transplanted HuCNS-SC cells have been shown to engraft and survive long-term, this suggests the possibility of a durable clinical effect following a single transplantation. StemCells believes that HuCNS-SC cells may have broad therapeutic application for many diseases and disorders of the CNS, and to date has demonstrated human safety data from completed and ongoing studies of these cells in two fatal brain disorders in children.”
The proposed study will be conducted at the Balgrist University Hospital, in Zurich, which is a private, non-profit institution managed in accordance with economic principles. The clinic has three key areas of expertise: it is a highly specialised centre providing examination, treatment and rehabilitation opportunities to patients with serious musculoskeletal conditions; it is responsible for training future doctors studying at the University of Zurich in orthopaedics and paraplegiology and providing professional training for doctors and medical staff in the domains of orthopaedics, paraplegiology, rheumatology, anaesthesiology and radiology; it is a research centre dedicated to improving quality for healthcare in the future. The number of patients or inclusion/exclusion criteria for the trial was not mentioned in the press release. However a look at clinicaltrials.gov reveals the following:
The study is a 12 patient Phase I/II trial in which treated patients will also receive immune suppression so that the transplanted cells will not be rejected. The trial has the following inclusion/exclusion criteria:
Inclusion Criteria:
• T2-T11 thoracic spinal cord injury based on American Spinal Injury Association (ASIA) level determination by the principal investigator (PI)
• T2-T11 thoracic spinal cord injury as assessed by magnetic resonance imaging (MRI) and/or computerized tomography (CT)
• ASIA Impairment Scale (AIS) Grade A, B, or C
• Minimum of six weeks post injury for the initiation of screening
• Must have evidence of preserved conus function
• Must be at stable stage of medical recovery after injury
Exclusion Criteria:
• History of traumatic brain injury without recovery
• Penetrating spinal cord injury
• Evidence of spinal instability or persistent spinal stenosis and/or compression related to initial trauma
• Previous organ, tissue or bone marrow transplantation
• Previous participation in any gene transfer or cell transplant trial
• Current or prior malignancy
Success in treatment of spinal cord injury has been reported in the peer reviewed literature by Cellmedicine in which a patient was treated with a combination of cord blood hematopoietic and placental matrix mesenchymal stem cells http://www.intarchmed.com/content/pdf/1755-7682-3-30.pdf.
The advantage of the approach proposed by StemCells Inc is that only one injection of stem cells may be necessary . The disadvantage is that while the stem cells may generate neurons, it is difficult to imagine how one source of stem cells alone can recapitulate and accelerate the multicellular process involved in healing of the spinal cord.
Treatment of spinal cord injuries using stem cells is also underway by the company Geron who uses embryonic stem cell derived oligodendrocytes in patients with spinal cord injury.
Two previous trials have been reported in the area of spinal cord injury that used mesenchymal stem cells exclusively. In 2006 the group of Movilgia et al from Argentina treated two patients with spinal cord injury using an interesting protocol of T cell plus MSC. Forty-eight hours prior to NSC implant, patients received an i.v. infusion of 5 x 10(8) to 1 x 10(9) AT cells. NSC were infused via a feeding artery of the lesion site. Safety evaluations were performed everyday, from the day of the first infusion until 96 h after the second infusion. Patient 1 was a 19-year-old man who presented paraplegia at the eight thoracic vertebra (T8) with his sensitive level corresponding to his sixth thoracic metamere (T6). He received two AT-NSC treatments and neurorehabilitation for 6 months. At present his motor level corresponds to his first sacral metamere (S1) and his sensitive level to the fourth sacral metamere (S4). Patient 2 was a 21-year-old woman who had a lesion that extended from her third to her fifth cervical vertebrae (C3-C5). Prior to her first therapeutic cycle she had severe quadriplegia and her sensitive level corresponded to her second cervical metamere (C2). After 3 months of treatment her motor and sensitive levels reached her first and second thoracic metameres (T1-T2). No adverse events were detected in either patient (Moviglia, G.A., et al., Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy, 2006. 8(3): p. 202-9).
Pal et al from Stemeutics in India reported 30 patients with clinically complete SCI at cervical or thoracic levels were recruited and divided into two groups based on the duration of injury. Patients with <6 months of post-SCI were recruited into group 1 and patients with >6 months of post-SCI were included into group 2. Autologous BM was harvested from the iliac crest of SCI patients under local anesthesia and BM MSC were isolated and expanded ex vivo. BM MSC were tested for quality control, characterized for cell surface markers and transplanted back to the patient via lumbar puncture at a dose of 1 x 10(6) cells/kg body weight. Three patients had completed 3 years of follow-up post-BM MSC administration, 10 patients 2 years follow-up and 10 patients 1 year follow-up. Five patients have been lost to follow-up. None of the patients have reported any adverse events associated with BM MSC transplantation (Pal, R., et al., Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy, 2009. 11(7): p. 897-911)
A search of clinicaltrials.gov for ongoing trials using stem cells in patients with spinal cord injury reveals the following:
1. Cairo University is performing a Phase I/II trial in 80 patients with spinal cord injury who are receiving autologous bone marrow derived stem cells. The trial includes patients that are treated with stem cells and receive physical therapy versus patients receiving physical therapy alone. The trial has completed enrollment and recruited patients who had injury 8 months to 3 years before entering the trial.

2. RNL Bio from Korea is performing a Phase I study on 8 spinal cord injury patients who had their injuries more than two months before entering the study. The cells administered are 40 million autologous adipose derived cells, given intravenously. The trial enrollment is completed and the Principle Investigator is Dr. SangHan Kim, MD from the Anyang Sam Hospital.

3. International Stemcell Services Limited from India is doing a 12 patient Phase I/II trial administering autologous bone marrow into patients after spinal cord injury. The trial enrollment is completed and the Principle Investigator is Dr.Arvind Bhateja, from the Sita Bhateja Speciality Hospital.

4. TCA Biosciences from Louisiana is performing a 10 patient Phase I trial using autologous bone marrow mesenchymal stem cells. The trial enrollment is completed.

5. The Memorial Hermann Healthcare System is doing a study using autologous bone marrow cells in children aged 1-15 using autologous bone marrow cells. The study plans to enroll 10 patients.

6. The Hospital Sao Rafael from Brazil is doing a 10 patient study using autologous bone marrow in spinal cord injury patients.
This exploration of clinicaltrials.gov tells us that relatively little is being performed in terms of stem cell therapy for spinal cord injury. Given the success of Cellmedicine at treating this condition, it will be interesting to see the outcomes of the other ongoing trials.

Filed Under: Adult Stem Cells, Clinical Trials, Spinal Cord Injury, Stem Cell Research Tagged With: , , , ,
January 3, 2011 by

Advanced Cell Technology Receives FDA Clearance For Clinical Trials Using Embryonic Stem Cells to Treat Age-Related Macular Degeneration

Business Wire

Advanced Cell Technology, a biotechnology company based in Marlborough, Massachusetts which specializes in the development and commercialization of cell therapies for the treatment of a variety of diseases has been awarded FDA clearance to begin a clinical trial implementing human embryonic stem cells (hESCs) to treat Age-Related Macular Degeneration (AMD).

AMD has two forms, wet and dry, dry AMD being the most prominent, accounting for almost 90% of AMD cases. Dry AMD is the leading cause of blindness in people over the age of 55. Blindness results from the loss of retinal pigment epithelial cells, a single layer of six hexagonal cells just outside the neurosensory retina, responsible for nourishing the macula, the part of the eye responsible for high acuity vision.

The Phase I/II clinical trial will be performed at the Jules Stein Eye Institute at UCLA and the Opthalmology Department at the Stanford School of Medicine. The trial will determine the safety and efficiency of the RPE cells following sub-retinal transplantation. The proposed therapy uses RPE cells derived from hESCs to replace the diminished levels of RPE cells in the diseased patient. The company hopes to show that the RPE cells can be injected into to the retinal space in order to slow or halt the progression of AMD.

http://www.businesswire.com/news/home/20110103005348/en/Advanced-Cell-Technology-Receives-FDA-Clearance-Clinical

Filed Under: News, Stem Cell Research Tagged With: , , , , ,
December 29, 2010 by

Increasing Efficacy of Stem Cell Therapy for Spinal Cord Injury

Jin et al. Spine (Phila Pa 1976).

Clinical trials of stem cells for treatment of spinal cord injury are currently being conducted in the United States and abroad. For example, the Covington Louisiana company TCA Cellular Therapy LLC is recruiting 10 patients with spinal cord injury to receive intrathecal infusion (lumbar puncture) of autologous, ex vivo expanded bone marrow-derived mesenchymal stem cells. Completed clinical trials have demonstrated some rationale that stem cells may be useful. For example, Kumar et al. (Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: A phase I/II clinical safety and primary efficacy data. Exp Clin Transplant. 2009 Dec;7(4):241-8) reported on 297 spinal cord injury patients that were treated with their own bone marrow cells injected intrathecal. 33% of the patients reported an objective improvement.

As with other clinical trials of stem cell therapy, it appears that in the area of spinal cord injury there still remains room for improvement. We at Cellmedicine have reported a stunning improvement in a spinal cord injury patient by using a combination of CD34 and mesenchymal stem cells, which was recently published http://www.intarchmed.com/content/pdf/1755-7682-3-30.pdf. Unfortunately this was only one patient and more studies are required.

In an attempt to improve efficacy of stem cell therapy for spinal cord injury, a group from the Department of Neurosurgery, Spine and Spinal Cord Institute, at the Yonsei University College of Medicine, Seoul, Republic of Korea, has created an artificial method of increasing growth factor production from stem cells of the nervous system called neural progenitor cells. Previous studies have shown that neural progenitor cells are capable of treating several models of spinal cord injury, however their effects appear to be transient. Vascular endothelial growth factor (VEGF) is a protein that increases blood vessel production in tissues and has been previously demonstrated to stimulate integration of nervous system cells after spinal cord injury. Since increasing VEGF production could hypothetically increase efficacy of neural stem cells, a series of experiments were performed in order to generate modified neural stem cells which have enhanced VEGF production.

It is known that insertion of a gene into a cell can cause the cell to produce the protein made by the gene. So theoretically all the researchers had to do is to transfect (insert) the VEGF gene into the neural stem cells and the neural stem cells would be more effective. The problem with this is that too much VEGF can have negative effects. A more attractive approach would be to program the progenitor cells in such a manner so that they produce VEGF only when it is necessary. During spinal cord injury, the area of damage is associated with reduced oxygen, a condition called hypoxia. Ideally one would want to engineer the stem cells in a manner so that they produce VEGF only during times of hypoxia. One way of doing this is to control the expression the gene by using an inducible promoter.

Promoters are pieces of DNA that control expression of genes that are in front of them. Some promoters always turn on gene expression (these are called constitutive promoters), others turn on expression only under specific conditions (these are called inducible promoters. The promoter that turns on erythropoietin is an inducible promoter. Erythropoietin is made by the kidney and stimulates production of red blood cells. Its expression is turned on under conditions of lack of oxygen. This is why people who live in high altitudes have higher expression of erythropoietin. The scientists in the current publication developed a genetically engineered neural stem cell that contains the VEGF gene under control of the erythropoietin promoter. What this means is that the cells will be producing VEGF only under conditions of hypoxia. In order to selectively detect the areas of hypoxia, the scientists also developed stem cells that have the luciferase gene in front of the erythropoietin promoter. Luciferase is a protein that generates light and allows for easy detection in vitro and in vivo of the hypoxic cells.

The scientists found that the stem cells administered during hypoxia generated significantly higher concentrations of VEGF, which was associated with the promoter being turned on, as assessed by luciferase expression. Furthermore, rats receiving the VEGF expressing stem cells possessed a significantly lower amount of nerve damage and higher ability to recuperate after spinal cord injury.

These data suggest that it is feasible to combine inducible promoters with stem cells in order to augment various activities of the stem cells. This concept could be applied to numerous settings. For example, mesenchymal stem cells are known to selectively migrate to areas of inflammation. In the setting of cancer, mesenchymal stem cells could be transfected with genes that are encoding toxic substances. This way chemotherapy could be targeted only to cancer cells and therefore have a better safety profile.

Gene therapy has failed to a large extent because of lack of ability to control where the genes are administered. It may be possible that advancements in stem cell technologies will allow for a rebirth of gene therapy in that the stem cells may be used to deliver genes only to the tissues where they are needed.

Filed Under: Adult Stem Cells, News, Spinal Cord Injury, Stem Cell Research Tagged With: , , , , , ,
December 27, 2010 by

Time to end stem cell institute CIRM

Wesley J. Smith , San Francisco Chronicle

The California Institute for Regenerative Medicine (CIRM) was created in 2004 as a result of the California Proposition 71, which called for a new bond issue to generate 3 billion dollars in order to support stem cell research in the State. In part, the institute was created as a response to President George W. Bush’s order restricting federal funding of embryonic stem cell research. The hope behind this enormous influx of cash to stem cell research was based on the popular belief that the State would have reduced medical costs, as well as treatments for many of the debilitating diseases that could benefit from stem cell therapy.

According to the author of the article, who is a senior fellow at the Discovery Institute’s Center on Human Exceptionalism and a consultant to the Center for Bioethics and Culture. “The CIRM hasn’t come close to fulfilling those promises. Here’s why California voters should reject the bond issue and shut the agency down in 2014…”

His rationale is that a) CIRM was created primarily to fund human cloning for research and embryonic stem cell research. So far, cloning has failed and embryonic stem cell cures, if they ever come, are a very long way off; b) Questionable uses of taxpayer’s funds. Specifically, $300 million went to help pay for plush research facilities, particularly those associated with board members of CIRM; c) Members of CIRM are paid exorbitant salaries. For example, the head of CIRM makes just under $500,000 a year, Art Torres, a board member and former chairman of the California Democratic Party, works four days a week – for a whopping $225,000 a year.

It is our opinion that basic research is critical for development of new therapies and for advancement of medicine. Therefore, conceptually, there is nothing wrong with supporting the use of taxpayer’s dollars for stem cell research. The issue that we have revolves around what research gets funded and how those projects are in line with the goals for which the funds were donated.

In the “drug development cycle” the first step is basic research and discovery of a biological mechanism of action associated with the disease. The second step is understanding how to manipulate the interaction. The third step is developing an intervention that may theoretically be useful and testing it in animal models of diseases. The fourth step, which is considerably more difficult, is to test the putative therapy in humans either at a low dose in healthy volunteers, or in terminal patients. This usually involves 10-40 patients and is formally called a Phase I clinical trial. Phase II clinical trials are the fifth step of developing a therapeutic. This involves 30-100 patients and assesses efficacy of the therapy in patients with disease. The last step of developing a drug involves conducting Phase III clinical trials, whose aim is to see whether the putative therapy induces therapeutic effects in a double blind, placebo controlled manner.

The majority of research funded by CIRM covers projects that are at the first to third steps, that is, from identifying new biological pathways, to trying to treat mice. Very few CIRM funded projects supported adult stem cell companies that are using their cells to treat patients. We anticipate that with more articles such as the one published by Wesley Smith, CIRM will become more cognizant of the reason why taxpayers supported the Institute: to develop cures faster. Indeed, one can see this increasing support in CIRM for adult stem cell companies in that in October of this year only 5 of 19 grants were for embryonic stem cell research.

Filed Under: News, Stem Cell Research Tagged With: , , , , , ,
May 20, 2010 by

Pluristem’s Off-The-Shelf Placenta-Derived Cell Therapies

Pluristem announced that its "off the shelf" placental stem
cells will be the focus of upcoming talking at investor and medical
conferences. The company Pluristem is currently in Phase I trials assessing its
unique bio-reactor expanded placental stem cells for the treatment of critical
limb ischemia. In contrast to other therapies that use the patient’s own stem
cells (called autologous), the advantage of the "universal donor" or
"allogeneic" approach is that large numbers of cells can be generated according
to defined conditions. Additionally, universal donor cells can be administered
several times at a number that is limited only by the desire of the physician to
escalate the dose. In the autologous situation stem cells are usually taken
from the bone marrow, making it difficult to perform multiple extractions.

Pluristem will present at the International Society for
Cellular Therapy’s (ISCT) 16th Annual Meeting in Philadelphia some updates on
its ongoing programs.

"We recently reported interim top-line results from our
Phase I clinical trials demonstrating that PLX-PAD is safe, well tolerated and
had improved the quality of life of CLI patients in the studies," said Zami
Aberman, Pluristem’s chairman and CEO. "With PLX-PAD, we have the unique
opportunity to utilize a single source of cells, the placenta, to treat an
unlimited number of CLI patients. Our presentations at the ISCT Annual Meeting
and other conferences will highlight the potential of PLX-PAD as well as our
core technology that enables the cost-effective development of cell therapies
derived from the human placenta."

There are several other companies pursuing "universal
donor" stem cells. Medistem, the licensor of technologies used by Cellmedicine
has developed such a cell from the endometrium, called "Endometrial Regenerative
Cells" that are currently subject of an IND application for use in critical limb
ischemia. Athersys is using bone marrow derived universal donor stem cells for
treatment of heart failure. The most advancement in this area comes from the
company Osiris Therapeutics which also uses bone marrow derived cells to treat a
variety of conditions, although all are still in clinical trials.

In
the majority of cases universal donor cells are related directly or indirectly
to mesenchymal stem cells. These cells, originally discovered by Dr. Arnold
Caplan, express low levels of proteins that are seen by the immune system, thus
allowing them to be transplanted without matching. Additionally, they also
produce proteins that actively suppress the immune system from killing them. In
diseases associated with abnormal immunity mesenchymal stem cells have shown
promise. Cellmedicine has published on use of mesenchymal stem cells in
treatment of multiple sclerosis

Filed Under: Adult Stem Cells, News, Stem Cell Research Tagged With: , , ,
May 17, 2010 by

Stem Cell Institute Panama Clinic Case Report of Successful Treatment of Heart Failure Patient Published

Adult stem cell therapy is currently in numerous clinical trials in the United States and Internationally. A sample of ongoing trials can be seen at
www.clinicaltrials.gov if you search for the words "stem cell". In clinical trials the objective is to determine safety (in Phase I), efficacy in an unblinded manner (Phase II) and efficacy in a blinded manner (Phase III). Numerous stem cell clinical trials are in Phase II, meaning that although safety has been established there is a question of efficacy. Patients with terminal
diseases sometimes make the informed decision not to wait until efficacy trials are completed and to go to stem cell clinics that offer similar procedures being
performed in clinical trials, but without the risk of offering the patient a placebo. The additional benefit to patients of making this choice is that they are offered treatment rapidly, whereas getting into a clinical trial could mean months on a waiting list.

The stem cell clinic Cellmedicine has been offering this choice to patients. Unlike other stem cell clinics, Cellmedicine has made it a priority to publish its protocols, scientific rationale, and outcomes in the peer reviewed literature. This means that all the scientists and doctors in the world can learn about the work being performed at Cellmedicine and offer comments/suggestions on it.

Today Cellmedicine announced publication of a paper in the peer reviewed journal, International Archives of Medicine, of a patient with terminal heart failure who underwent profound recovery after receiving adult stem cell therapy. The publication is freely available at

http://www.intarchmed.com/content/pdf/1755-7682-3-5.pdf.

The patient discussed in the report was administered adult stem cells in November 2007, when his heart had an ejection fraction of 25-30%. The ejection fraction is a quantitative measurement of the heart’s pumping activity. On June 2008, August, and Oct 2009, this marker of function increased to 40%. The patient reported a major improvement in quality of life. Additionally, proteins in the blood associated with heart failure were decreased.

Given that the report was based on only one patient, doctors at the clinic are excited but still caution in their statements.

"Stem cell therapy is a new science, and although the results discussed in the paper are promising, only the conduct of double-blinded, placebo controlled trials will allow definitive conclusions to be drawn," said Dr. Paz Rodriguez, Medical Director of the Cellmedicine Panama clinic and coauthor of the study.

In the publication, Cellmedicine provides detailed rationale for how the stem cell therapy may be affecting the process of heart failure. Data from other studies was described which states that stem cells can:

a) Directly differentiate into new heart cells

b) Stimulate the body’s ability to generate new heart muscle by activating dormant stem cells that already exist in the heart

c) Cause formation of new blood vessels that accelerate the healing process.

Heart failure is only one of the conditions that Cellmedicine treats.

"To date our group has published results on multiple sclerosis, non-ischemic heart failure, and Duchenne Muscular Dystrophy patients in collaboration with major
American Universities including University of California San Diego, Indiana University, and University of Utah. By publishing our data in a scientific forum, we welcome discussion and interaction, which will lead to advanced patient care not only in Panama City but internationally," concluded Dr. Paz Rodriguez.

Filed Under: Adult Stem Cells, Heart Disease, Heart Disease, News, Stem Cell Research, Stem Cell Therapy Tagged With: , , ,
March 8, 2010 by

Stem cell therapy shows early promise: Celgene

Crohn’s disease is a favorite amongst mesenchymal stem cell
development companies. This may be because on the one hand, this type of stem
cell possesses anti-inflammatory properties, and on the other hand it has the
potential to regenerate injured tissue. Additionally since the quality of life
of patients with advanced Crohn’s Disease is so poor, and current treatments are
generally ineffective at addressing the root cause, that new treatments usually
receive much support from regulatory agencies. Crohn’s disease is characterized
as a chronic inflammatory condition of the gastrointestinal tract. It is
believed to affects almost one million people in the United States.

Today Celgene announced Phase I safety data on its
placental mesenchymal stem cell product PDA-001 in a trial of 12 patients. The
patients suffered from active moderate-to-severe Crohn’s and were unresponsive
to at least one prior conventional therapy. The treatment with stem cells
comprised two infusions of PDA-001 one week apart. The patients were divided
into 2 groups with 6 patients being administered a lower number of cells and six
a higher number.

According to Celgene, "The study met its primary safety
goal and demonstrated encouraging signs of clinical benefit, including clinical
remission among four patients in the low dose group". Interestingly the company
declined to speculate on why the lower number of cells elicited superior
benefit. As an interesting aside, the company Osiris Therapeutic conducted a
similar clinical trial in Crohn’s Disease using stem cells derived not from
placenta but from bone marrow sources.

The CEO of Celgene’s Cellular Therapeutics unit, Dr. Robert
Hariri stated "We are encouraged that in these patients with Crohn’s disease our
unique, placenta-derived therapies show signs of clinical benefit," he continued
"We will continue to aggressively pursue the clinical development of this and
other cellular therapies derived from what we see as one of the richest sources
of uniquely functional and versatile cells."

The company anticipates moving into Phase II clinical
trials not only in the area of Crohn’s but also in other degenerative
indications.

It is an interesting point that the cells were administered
intravenously. There are some groups that believe stem cells only work if
administered locally. This study suggests that the need for local injection may
not be as important as some others believe. Additionally, since companies like
Cellmedicine use various mesenchymal stem cell sources, the current results
provide US-based scientific evidence supporting at least the rationale for this
approach.

Filed Under: Adult Stem Cells, Clinical Trials, Crohn's Disease, News, Stem Cell Research Tagged With: , ,
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