Dr. Riordan discussed types of stem cells used in treatments with a focus on adipose and umbilical cord derived stem cells, including their roles in immune system modulation, inflammation reduction and tissue repair:Autoimmune diseases and spinal cord Injury are highlighted. Dr. Riordan is the Founder of the Stem Cell Institute in Panama City, Panama.
November 29, 2012 by
Non-controversial stem sells: rationale for clinical use: Neil Riordan, Ph.D. – (Miami)
November 29, 2012 by
Giving birth after stem cell treatments for spinal cord injury
Trish Stressman and her husband Scott discuss how stem cell therapy at the Stem Cell Institute in Panama allowed her to recover to the point at which she could safely give birth and care for her newborn daughter, Savannah Hope.
Prior to stem cell treatment, Trish had no core muscles and would not have been able to even safely hold a baby, let alone care for one. Since stem cells, that’s all changed. Congratulations Trish, Scott and Savannah Hope!
February 15, 2012 by
Stem Cells in Theory and Practice
Dr. Douglas J. Herthel of Alamo Pintado Equine Medical Center in Los Olivos, California was one of the first practitioners to use stem cells, beginning in 1995. Herthel used stem cells from bone marrow to treat ligament and tendon injuries in horses. The results from these treatments were so promising that he began using stem cells to treat other various conditions as well.
The treatment has since been used to treat common equine issues such as laminitis, as well as spinal cord injuries. A dramatic example is that of a donkey who suffered a spinal cord injury as was quadriplegic. The donkey regained full function following a stem cell treatment. “It’s certainly an exciting time to be in the veterinary field,” Dr. Herthel said. “You’re talking about potential cures for things, rather than just palliation. And you’re also talking about maybe less pharmacological use.” Adair, an Irish Draught Cross horse had a very severe case of chronic forelimb laminitis, so severe in fact, that without a dramatic improvement he would have to be euthanized. Adair was treated with stem cells in early 2010, 48 hours following treatment he appeared to be in less pain and six weeks later, his hooves had grown almost halfway back.
Dr. Johnson, Adair’s owner, started using stem cells in 2001 to treat tendinitis in racehorses. “The funny thing about science or lack thereof in clinical practice is you try something for what has historically not been an easy problem to fix, and you have some limited success, and you carry on,” Dr. Johnson said. Some doctors performing stem cell treatment extract and process the cells in house, while others order stem cells from another horse. Many doctors send tissue samples to Vet-Stem Inc. or other laboratories to process the cells. Dr. Robert J. Harman, Vet-Stem’s chief executive officer, said his company has processed stem cells from fat samples for about 8,000 patients since starting in 2004. About 4,000 veterinarians have completed the Vet-Stem credentialing course on stem cells as a therapy. “Once they’ve been through the course, most people are pretty strong believers that this has a place in veterinary medicine,” Dr. Harman said.
Vet-stem treats mostly horses, as well as some dogs and cats. The treatments for horses are generally for tendon and ligament injuries, while most dogs receive treatment for arthritis. Many of the dogs treated are athletes, but some are also family pets. While this is good news for people who want to see the best treatment given to man’s best friend, others caution against getting too excited over the current stem cell therapies.
Dr. Brennen A. McKenzie of Adobe Animal Hospital in Los Altos, California believes that the evidence of efficacy is preliminary. He believes that the clinics should offer the treatment as an experimental treatment in the form of a clinical trial.
A new organization, the North American Veterinary Regenerative Medicine Association, is seeking to act as a clearinghouse of information on stem cells in veterinary medicine, said Dr. Owens, director of the UC-Davis Regenerative Medicine Laboratory and NAVRMA secretary-treasurer. Hundreds of practitioners and researchers have expressed interest in being a member of the NAVRMA, and the first meeting will be in June.
The FDA has the authority to regulate the use of stem cells in animals, as they have done in humans. However, as of yet there are no specific regulations regarding the treatment of animals with stem cells.
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.
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.
July 31, 2010 by
Stem Cells for Spinal Cord Injury
The use of mesenchymal stem cells for a variety have
diseases has been published. This includes conditions such as heart failure,
liver failure, stroke, and lupus. One of the attractive features of mesenchymal
stem cells is that they can differentiate into numerous tissues while at the
same time exerting anti-inflammatory activities.
In the situation of spinal cord injury, mesenchymal stem
cells are thought to produce various growth factors that contribute to
regeneration of the damaged nerve. In the paper by Park et al the question was
asked whether Schwann Cells that are differentiated from mesenchymal stem cells
may be a more potent source of therapeutic growth factors. This question was
raised in part because the natural function of Schwann Cells is to produce
factors that accelerate new neuron formation.
The researchers used a growth factor-based differentiation
media to induce the transformation of mesenchymal stem cells into cells that
resemble Schwann Cells. The resulting cells developed a morphology similar to
Schwann Cells and expressed proteins that are specific to this cell type such as
the p75 neurotrophin receptor.
It was found that the Schwann Cells generated from the
mesenchymal stem cells expressed higher amounts of the growth factors hepatocyte
growth factor (HGF) and vascular endothelial growth factor (VEGF) when compared
with non transformed mesenchymal stem cells. When the newly generated cells
were cultured with a neuronal cell line called Neuro2A, a large increase in the
proliferation of the cell line was noted with a decrease in spontaneous cell
death. Transplantation of the artificially generated Schwann Cells into an ex
vivo model of spinal cord injury dramatically enhanced axonal outgrowth. This
was blocked by antibodies to HGF and VEGF.
The authors propose that artificially generated Schwann
Cells without genetic modification are useful for autologous cell therapy to
treat nervous system injury.
One
important question that was not addressed is to what extent are the Schwann
Cells generated from mesenchymal stem cells seen by the immune system. In other
words, is it possible to use Schwann Cells in a universal donor fashion the same
way that mesenchymal stem cells can be used.
December 11, 2009 by
Effort to Regenerate Injured Spinal Cords Turns to a New Model
The salamander has incredible regenerative ability. In addition to ability to grow back severed limbs, salamanders have profound plasticity of neurons and can regrow severed nerve endings at a much higher efficiency than mammals. Given that we live in an age where every gene of the body is known (genomics), almost every major protein is sequenced (proteomics), and more recently the majority of small molecules have been elucidated (metabolomics), one of the major pushes in research is to use this knowledge to understand old mysteries such as the regenerative ability of salamanders.
A multi-institutional scientific team in cooperation with the University of Florida McKnight Brain Institute’s Regeneration Project received a $2.4 million National Institutes of Health Grand Opportunity grant to study regenerative process of the Mexican axolotl salamander with the aim of applying biological lessons learned to spinal cord injury.
Dr. Edward Scott principal investigator for the collaborative grant and director of the McKnight Brain Institute’s Program in Stem Cell Biology and Regenerative Medicine stated "The axolotl is the champion of vertebrate regeneration, with the ability to replace whole limbs and even parts of its central nervous system. These salamanders use many of the same body systems and genes that we do, but they have superior ability to regenerate after major injuries. We think that studying them will tell us a lot about a patient’s natural regenerative capacities after spinal cord injury and nerve cell damage."
Discoveries in other species have been a critical part of biomedical research. For example, the process of RNA interference, which won the Noble Prize in Medicine for 2006 was actually discovered as a phenomena in Petunia Flowers. The toll-like receptors, which revolutionized medical knowledge of how the immune system works were originally identified in fruit flies. The current project seeks to find molecules associated with regeneration and to attempt to replicate them first in animals and subsequently in humans.
The multidisciplinary "Regeneration Project" team is also supported by private foundations such as the Thomas H. Maren Foundation and the Jon L. and Beverly A. Thompson Research Endowment, the UF Office of the Vice President for Research, and an anonymous donor.
October 30, 2009 by
Geron Could Resume Stem Cell Trial
The use of embryonic stem cells has generally been a subject of ethical discussion and debate. On the one hand the argument is made that sacrificing a human life should never be performed to potentially save another. On the other hand some believe that the fertilized eggs from which embryonic stem cells are extracted from are not human life and therefore there should be no issue. Unfortunately, such discussions have overshadowed the public image of "stem cells", and examination of potential medical adverse effects of embryonic stem cells often is ignored in public discussions. One example of politics overshadowing medical facts may be the hastily granted FDA approval of Geron to begin human clinical trials with embryonic stem cells, an approval that was granted on the same day as President Obama’s Inauguration and then subsequently retracted.
The company Geron, located in Menlo Park and originally founded by Michael West, has been working in the area of regeneration for more than a decade. It was Geron that controls the intellectual property for the life-extending molecule telomerase, and it also was Geron that funded the studies which resulted in creation of human embryonic stem cells. One product that Geron chose to develop is human embryonic stem cells that are differentiated into nervous system cells, for use in treatment of patients with spinal cord injury. While it is common knowledge to scientists but not to the public that embryonic stem cells cause cancer, Geron through treating the cells with various chemicals, believes it has generated a cellular product that does not pose the risk of cancer.
After numerous animal experimentations, including small and large animals, Geron was granted FDA approval for a Phase I clinical trial in 10 patients that had spinal cord injury within 7-10 days. This approval was linked to political motives by some. According to Robert N. Klein, the chairman of California’s $3 billion stem cell research program, "I think this approval is directly tied to the change in administration," said He said he thought the Bush administration had pressured the F.D.A. to delay the trial.
The approval was withdrawn in August, 2009 before any patients were treated. The trial was placed on what is called "clinical hold", meaning that patients cannot be treated until more data is submitted. This was because some animals in the studies were seen to develop abnormal cysts.
In the press release today, Geron stated that subsequent to their recent discussions with the FDA, they believe they will have sufficient new animal data to allow for continuation of the trial sometime in thei third quarter of 2010.
August 24, 2009 by
New Adult Stem Cell Facility Opens in Maryland
RNL Biostar Inc., a subsidiary of the Seoul-based company RNL Bio Inc., has been based in Rockville, Maryland since 2006. Now, in addition to its facility at the Technology Development Center, it plans to add a new facility in Germantown, worth $6 million, to which the company also plans to add 50 newly hired employees over the next 3 to 5 years. The new positions will include manufacturing technicians and lab personnel in addition to administrative personnel. According to Donna Lee, director of business development at RNL, "There will be pretty big growth spurts because of the amount of work we have."
The new RNL facility will be converted from an already existing structure, which currently occupies nearly 10,000 square feet and comprises a combination of labs and office suites. RNL Biostar projects that its facilities will occupy 20,000 square feet by 2014.
Currently RNL is in Phase II clinical trials for the testing of its proprietary adult stem cell products for the treatment of osteoarthritis and Buerger’s Disease, which is an inflammatory and blood clotting condition. Additionally, the company has received FDA authorization to commence clinical trials with its adult stem cell product in the treatment of spinal cord injury, which are scheduled to start at the end of the year.
RNL’s proprietary products are formulated from adult stem cells that are harvested from adipose (fat) tissue. According to Ms. Lee, "In Maryland, the fat samples come to our lab here first. People send in their fat and we extract stem cells out of the fat and ship them in nitrogen tanks to Korea, where cells are cultured and multiply. We have helped a lot of people with rheumatoid arthritis with a one-time IV injection. It’s really amazing to watch."
However, the U.S. citizens who donated their own adipose-derived adult stem cells must travel to China or Japan for the injections, since such treatments are not allowed in the U.S., due to a severely antiquated FDA.
RNL has also developed a stem-cell-based hand cream.
