Anand Basu, Reuters
Pluristem is an Israeli company that is publicly traded on NASDAQ and has been working on a “universal donor” stem cell therapy that originates from cord blood mesenchymal stem cells. Key to Pluristem’s intellectual property are a series of patents on three dimensional bioreactors that allow for mass production of these cells. Interestingly, it is unclear to us who holds the intellectual property on the cells themselves. For example, Osiris holds the patents to many types of mesenchymal stem cells, ViaCell holds patents on some of the placental and cord blood mesenchymal cells, Celgene also holds patents on some of the cord blood and Wharton’s Jelly mesenchymal stem cells. Nevertheless, Pluristem has been pushing forward in development treatments, initially for post bone marrow transplant hematopoietic engraftment, and more recently for treatment of the terrible condition critical limb ischemia, which causes amputations in approximately 150,000 patients per year in the USA. Currently Pluristem planning to conduct its Phase II/III trials for critical limb ischemia in the second part of 2011. Given the success of the company in its clinical development programs, the CEO Zami Aberman recently announced that they will be working on their own towards commercialization. This is in contrast to other deals that we have seen in the recent past, such as the $1.7 billion deal between Pharma company Cephalon and the Australian stem cell company Mesoblast.
The ability to general large number of mesenchymal stem cells is a very important feature that gives the company a competitive edge over others in the space. Specifically, the use of bioreactor technologies allows for much higher production yields and a lower cost of production. Although the patent situation is somewhat uncertain for Pluristem, at the end of the day, numerous jurisdictions do not allow patenting of cells, so it may be feasible that the bioreactor patents that Pluristem has may be sufficient to protect the company as it is growing.
Mr. Aberman stated in a recent interview with Reuters “We do not need to raise money and we have sufficient capital to move the company to the end of Phase III studies,” Pluristem, which raised about $38 million in a public offering last month, plans to start a Phase II/III trial in both Europe and the United States to treat critical limb ischemia (CLI) in the second half of the year. He continued “We have been approached by a variety of pharmaceutical companies interested in cooperating not only on CLI but (also) for additional indications like inflammatory bowel disease, multiple sclerosis and orthopedic indication. However currently we are focusing on finding a marketing partner once our pivotal trials are underway. ”
In contrast to other companies that are working in this space and require processing of the patient’s own bone marrow as a source of stem cells, the Pluristem approach revolves around the concept of universal donor stem cells that are stockpiled and ready for use.
“The fact that we can do the treatment on demand because we have an off-the-shelf product is crucial, since CLI patients require immediate treatment,” Aberman said.
There have been previous studies performed in critical limb ischemia using mesenchymal stem cells. Mesenchymal stem cells can be used either autologous or allogeneically (meaning from another donor). Below we will list some of them.
For example, In 2010 Lasala et al reported combination cell therapy including EPCs and mesenchymal stem cells (a source of pericytes progenitors and angiogenic regulators) may represent a preferential stimuli for the development of blood vessels. In this phase I clinical trial, patients with LI were infused with a cell product consisting of autologous bone marrow-derived mononuclear and mesenchymal stem cells. After 10 2 months of follow-up, efficacy assessment demonstrated improvements in walking time, ankle brachial pressure, and quality of life. Concomitantly, angiographic and 99mTc-TF perfusion scintigraphy scores confirmed increased perfusion in the treated limbs. These results show that the use of a combination cell therapy appears to safe, and feasible in patients with CLI (Lasala, G.P., et al., Combination stem cell therapy for the treatment of severe limb ischemia: safety and efficacy analysis. Angiology, 2010. 61(6): p. 551-6.).
It was previously demonstrated in a rat model of critical limb ischemia that MSC are superior to bone marrow mononuclear cells in terms of angiogenic potency and limb preservation. This was suggested to be in part based on the ability of MSC to withstand the ischemic environment better than bone marrow mononuclear cells, as well as their ability to differentiate not only into endothelium but also smooth muscle (Iwase, T., et al., Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovascular research, 2005. 66(3): p. 543-51). A comparison between bone marrow mononuclear cells and bone marrow MSC was made in 41 patients with CLI who had type II diabetes. The ulcer healing rate of the BMMSC group was significantly higher than that of BMMNCs at 6 weeks after injection (P=0.022), and reached 100% 4 weeks earlier than BMMNC group. After 24 weeks of follow-up, the improvements in limb perfusion induced by the BMMSCs transplantation were more significant than those by BMMNCs in terms of painless walking time (P=0.040), ankle-brachial index (ABI) (P=0.017), transcutaneous oxygen pressure (TcO(2)) (P=0.001), and magnetic resonance angiography (MRA) analysis (P=0.018). There was no significant difference between the groups in terms of pain relief and amputation and there was no serious adverse events related to both cell injections. The authors concluded that BMMSCs therapy may be better tolerated and more effective than BMMNCs for increasing lower limb perfusion and promoting foot ulcer healing in diabetic patients with CLI (Lu, D., et al., Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: A double-blind, randomized, controlled trial. Diabetes research and clinical practice, 2011).
The ability to use universal donor cells in the context of critical limb ischemia is advantageous in that the bone marrow of patients does not need to be punctured. Usually patients with critical limb ischemia have numerous co-morbidities that makes bone marrow aspiration extremely difficult. Additionally, it is almost impossible to performed secondary transplants. In the area of critical limb ischemia, it may be important to perform multiple injections for additional therapeutic effects. Another advantage of universal donor cells is that many times the bone marrow of patients with critical limb ischemia are insufficient in ability to produce cytokines or stimulate angiogenesis in vitro or in vivo. The administration of selected cells that are purified for maximal potency possesses a therapeutic advantage. Disadvantages of the Pluristem approach include the possibility of knock-off technologies due to the lack of a patent on composition of matter on the cells. Worse yet, companies such as Celgene and now PerkinElmers possess intellectual property on cells derived from the placental matrix. It will be interesting to see how these patents play out in terms of enforceability.
Pluristem to develop stem cell therapy on its own: CEO
Stem Cell Technique Could Help Those With Fast-aging Disease
February 23, 2011
Hutchinson-Gilfod progeria syndrome is a fast-aging disease that is rare, has no cure, and is fatal. Children with this disease undergo rapid aging and generally do not live to their teens. It is caused by a single mutation of the LMNA gene, which results in a defect in the production of lamin A, a protein which is required to build the membranous shell around genetic material. The majority of children with Hutchinson-Gilford progeria die from complications pertaining to hardening of their blood vessels. Fortunately, this disease is very rare, as only 64 children in the world are known to have it, however due to the small number of patients suffering from this disease, there are very few opportunities to study it and thus form any type of treatment.
New technology has introduced a new possibility in the treatment of this progeria. In the past five years, scientists have begun using targeted retroviruses that selectively alter DNA in order to cause a regression of cells from the muscle or skin into their stem cell form, pluripotent stem cells. Pluripotent stem cells have the potential to form various different types of cells in the body, depending on where they are transplanted to.
The cells that were taken from the patients were regressed back to their pluripotent stem cell stage by a research team led by Juan Carlos Izpisua Belmonte and Guanghui Liu at the Salk Institute in La Jolla, California. The researchers found that after this regression, the cells from the patients no longer contained the information that corresponded to diseased cells. However, despite the absence of the mutation in the stem cell state, these cells would not necessarily be rid of the defect which sets the fate for the disease. The resetting of the cells does allow for the scientists to study the progression of the disease its beginning.
Liu’s lab is working on a technique that will fix the genetic mutation responsible for the progeria in hopes of developing a treatment or even a cure for the disease. “Hopefully our efforts will be useful to generate … [non-symptomatic] progeria cells and help those progeria patients in the near future,” he said.
PRECISE: Adipose-derived stem cells show utility as therapy
Cardiology Today
PRECISE is The Randomized Clinical Trial of Adipose-Derived Stem Cells in Treatment of Non Revascularizable Ischemic Myocardium, a double blind, placebo-controlled trial involving 27 patients with chronic ischemic heart disease with HF, angina or both, who were not eligible for percutaneous or surgical revascularization. The patients in the study underwent a liposuction to remove adipose tissue from their abdomen, the stem cells were separated and then reinjected directly into the heart. Placebo patients received the same treatment however were injected with placebo in place of stem cells. “These patients were not even able to be transplanted. So these were very high-risk, no-option patients,” said Francisco Fernández-Avilés, MD, with the department of cardiology, Hospital General Universitario Gregorio Marañón, Madrid, and PRECISE investigator.
The patients who were treated with stem cells had improved infarct size at 6 months and peak oxygen consumption compared to the placebo patients. “In my opinion, the results of the PRECISE trial are good enough to reconsider the possibility to start a larger scale randomized trial comparing cells to placebo in terms of left ventricular function, mainly clinical outcomes [like] mortality, HF and ischemia,” Fernández-Avilés said. For the years ahead, Fernández-Avilés said in patients with chronic HF and viability, the answer for stem cell therapy is adipose tissue, “and for patients with no viability, in my opinion, we need more basic investigation to find more effective cells.”
Stem Cells Help Women Regrow Breasts After A Mastectomy
By Lucy Johnston
Scientists in the UK and Australia have been implementing a new technique to benefit women who have had a mastectomy to remove cancerous cells. The technique involves placing a special plastic mould under the skin and then injecting the area with the patient’s own stem cells. The cells are cultured from adipose tissue that is removed from the patient by liposuction. The stem cells are removed from the fat tissue and grown to a larger number, then recombined with the fat and injected back into the body. Results generally take from six months to a year, over which the fat and stem cells grow slowly until new breast tissue is formed. Since the tissue is grown by the patients’ own body, the breasts look and feel natural and are much more comfortable than silicone implants.
The treatment was discovered by observing the way the body reacts to wounds. “Nature doesn’t like a vacuum,” said Professor Wayne Morrison of Melbourne University, who has performed the procedure himself, “so the chamber itself, because it is empty, tends to be filled in by the fat. We observed this and decided it could be used to help treat women who’d lost their breasts to cancer. Fat cells can grow to fill a void in the same way that the body repairs tissue damage. Our research shows fat continued to grow until it had filled the area where there had once been a natural breast. We attach the area to a blood supply from the chest or under the arm which helps the fat grow. The mould used by surgeons helps create a breast shape in which the fat forms.”
The current treatment for mastectomy patients involves taking tissue from the buttock to form a new breast. The results of this treatment are variable, however, and the implementation of the use of stem cells will hopefully improve the outlooks for women. The treatment could also have potential for cosmetic surgeries as well, possibly replacing saline or silicone implants, which have been associated with various side effects.
Professor Morrison said: “We hope the technology will have a significant impact around the world. There are a lot of women who don’t have reconstructive surgery for whatever reason or have silicone breast implants but this will give them their own tissue back.”
The patients that have been treated so far have had very impressive results, according to Professor Kefah Mokbel, consultant breast surgeon at St. George’s Hospital, London. The plastic scaffolding used as a mould must be removed surgically, however the procedure is minimally invasive. Researchers hope to develop a biodegradable scaffold which will dissolve once the implant has grown. The treatment is also not used on women who have been cancer free for less than a year, in order to prevent the stem cells from causing further tumor growth.
UCL Scientists Develop Magnetic Nanoparticles to Track Neural Stem Cells
Azo Nanotechnology
Neural stem cells have recently been shown to possess qualities that make them promising candidates for stem cell replacement therapy and spinal cord reconstruction. Researchers at University College London have recently discovered magnetic nanoparticles that could be used to track neural stem cells following their injection. This would allow for the stem cells to be followed throughout the treatment and repair process. Nguyen TK Thanh of the Davy Faraday Research Laboratory, UCL Physics and Astronoly and the Royal Institution believes that the hollow biocompatible cobalt-platinum nanoparticles that have been attached to stem cells will be a very efficient way of monitoring the progress of the cells.
Magnetic Resonance Imaging (MRI) parameters were designed in order to optimize the conditions of monitoring. After establishing these parameters, the nanoparticles were transplanted into organotypic spinal cord slices, and the efficacies of the parameters of MRI were confirmed. ‘The new method demonstrates the feasibility of reliable, noninvasive MRI imaging of nanoparticle-labelled cells,’ says Thanh.
‘Magnetic nanoparticles are emerging as novel contrast and tracking agents in medical imaging,’ says Samir Pal at the California Institute of Technology, US, an expert in biological-nanoparticle interactions. ‘When used as a contrast agent for MRI, the nanoparticles allow researchers and clinicians to enhance the tissue contrast of an area of interest by increasing the relaxation rate of water.’
Thanh is hopeful that these nanoparticles will contribute to stem cell replacement therapy for many central nervous system diseases. She is also working towards developing nanoparticles that can be used to diagnose and treat these diseases.
Test Tube Meat No Longer Science Fiction, Dutch Researchers Say
Rudy Ruitenberg
The idea of growing meat in a laboratory was developed in 1950, however was not patented until 1999. Due to more recent scientific discoveries, this idea is now becoming a reality. This development may help to ease environmental damage caused by the enormity of the animal farming market. Around 70 percent of farmland is used for the production of meat and livestock industry account for 18 percent of greenhouse-gas emissions.
This project is being led by Henk Haagman at the University of Utrecht, he and his team are using stem cells to grow muscle tissue. The reality of buying lab-grown meat in the supermarket may be a few years away, however this development is the first step in the mass production of engineered meat.
“The project will be a success if in four years time it’s clear under what conditions consumers will eat in-vitro meat,” said Cor van der Weele, a philosopher leading the study of the ethical and social issues of cultured meat. Meat produced in a laboratory is “not a meat replacement, it’s real meat,” Van der Weele said. “I’ve been calling it in-vitro meat recently, that’s the technical name,” Van der Weele said. “Cultured meat isn’t appealing and creates too much of a ‘yuck’ reaction.”
Curious? The Science of Skin Care
Caiti Currey
Stem cells have become a highly talked about subject in the treatment of many diseases and health problems, and have now come into the limelight as a possible treatment for skin rejuvenation. Men and women alike are constantly seeking a product that will reduce the signs of aging, and stem cells have now been proven to act as such.
Lilacs are a very popular flower for many reasons, but a new discovery has shown that stem cells in lilac leaves can reduce the signs of aging and rejuvenate the skin. The leaf stem cell is a very effective antioxidant, protecting the skin from the damage that can be caused by free radicals. Stem cells from grapefruits are also known to function as protection from damage. Swiss apple is also known for its ability to preserve, protect and stimulate the growth of human stem cells.
Dr. Jennifer Linder, Chief Officer for PCA SKIN has used these plant stem cells to develop products that have been proven to be beneficial to the skin. The Rejuvenating Serum uses epidermal growth factor technology to stimulate cell and skin renewal.
France’s first ‘saviour baby’ is born in Paris
Antoine Mariotti , France 24 International
A ‘saviour baby’ is a relatively new term that has come in to practice with modern medical revelations allowing for genetic selection at the embryonic stage of development. The first savior baby in France was born in Paris on February 8, 2011. The boy, named Umut Talha, meaning “our hope” in Turkish was born to Turkish parents and has two siblings who suffer from a genetic blood disease called Beta thalassemia. Beta Thalassemia reduces the production of hemoglobin, the iron-containing protein in red blood cells that carries oxygen to cells throughout the body. People who suffer from this disease are generally anemic and have an increased risk of developing blood clots. Blood transfusions are required to frequently replenish the red blood cell supply, and is the treatment currently being delivered to Umut’s older sister.
With Umut’s birth, the need for these frequent blood transfusions will be eliminated. Umut’s parents’ began the process of having a saviour baby a little more than a year ago. The process involved screening embryos for the disease, and then genetically selecting an embryo free of the disease. Umut was indeed born disease free and the stem cells from his umbilical cord will be used to cure his sister of her disease. The process will be repeated soon to cure Umut’s four year old brother as well.
Skin-cell spray gun drastically cuts healing time for burns
In the past, the most common way to treat first to second degree burns is with skin grafts, a process that includes taking pieces of skin from uninjured parts of the patient’s body or grafting artificial skin and grafting them over the burned area. This treatment was somewhat effective, however resulted in a recovery period of several weeks to several months. A new treatment has been developed that drastically decreases the amount of time required for a burn to heal.
A “gun” that has been developed to spray a layer of the patient’s own skin stem cells onto the wounded area has proved to be very successful. This type of treatment has been used since 2002 in Australia, Dr. Fiona Wood uses an aerosol system to spray on cultured skin cells.
The process necessary to initiate this treatment is very minimal, a biopsy is taken from the patient’s undamaged skin, healthy stem cells are isolated and an aqueous solution containing the cells is inserted into the gun and then sprayed on. The “gun” uses an electronically controlled pneumatic device that functions similar to a paint ball gun. After the cells are applied, a specially developed dressing is applied along with two sets of tubes, one functioning as an artery, supplying electrolytes, antibiotics, amino acids and glucose to the wounded area, and one set acting as a vein.
Currently, the treatment is only effective on second-degree burns, healing these within days rather than weeks or months required with previous treatments.
Injured Liver Calls in Bone Marrow For Help?
Li et al. Cells Tissues Organs
It is known that administration of bone marrow cells into patients with liver failure has the ability to improve enzyme function and overall health http://www.youtube.com/watch?v=DdH6Mm4w98I. Additionally, numerous animal models have demonstrated that injection of various types of stem cells can result in regeneration of injured liver tissue. For example, Manuelpillai et al demonstrated that injection of human mesenchymal stem cells derived from the amnionic membrane into immune competent mice whose livers were damaged by carbon tetrachloride results in reduction in liver injury http://www.ncbi.nlm.nih.gov/pubmed/20447339. Even more interesting, administration of compounds that “instruct” bone marrow cells to enter circulation such as G-CSF, have been demonstrated to improve liver function and actually prevent mortality after liver injury http://www.ncbi.nlm.nih.gov/pubmed/20881764. This is relevant because G-CSF is a medication that is FDA approved and possesses a favorable safety profile.
One of the main scientific questions in the area of liver failure is whether the liver is actually “calling in” bone marrow stem cells to try to heal it after liver damage, or whether the therapeutic effects of stem cells in liver failure are an epiphenomena. In situations of cardiac damage after an acute myocardial infarction it has been demonstrated that the injured tissue causes upregulation of the protein SDF-1, which recruits bone marrow stem cells into the heart in order to promote healing. Whether similar mechanisms are at play in liver injury is not known. Part of the puzzle has to do with the fact that liver injury is a more chronic process than heart attacks and therefore recruitment of stem cells may be occurring at a much lower level. Alternatively, it is also known that chronic inflammatory processes actually suppress stem cell activity. So it may be that in chronic liver failure the stem cells are actually inhibited from possessing regenerative function.
This question was addressed in a recent study in which the gene expression profile of bone marrow cells was examined in animals with liver failure induced by administration of the hepatotoxin D-galactosamine to rats. To assess gene expression the Affymetrix GeneChip Rat Genome 230 2.0 Array was used, which quantifies gene expression of every gene in the rat genome. The scientists found that more than 87.7% of the genes/probe sets that were upregulated more than 2-fold in the bone marrow cells of rats with liver failure were also expressed by the liver cells, including 12 genes involved in liver development, early hepatocyte differentiation and hepatocyte metabolism. The concurrent upregulation of these genes was verified by the technique of reverse transcriptase polymerase chain reaction (RT-PCR).
The scientists also found that 940 genes were expressed in both the bone marrow cells of rats with liver failure and the hepatocytes of rats with liver failure but not in control cells. Specifically, many of the genes that were uprgulated in both the bone marrow and the liver seemed to be involved in regeneration of damaged tissue.
These data support the concept that the bone marrow stem cells can respond in similar ways to liver cells to injury. The hypothesis has been proposed by the authors that the bone marrow acts as a reservoir for the stem cells that are capable of regenerating liver. The mass amount of data in this publication is very interesting and requires detailed analysis to make sense of.
