January 15, 2012 (Vol. 32, No. 2)

Gail Dutton

Stem cell therapy is redeeming itself after striking failures. With therapies well into clinical trials, successes are accumulating.

Among the success stories is the first mesenchymal stem cell (MSC) therapy to reverse the side effects of radiation for hematopoiesis, radiological burns, and gut disorders, which was developed at the Institute of Nuclear Safety in France.

“We have demonstrated that MSC treatment is a promising approach for the medical management of gastrointestinal disorders after irradiation, specifically in the context of acute cutaneous and muscle damage,” reports researcher Alain Chapel, Ph.D. That work involved five patients at the Percy Hospital in Clamart, France. Three additional patients were successfully treated for over-exposure for pelvic radiotherapy.

Dr. Chapel will present details of his work this month at Select Biosciences’ “Stem Cell” conference in San Diego. Several other speakers gave GEN a preview of their presentations as well.

Dr. Chapel insists that his method of using stem cell therapy as a treatment for radiation damage is unique. “All the other treatments for radiation accidents or over-dosage have failed.

“We are trying to improve the stem cell therapy of gut, muscle, and skin disorders after single-dose radiation. We use a fractionated dose of irradiation in rats, in a model close to radiotherapy, to reverse late side effects using different protocols of cell therapy.” So far, Dr. Chapel’s lab has evaluated adipose and gingival tissue. Induced pluripotent stem cells are under investigation.

Earlier work by Dr. Chapel showed that human MSCs migrated through bone marrow and other tissue, and indicated the possibility of targeted delivery. Engraftment appeared to be related to the dose and geometry of the irradiation.


SanBio began clinical trials last September for SB623, a therapy that restores motor function to stroke patients up to three years after the stroke. The standard treatment, in contrast, must be administered within four hours of the stroke for it to be effective.

In preclinical studies, motor function improvements were seen one week after administration and returned to near baseline (pre-stroke) levels in six months in rat models, according to Casey Case, Ph.D., vp of research. “The limitations or their potential in humans are not yet known.”

SB623 is not a cell-replacement therapy. “It’s a supportive cell therapy,” Dr. Case emphasizes. It is allogeneic, not autologous, but doesn’t require cyclosporine for immune suppression. It is injected directly into the impaired region, thus permitting lower doses without systemic effects. These cells are naturally eliminated by the body after about one month, although motor function seems to continue to improve. The working hypothesis is that these mesenchymal stem cells promote an environment in which damaged cells recover. “The exact mechanism of action, however, is still an area of active research,” Dr. Case notes.

Six weeks into the Phase I/IIa trial, results appear promising. Dr. Case says that the first two patients have experienced no adverse events, and others are being actively recruited. No information is available yet regarding improvements in motor function. In addition to stroke treatment, it may also be useful in treating other neurological deficits, possibly including traumatic brain injury, Parkinson disease, and spinal cord injury.

The therapy is based upon MSCs from the bone marrow of normal, healthy donors. They are grown and transfected with the plasmid encoding notch1 and, ultimately, are stored cryogenically. Other projects using this same platform are in the early stages of development. SanBio has active developmental partnerships with Teijin Limited and Dainippon Sumitomo Pharma Co.

Cardiotoxicity Studies

At Stanford University, researcher Paul Burridge, Ph.D., has developed a universal system to develop cardiomyocytes from stem cells. Dr. Burridge develops stem cells from skin fibroblasts or blood cells. “There are no good human models to test the cardiotoxicity of new drugs,” Dr. Burridge explains. His work aims to resolve that situation by developing cardiomyocytes as a toxicity screen.

His mid-term objective is to make cardiomyocytes from patients with a given disease and try to recapitulate that disease. “Now, my work is looking to model disease. About seven percent of breast cancer patients experience chemotherapy-induced cardiotoxic effects.” His goal is to determine why only a subset of breast cancer patients experience these effects and whether they can be stopped.

The long-term goal is to use these cardiomyocytes for engraftment. In this case, scientists can form a patch of cells like a band-aid that a surgeon could implant into the heart to improve cardiac function.

“We’re about 10 percent of the way along,” Dr. Burridge says. “We have a very effective way to turn stem cells into cardiomyocytes.” The stem cell lines that differentiate into cardiomyocytes are not all identical. “Every stem cell line has its own level of gene expression, and not all are in a state that is suitable for differentiation. By putting them in 3-D forms with low oxygenation and special media to encourage differentiation (which includes growth factors), we can overcome some of those differences.”

Typically, Dr. Burridge says, researchers perfect one cell line. “I’ve developed this method using 11 different cell lines, created in various ways and from various materials.” Using that approach, “approximately 95 percent of the cell balls will contract. Of those cells, 60–70 percent are cardiomyocytes. The rest are mostly fibroblasts, which comprise about 50 percent of the heart.”

Scientists at Stanford University have created a way to develop cardiomyocytes from stem cells. Mid- and long-term objectives include making cardiomyocytes from patients with a given disease and recapitulating that disease and using the cardiomyocytes for engraftment.

Improved Drug Screening

In Japan, ReproCELL is developing human iPSC-derived cardiomyocytes, neurons, and hepatocytes for applications in drug discovery including toxicity assays and ADME testing. “We believe iPSC technology will become mainstream in drug screening in the near future,” notes Chikafumi Yokoyama, Ph.D., CEO.

Today, immortalized cell lines are widely used in primary screening, but those cell lines lack their original functions. Primary cells, on the other hand, have diminished function, limited sources, and significant lot-to-lot variation.

ReproCELL’s iPSCs, in contrast, “combine the advantage of immortalized cell lines and primary cells, offering “infinite in vitro expansion and functional differentiated cells, so they can be supplied infinitely from pharmaceutical companies,” Dr. Yokoyama explains.

“The differentiated cells are especially suitable for second and third screenings, in hit-to-lead and lead-optimization stages where more predictable efficacy and adverse effects can be measured at mid-to-high throughput,” Dr. Yokoyama continues. The benefit is fewer animal tests and accelerated drug screening.

In the industry, one of the challenges has been to improve cell quality so iPSCs are comparable to primary cells. ReproCELL has developed iPSC-derived hepatocytes that are comparable to primary cells in terms of CYP3A4 activity. Those hepatocytes are scheduled to launch this spring.

“The differentiation efficiency is more than 90–100%. We are developing a cryopreservation system in which the activity can be maintained at a high level,” Dr. Yokoyama adds. “We have obtained positive data so far and will continue to improve the process.

“CYP3A4 is the most important enzyme for drug metabolism,” he notes. After the initial release, ReproCELL plans to release hepatocytes at six month intervals that express other specific types of enzymes.

Last October, ReproCELL launched a new product line of frozen, single cardiomyocyte cells, called ReproCardio2. “The frozen cells can be formed as a thin layer in 96-well plates for use in coded aperture imaging systems,” according to Dr. Yokoyama. “In addition, the single cells can be re-aggregated to be beating clusters, which are applied to MEA systems to measure the field potentials. Cardiotoxicity can be detected with tested compounds in both measurement methods.”

Off-the-Shelf Cells

Presenting at the “Stem Cell Summit”, Athersys president and COO B.J. Lehmann will outline initial clinical results from the company’s MultiStem™ trials. These off-the-shelf cells can be administered by IV line, catheter, or injection, and eliminate the historical stem cell therapy issue of donor matching, he says.

Several clinical trials are under way. One Phase II trial with Pfizer treats moderate-to-severe ulcerative colitis. “We expect top-line readouts by early 2013,” Lehmann says. A study evaluating MultiStem for ischemic stroke is also in Phase II. Additionally, “we recently completed a Phase I trial in acute myocardial infarction. It was a small study, but we saw meaningful improvement in cardiovascular function.”

Athersys also recently completed enrollment for the repeat-dose arm of a two-arm Phase I trial for graft vs. host disease (GvHD). Top-line results from the single-dose arm of that study are encouraging, reducing the severity and incidence of GvHD. Historically, moderate-to-severe GvHD occurs in 30–50% of matched related hematopoietic stem cell transplants and 50–70% of matched unrelated donor recipients. Among Athersys’ high-dose patients, “We saw less than 10 percent GvHD,” Lehmann says.

The cell product provides benefits from therapeutically beneficial proteins, Lehmann explains. MultiStem cells hone to the site of the injury or an activated immune response. The cells respond to the specific situation, initiating a multimodal response. According to Lehman, “MultiStem offers a new therapeutic modality, a new way of treating disease that could complement current biological and pharmaceutical approaches.”

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