April 1, 2007 (Vol. 27, No. 7)

Nina Flanagan

Market Is Estimated to Have a $500 Billion Potential

The idea of growing an organ from one’s own cells or healing spinal cord injuries with cells transformed from embryonic stem cells used to be considered fodder for science fiction movies, but no more. Companies are not only developing technologies that can do exactly that, but these methods provide real potential to cure certain conditions and diseases.

According to “2020—A New Vision: A Future for Regenerative Medicine”, from the U.S. DHHS, regenerative medicine has the potential to exceed $500 billion within the next 20 years. Companies will be coming together to share their progress in this area at the “Termis North America Tissue Engineering and Regenerative Conference”, to be held in June. Some of the innovations they will be presenting are highlighted in this article.

Regenerating Organs

Tengion (www.tengion.com) has initiated what it claims is the first Phase II trial for the approval of a regenerated human organ. The urinary neo-bladder will be tested in 10 children with spina bifida who have failing bladders that predispose them to kidney failure. Developed through over 20 years of research at Children’s Hospital Boston, the construct avoids the side effects associated with today’s standard of care, which uses a piece of the patient’s bowel tissue.

“While the bowel is compliant tissue, that procedure has well-documented and frequent side effects,” explains Gary Sender, Tengion’s CFO. “Our technology has the promise to eliminate all the complications around this bowel surgery.”

To create the regenerated organ, a surgeon takes a biopsy of healthy cells from the failing bladder and sends them to Tengion’s GMP pilot manufacturing facility. There, technicians isolate cells responsible for growth, grow them over a period of weeks, and then seed them, with progenitor, smooth muscle, and urothelial cells, onto a biodegradable scaffold that is shaped like a bladder. A surgeon then implants the neo-bladder construct into the patient.

“The presence of the scaffold kicks in the body’s regenerative ability,” states Sender. As the body regenerates the tissues and provides revascularization over a few months, the scaffold dissolves. “After a period of time, the new organ is indistinguishable from the native organ.” This technology has already been successfully used in seven children with spina bifida; the results were published in The Lancet last year.

A second clinical trial will be starting in a few months with 10 adults suffering from spinal cord injuries who have failing bladders. “There are many different diseases of the bladder where we think our technology can be applicable. There’s no risk of rejection, and we hold the exclusive license,” adds Sender. The company is also pursuing applications in the cardiovascular area to use the technology to potentially grow different types of vessels.

Adult Stem Cells

Researchers at the Children’s Hospital of Pittsburgh have discovered a population of stem cells within skeletal muscle that can be used to repair bone, muscle, and cardiac tissue. “The population is very early progenitor cells. The beauty of it is we can do autologous transplantation,” says Johnny Huard, Ph.D., director of the Children’s Hospital Stem Cell Research Center.

Dr. Huard says they have been able to grow up to a googol (10100) of these cells, but the quality somewhat declines as they are expanded. In addition, the researchers discovered that these cells may derive from blood vessels and that periocytes appear to be the origin. “This may explain why there are stem cells in a lot of tissues, like fat, liver, brain, that are all vascularized, but they don’t show up in cartilage.”

His group has been using these cells to repair muscle and improve muscle force in animal models with Duchenne muscular dystrophy. To date, after injection with the cells, bone healing and cardiac repair occurs within six to eight weeks—depending on the animal and injury model. In addition, the cells have the potential for muscle healing after sports and military injuries by blocking the formation of scar tissue.

Clinical trials recently started using the adult stem cells in patients with bladder dysfunction due to a weak bladder neck. The cells are used initially as a bulking agent, with the idea that they will form functional tissue within the urethral sphincter to prevent the leakage of urine. So far 11 patients have been injected with the cells. The first part of the study is for 48 female patients with stress urinary incontinence; the second part is for 48 male patients postprostatectomy.

Cook Myosite (www.cookmedical.com), which has licensed technologies related to the stem cells, is performing all aspects of the clinical trial.

Dr. Huard says that there will be a paper published within the next few months describing his research discovery that male and female cells exhibit different repair capabilities. For example, female cells work better for muscle repair, but this information will have to be further analyzed before it can be translated into clinical trials.

Human Embryonic Stem Cells

Despite the ethical and political controversies surrounding human embryonic stem cells, researchers are moving forward to develop these cells to alleviate diseases and repair the body. Advanced Cell Technology (www.advancedcell.com) has several projects using hESCs they would like to move into the clinic. “We have published a paper showing, for the first time, that we can create RPE (retinal pigment epithelium) from human embryonic stem cells,” says Robert Lanza, M.D., vp, research and scientific development.

RPE is the layer of cells that maintains the photoreceptors, cones, and rods and enables vision. “We’re hoping to transplant these cells to attenuate vision loss or prevent further progress of macular degeneration,” he adds. In addition, a recent paper by Dr. Lanza’s group shows the same RPE can significantly attenuate visual loss in animal models due to RPE loss.

“We were able to significantly rescue the photo receptors and saw about 100% improvement in visual acuity in the animals transplanted with these cells,” says Dr. Lanza. Furthermore, he reports that histopathology shows cones and rods in the petri dish. “In fact, we actually see little eyeballs. We’ve now been able to create precursors that create photo receptors, and the hope is to reverse blindness.”

Another project under development involves creating certain hematopoetic precursors from hECs. “We have created a hemangioblast, which has been theorized to form our entire immune, vascular, and hematopoetic system.” These cells are being studied in various animal models. “We found that we can cut the death rate after a heart attack in half and restore blood flow to limbs that would otherwise require amputation, within a month after injection,” states Dr. Lanza. In addition, the cells have accelerated the parameters of wound healing threefold.

The company also developed a technology using a single blastomere from human embryos to create cell lines without damaging or destroying the embryo. Dr. Lanza says this is important because it alleviates some of the ethical concerns. Also, there remains hope that the government will allow these cells to be added and used by researchers. “It has only been recently that some of the controversy has subsided. Many think this research is not going to materialize for years to come, but we are filing an IND at the end of this year.”

Bioengineering future therapies will potentially include human cells. However, there are many difficulties involved in finding appropriate cells in the right amounts and quality to study and make scientific decisions on whether the cells mimic the system in the body. Also, “you want to acquire human cells and tissues in an ethical manner, so you have to have consent,” states Nancy Dock, Ph.D., director of tissue acquisition at Lonza Walkersville (www.lonza.com), which offers two cell model lines, Clonetics® and Poietics™, for research.

“You want to make sure the person the cells derived from has consented, as well as next of kin, and that the cells don’t come from someone with a disease that could interfere with the cell’s functioning and scientific findings. Companies like ours deal with the issues of how tissues and organs are accessed all the time,” states Dr. Dock. “Part of our approach is to make sure researchers are aware that they need to go through this process upfront and get consent. We’re encouraging people to think about that at the beginning of a project, not the end.”

Dr. Dock notes that current screening tools are good and help ensure organs and tissues are used safely. She adds that part of the focus of the meeting will be to look at novel ways of appropriately obtaining human cells and expanding them, as well as other issues, like cell preservation. “You may be able to get a lot of cells, but they may not replicate or grow well,” states Dr. Dock. Cell sampling and tissue biopsy are also big issues.

“If you are looking to make a cure for a particular disease and it has to do with how well a cell functions, then you want to make sure you have representative examples of those cells that reflect the whole population. That’s not so easy. People have been exposed to many different factors throughout their lives. You have to make sure what you’ve isolated is the correct cell, and it does what it’s supposed to do in the lab. Then you must infer from that what the cell is going to do in the body.”

On-demand Embryonic Stem Cells

Researchers at Geron (www.geron.com) have developed a model to distribute embryonic stem cell therapies on-demand to patients. “The concept of making cell-based therapies more like traditional biologics, which can be manufactured in bulk-batch scale, cryopreserved, and distributed, allows individuals to obtain cells via an on-demand basis,” explains Jane Lebkowski, Ph.D, senior vp, regenerative medicine, for Geron.

Dr. Lebkowski says that this model has worked due to the properties of embryonic stem cells. The company has demonstrated that its initial product, GRNOPC1 (Geron oligodendrocyte progenitor cell), based on human embryonic stem cells, produces multiple nerve growth factors that stimulate and regenerate neurons damaged during spinal cord injury. Recent studies also showed the product remyelinates nerves that become demyelinated after injury. “This therapy is intended to remyelinate and insulate the axons, so they can allow for the appropriate nerve pulses.”

To produce GRNOPC1, the company took undifferentiated embryonic stem cells and differentiated them into the oligodendrocyte progenitor cells. It then created a master cell bank and can currently produce up to 100 doses at a time. Once the cells are cryopreserved, they are available on demand.

This model required the development of many technologies, and the challenges were many, according to Dr. Lebkowski. They included how to culture the embryonic cells and how to define the correct media components, which is still evolving. Other difficulties included some of the animal models (cell rejection) and having well-defined markers to understand the cell population. “Our next big hurdle will be clinically testing,” Dr. Lebkowski states. The company plans to file an IND at the end of this year. Other potential applications include heart failure and diabetes.

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