October 15, 2009 (Vol. 29, No. 18)

James Netterwald, Ph.D.

Symbiotic Relationship Expected to Lead to New Therapies for Diseases

Akin to the transition from winter to spring, stem cells regenerate life. Their regenerative role in the human body is the subject of intensive research aimed at producing the next generation of effective cell-based cures for various human diseases. Researchers from around the globe gathered to present current stem cell technologies and their use and importance in regenerative medicine at the “World Stem Cell Summit” held in Baltimore last month.

Doris A. Taylor, Ph.D., director of the Center for Cardiovascular Repair at the University of Minnesota, spoke about the role that stem cells play in the prevention, treatment, and cure of diseases associated with aging; she sees aging as “a failure of stem cell-mediated endogenous repair.”

Dr. Taylor explained that in order to prevent or reverse the onset of disease, it is necessary to decrease inflammation by mobilizing stem cells to the site of repair early in the pathogenesis of the disease. Stem cell treatments for such diseases function by repairing or replacing pathologic organ vasculature and parenchyma, which slows or “cures” the disease by building new tissues, vasculature, and organs.

Dr. Taylor’s use of stem cells as reparative tools involves cells derived from a variety of sources, including bone marrow, peripheral blood, cord blood, and embryonic and inducible pluripotent cells. These stem cell technologies are critical to building new tissues, vasculature, and organs, and are thus crucial for regenerative medicine.

Dr. Taylor is also exploring the reversal of endothelial dysfunction as well as differences in atherosclerosis between men and women, showing sex-based differences in stem cell number and function. Other areas of interest include bio-organogenesis, which involves a novel technology to construct various functional organs, including heart, liver, pancreas, and kidney.

Researchers at the University College, London, and collaborators at Moorfields Eye Hospital, are using an adult stem cell therapy to treat patients with damaged corneas that occurred as a result of chemical burns.

Eye Injury

Stem cells are also crucial for regenerating tissue that has been damaged by trauma. Chris Mason, M.D., Ph.D., professor of regenerative medicine at the University College, London, gave a talk on regeneration of tissue after eye injury. The research he presented was performed in collaboration with a number of clinical groups and employed both adult and embryonic stem cells.

He spoke specifically about a collaboration with Julie Daniels, Ph.D., director of the Cells for Sight Tissue Bank at Moorfields Eye Hospital, involving an adult stem cell therapy used to treat patients with damaged cornea that occurred as a result of a chemical burn.  “Normally after simple trauma, the corneal cells would grow back, but in the case of an alkali injury, which can permanently destroy the cornea and the replenishing stem cells, they do not,” Dr. Mason said.

“After taking stem cells from the good eye, we processed them under GMP conditions that included seeding them on a contact lens, which is then stitched over the surface of the damage eye. The stem cells then migrate in and restore normal vision in about 80% of patients.” He added that this is a good example of a manually processed, autologous therapy using adult stem cells that has produced excellent clinical results.

According to Dr. Mason, it is challenging to take “basic science through to safe, effective, and affordable cell therapies suitable for routine clinical practice. Stem cell therapies are only of value to mankind if we can successfully translate them into real therapies to treat serious diseases.”

Human embryonic stem cells were genetically modulated by homologous recombination to generate an Olig2-GFP knock-in reporter. (Ying Liu/Life Technologies)

Mesenchymal Stem Cells

Translation of stem cell technologies into tools of regenerative medicine is also a mission being undertaken by pharmaceutical and biotechnology companies. Case in point is recent stem cell research at Roche that is focused on the use and development of mesenchymal stem cells (MSCs), partly for the purpose of advancing regenerative medicine.

Global alliance director Alain A.G. Vertès, Ph.D., discussed Roche’s long-term vision to develop cell therapeutics that target specific diseases and maximize patients’ clinical benefits and lower safety risks—a project that is just entering the implementation phase.

“In addition to this therapeutic approach, Roche is also conducting research on induced pluripotent stem cells and, when necessary, human embryonic stem cells, in order to enable their use in drug discovery with the ultimate objective to develop more efficacious and always safer drugs,” said Dr. Vertès. “Initially, we will focus on leveraging the immunomodulatory properties of MSCs, however, as our knowledge of their regenerative properties increase, we hope to be able to address disease where regeneration will be the primary mechanism of action.” 

Dr. Vertès concluded by saying that, much still needs to be learned by the scientific community and the hope is that regenerative live-cell therapeutic products could be commercialized in the not too distant future to bring innovative medicines to patients who need them.

Manufacturing Cell Therapies

Another presenter from the pharmaceutical industry was Dave Smith, head of cell therapy for Lonza’s bioscience business unit. Lonza manufactures cell therapies on a large scale for a number of cell therapy companies. It is focused on manufacturing such therapies in the most cost-effective way, which requires that manufacturing process be conducted on a large scale.

“We’re focused on scaling up production from a lot of 50 or 100 doses, to manufacturing 500 to 1,000 doses per lot, which drastically lowers the cost of goods,” said Smith. “The reason this becomes so important is that the lower the cost per dose, the broader access patients will have to the therapeutic.” Lonza has developed a number of process improvements for reducing the cost of manufacturing of stem cell therapies and will be presenting many of them at the meeting. The presentation will review the costs, the bottlenecks, and potential solutions to reduce the cost of goods.

Growth Media

In order to utilize stem cell-based therapeutics in regenerative medicine, researchers first must be able to grow these cells on a large scale. Stem cells often have stringent growth requirements, with each cell type requiring a different set of growth media components.

Based on this need, Invitrogen, part of Life Technologies, set its sights on creating defined media and other reagents for stem cells. “There are 85 clinical trials that are now being run based on stem cell therapy, as listed in the National Institutes of Health clinical trials database, and all of them need a way to manufacture their cells under a regulatory regimen,” said Mahendra Rao, M.D., Ph.D., vp of R&D. And those manufacturing processes will require defined growth media.

Dr. Rao talked about some of Invitrogen’s recent stem cell technologies. “Our focus has been on the two stem cell types on which most of the clinical trials were being performed—mesenchymal and embryonic stem cells.”

In order to provide researchers with a more defined media for stem cell growth, Invitrogen needed to eliminate serum from its stem cell media formulas, and the company has been successful at developing whole cell growth systems for stem cells, Dr. Rao said. These media were designed to enable researchers to manufacture stem cells on a large scale. 

Cell purity is essential for reliable and reproducible screening, and cell type-specific technologies that do not alter cell viability are critical to establishing successful screening models, noted Dr. Rao, who also presented a bead-based technology developed by the company’s Dynal division, which allows for positive selection using a detach-a-bead system or a depletion process using negative selection. These technologies are used to isolate and purify primary stem cells for use in drug and toxicology screening. 

In addition, Dr. Rao presented data on two of Invitrogen’s gene delivery systems for stem cells—a baculovirus-based system and the Jump-In™ vector system. The company uses integrase-based technology to target integration of a gene into a specific site in the genome. The Jump-In vector system allows the user to create multiple gene variants and to measure direct gene expression with high reproducibility and a high degree of control, he said.

“These two gene delivery technologies, combined with our ability to manufacture purified cells has really allowed us to do certain kinds of screening that were not possible before,” Dr. Rao added. 

Advancement of regenerative medicine is contingent upon developments in stem cell technologies, creating a symbiotic relationship that represents a current impetus for change in biomedical research. Technologies presented at this year’s “World Stem Cell Summit” will likely serve as the roadmap for such change.

Cells are stripped from a rat heart during the process of decellularization, leaving only the extracellular matrix intact.

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