Despite rapid advances in life science research, the bioindustry has been plagued by a slowdown in new drug, biologic, and medical device applications. Indeed, the FDA addressed this issue two years ago with the release of a white paper entitled Challenge and Opportunity on the Critical Path to New Medical Products.
Meanwhile, the cost of developing novel products has increased significantly. There is a concern that the development of new products and therapies could stagnate altogether, rather than delivering a biomedical revolution, as some expected.
According to the FDA, the problem is The applied sciences needed for medical product development have not kept pace with the tremendous advances in the basic sciences. The new science is not being used to guide the technology development process in the same way that it is accelerating the technology discovery process.
For medical technology, performance is measured in terms of product safety and effectiveness. Not enough applied scientific work has been done to create new tools to get fundamentally better answers about how the safety and effectiveness off new products can be demonstrated.
The research community is beginning to respond to the FDAs call with creative technologies for stem cell research, particularly in the area of devices, commercially scalable methods, assays, delivery methods, and industrial and manufacturing applications.
One of the nearest term stem cell applications is in the area of cardiac regeneration. Stephen Wnendt, Ph.D., senior vp of research and development at ViaCell (www.viacellinc.com), addressed the recent Cambridge Healthtech Stem Cell Research conference on with a paper on Development of Unrestricted Somatic Stem Cells from Umbilical Cord Blood for Cardiac Regeneration after Myocardial Infarction.
ViaCell specializes in cord blood and human oocyte storage as well as the development of human cells as medicine. Dr. Wnendts presentation focused on ViaCells cardiac disease program. The ability to regenerate damaged heart tissue could benefit those who suffer from the continued effects of myocardial infarction, or congestive heart failure. ViaCell is developing a cord-blood-derived stem cell product to address this need. In vitro studies have shown the ability of the cells to differentiate into endothelial cells and cardiomyocytes, and a study of 16 pigs with myocardial infarction has shown that the treatment can be effective. The company expects to file an IND to commence clinical trials in 2006 or 2007.
One of the main hurdles, according to Wnendt, is delivery of the cells to the heart. In the cardiac area, the most important thing is finding the appropriate delivery pathways.
One company developing strategies for delivering stem cell therapies to the heart is Boston Scientific (www.bostonscientific. com). Maria Palasis, Ph.D., director of cell biology and biotherapeutics, described the Stiletto intramyocardial direct injection catheter at the Stem Cells and Regenerative Medicine Conference held recently. The Stiletto is currently in Phase II trials, it injects a therapy directly into the ventricle by means of a telescoping needle whose end can be precisely directed to the location of an infarction.
Some of the complications of delivering cells or drugs locally to the heart are the inherent motion of the organ, the compatibility of the device with the treatment being injected, and the distribution of the therapy within the tissue. Other potential routes of cardiac delivery include intracoronary injection, adventitial delivery, epicardial injection, and pericardial injection.
The development of methods for delivering stem cell therapies to the heart is not straightforward. There are many complications and contradictions. Animal studies show that the success of a delivery method is different for a healthy heart than it is for a diseased heart.
There may be an additional mechanism where cells can find their way into the heart, which is not available for a normal heart, said Dr. Palasis. Many delivery devices in development for cardiac cell therapy are actually angioplasty catheters, and these devices come with their own complications.
If angioplasty catheters are going to be used for cell therapies, its important to look at potential for catheter materials to affect viability of cells. Guidewire lumens could be covered with lubricants. The FDA is aware of the compatibility issues. Both acute cell delivery and cell engraftment depend on the delivery method used.
MDS Pharma Services (www. mdsps.com) is addressing another area of need in stem cell technologies and tools: functional in vitro assays. In order to develop a stem cell treatment, theres a basic need for the ability to assay the success of that treatment. Mary Zacour, Ph.D., developed a quantitative cell-based assay to measure the function (or ability to bind and capture endogenous cells) of a cell-capture device. The device in question is a stent developed by OrbusNeich (www.orbusneich.com) that is currently marketed outside of North America, the Genous Bio-engineered R stent.
Dr. Zacours assay measures the cell binding capabilities of the stent, which is designed to promote attachment in vivo of the patients circulating endothelial progenitor cells. An intact endothelial layer is desirable because it promotes vascular homeostasis and reduces the likelihood of common adverse outcomes that are associated with bare metal stents, such as thrombosis or restenosis.
OrbusNeich engaged MDS to work with them to develop an in vitro cell-based functional assay for this product. Says Dr. Zacour, You cannot develop a device like this without having something where you can test step-by-step along the way what the device is going to do. That is where this assay comes in. Its a way of promptly and quantitatively looking at the ability of the device.
Markers for Embryonic Differentiation
In all of these cases, its apparent that the basic scientific principles of cardiac regeneration have advanced far ahead of any practical, commercial application, and that supportive tools and technologies have become a bottleneck for the development of a marketable therapy. Supportive methods are lacking in other fields of stem cell research as well, such as the study of embryonic stem cells.
At the Stem Cell Research Challenges conference held recently in La Jolla, CA, Peter Sartipy, Ph.D., from Cellartis (www.cellartis.com), presented the progress of an ongoing embryonic stem cell study, along with efforts to develop a quantitative method for evaluating human embryonic stem cell (hESC) differentiation.
His presentation cited a general lack of methods for quantitative evaluation of hESC differentiation and a goal of developing a rapid, sensitive, and quantitative method for detecting it. Cellartis assay uses quantitative PCR to measure levels of four genes in a combination not previously used for hESC.
However, expansion of the cells is slow and labor-intensive. I would pinpoint basic handling, culturing, and upscaling of undifferentiated cells as big issues and hurdles that need to be overcome. When moving into more industrial applications, we need to really solve the question of how to efficiently expand the cells, said Dr. Sartipy.
Scaleup and commercialization also present obstacles to Cambrex (www.cam brex.com). Cambrex focuses on adult-derived somatic stem cells, particularly mesenchymal stem cells from bone marrow. Cambrex provides cells for the research market as well as for cell therapy. Dan Marshak, Ph.D., vp and CTO, pinpointed a number of pitfalls in stem cell research in his presentatio entitled Commercial Challenges for Cell Therapy Manufacturing at Stem Cell Research Challenges. Many research processes that are used in the laboratory are not always appropriate for scaleup and commercialization.
Dr. Marshak cited a number of other problems to be solved en route to commercial stem cell therapy. Ethical questions plague the stem cell community, and restrictions based on differing societal and religious divisions complicate the development of therapies. As well, business considerations complicate the progress of stem cell research.
Financing has been challenging because it has been difficult to raise money from public markets. They dont always understand the final business model and the final product pathway, said Dr. Marshak.
One of the greatest hurdles for all companies working on stem cell treatments is the regulatory approval pathway. Stem cell treatments are dependent on so many supportive tools and technologies that the nature of the product becomes difficult to define, and thus the regulatory path becomes murky. Finding a regulatory pathway for stem cell therapy is a goal that will parallel the new FDA inititatives in tools for stem cell research.