coordinator of the Cell Therapy Program (TCUB) of the University of Barcelona Faculty of Medicine. He spoke at the workshop "Challenges and Risks of Research in Advanced Therapies" organized by Biocat and the TCUB on 20 January 2012 in Barcelona.
Opinion
Advanced therapies include drugs for human use that are based on genes, cells or tissue and are raising great expectations for alleviating diseases that currently have no treatment. These include three overarching areas of medicine: gene therapy, cell therapy and tissue engineering.
Gene therapy is the use of biologic drugs with an active ingredient based on nucleic acids (DNA, RNA, etc.), or what we call genetic modifications. Cell therapy is the administration of biologic drugs in which the main active ingredient contains live cells. The therapeutic properties of these drugs consist of both components secreted by cells and their intrinsic curative properties. However, tissue engineering deals with drugs based on cells or tissues that have been manipulated to regenerate, restore or substitute tissues, often called regenerative medicine. Therefore, advanced therapies mainly focus on diseases that affect widespread system such as the immune system, various organs at the same time, or organs like the brain which can’t be cured through transplants.
Increasing knowledge of stem cells opens up new avenues for treating a wide variety of diseases. There are different types of stem cells with different auto-regenerative and differentiation capabilities. Those known as pluripotent or embryonic stem cells are obtained from early-stage human embryos derived from in vitro fertilization processes that no longer serve a reproductive function. These cells have a great ability to expand in culture and the potential to differentiate into any type of tissue. However, embryonic stem cells can also create teratomas after being implanted, which makes them highly risky for clinical use at the moment. Pluripotent stem cells can also be obtained from adult cells such as skin cells, through genetic modification with four genes that allow for cell reprogramming. These cells, called iPSCs (induced Pluripotent Stem Cells) have the advantage of being created from the patient’s own cells, thus avoiding the risk of rejection during re-implantation. Nevertheless, iPSC are not free from teratoma generation, which is one of the main problems involved in the use of pluripotent stem cells.
Adult stem cells are those obtained from certain human tissues. Of the many types of tissues currently known to contain stem cells, the most studied varieties are the hematopoietic progenitors and mesenchymal stem cells obtained either from fat or bone marrow. In fact, autotransplantation of hematopoietic progenitors obtained from bone marrow to treat certain types of leukemia is the most accepted consolidated cell therapy today. There are also other consolidated therapies commonly accepted today, including the use of chondrocytes for various joint disorders, the expansion of keratinocytes to regenerate skin and the expansion of stem cells from the corneal limbus to repair damage on the surface of the eye.
As a result of their intrinsic properties, mesenchymal stem cells have been proposed as a drug for various diseases. Mesenchymal stem cells secrete substances with immunomodulatory, protective, antiapoptotic and angiogenic properties, among other factors. Therefore, their main targeted use is for immunologic diseases, including autoimmune and inflammatory diseases. The number of clinical trials being carried out with these cells is growing exponentially, despite the fact that there is little existing proof regarding the use of mesenchymal stem cells to alleviate the symptoms of any of the diseases being researched. The only clinical trial in Spain that has reached phase III using mesenchymal stem cells from fat is that led by Hospital La Paz in Madrid, which focuses on treating anal fistulae. Unfortunately, this trial didn’t yield the expected results.
Surprisingly, although advanced therapies are considered drugs today, 98% of all clinical trials in Spain are financed with public funds. The Spanish government is investing in the development of products that will have to be exploited by a pharmaceutical company. Cell production for drug use is costly, and this expenditure can only be absorbed by large pharmaceutical companies. Current European law requires that, in most cases, cells for therapeutic use be produced in cleanrooms according to Good Manufacturing Practice (GMP). This entails very strict quality systems that lead to even higher costs. Although there must be some control of cell production, it is incomprehensible that these same severe controls aren’t necessary, for example, for in vitro fertilization processes, which create a whole human being from a few cells.
In addition to these dichotomies, there is also a clear lack of coordination between Spanish public bodies that fund clinical trials and the body that is ultimately in charge of granting permission to carry them out, the Spanish Agency for Medicines and Health Products (AEMPS). While the Research Funding Department of the Ministry of Health, Social Services and Equality grants a not inconsiderable amount of funding for independent clinical research, €21 millions in 2011, AEMPS can later choose whether or not to grant permission to carry this research out. The fact that AEMPS permission isn’t a mandatory prerequisite to obtain funding sometimes makes it impossible to meet the objectives to be able to carry out the research or to, even, begin the clinical trials due to the lack of proper permits. In the Catalan arena, there is no other organization in this new area of medicine, nor in the legislative or coordination arenas. In recent years, the Government of Catalonia Department of Health has established an agreement with the Carlos III Institute of Health to promote regenerative medicine in Catalonia, money that goes almost exclusively to the Center of Regenerative Medicine in Barcelona (CMRB).
Our region’s potential in biomedical research is well known, with centers like the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and the Bellvitge Biomedical Research Institute (IDIBELL), as well as university centers like the University of Barcelona. At the same time, Catalonia is a leader in clinical trials in Spain, with Barcelona’s Hospital Clinic as the top example. All of these institutions have joined forces over the past two years in the Cell Therapy Program (TCUB), which aims to bring together those working in research and clinical applications of new advanced therapies. This groundbreaking initiative, as well as other efforts being undertaken in our region, shows Catalonia’s great potential in translation research in this field. This potential could be much more effective if it had the right coordination framework. The high costs of pre-clinical and clinical research, as well as current complex legal issues, make it necessary to create strategic plans and a collaboration structure in order to use the economic resources our institutions can devote to the various centers or structures that contribute to translational research in advanced therapies more effectively.
Events like La Marató de TV3, which devoted its latest edition to research into organ and tissue regeneration and transplants, show that the general population believes in the work carried out by research professionals. Therefore, now it is time to invest in the future, fostering research in advanced therapies for the improved wellbeing of our society.