Stem cell research and therapeutic innovation: not always a long-term perspective

When talking about stem cell research and its contribution to medical innovation, distinction should be made between embryonic stem cell research, believed to have almost infinite potential but with quite long-term perspectives, and adult stem cell research, which is already offering new therapeutic applications for otherwise incurable diseases. Today, adult stem cell-based therapies are in clinical development for a wide range of disorders1, and this field has indeed great potential to fill the gap in the market and help a large patient population with otherwise untreatable diseases. This is also generating an evolution in the regulatory framework2, as well as the issue of guidelines for responsible transition of stem cell research into appropriate clinical applications3, as witnessed by the very recent initiatives of the European Commission and of the International Society for Stem Cell Research.

Few potential therapeutic breakthroughs have promised as much as stem cells, and for such a long time: now, some of their possibilities are turning to reality, following scientific and technological advances from joint efforts of researchers in academic institutions and the biopharmaceutical industry.

Stem cell research with a therapeutic perspective is a field larger than life. In fact, it is a universe that should be split from the very beginning into two main planet systems: research involving embryonic stem cells, and research involving adult stem cells. Despite the almost infinite potential for embryonic stem cell-derived therapies, related ethical, regulatory and supply aspects imply that the evolution from research to medical practice must overcome a set of still open issues, besides those concerning scientific and medical progress. Therefore, translation from research into clinical investigation today derives from opportunities made available by adult stem cells: some of the new applications are very likely to reach the market in a few years, depending of course on regulatory approval procedures.

Sourcing adult stem cells is not limited by ethical concerns or supply availability, as they can be provided as autologous cells from the patient, or as allogeneic cells through voluntary donation. With respect to embryonic stem cells, adult stem cells are more limited in their differentiation ability: on the other hand, they should not have the same tumourigenic potential as embryonic stem cells. Some adult stem cells may have a level of inbuilt plasticity, thus allowing to use them to give origin to tissue types other than those from where they originated.

Some stem-cell-based therapies are already the clinical standard of care for several genetic and acquired disorders, such as haematopoietic stem cells transplants for leukaemia, or epithelial stem cell-based therapies for burns and corneal disorders. In fact, transplants of haematopoietic stem cells derived from the bone marrow are a tried and tested application for adult stem cell therapy, with many transplants carried out each year.

Current applications of adult stem cells to regenerate or repair tissues related to their origin include the transplant of haematopoietic stem cells to cure genetic disorders such as inherited immunodeficiency’s or thalassaemia, the transplant of mesenchimal stem cells to repair articular cartilage (with a perspective for more extended cartilage damage, like in arthritis), or the use of neural stem cell-based therapies for spinal cord injuries or neurodegenerative disorders such as multiple sclerosis and Parkinson’s disease. Examples of developments for use in a different tissue type include the potential for haematopoietic stem cells to be used for repair of heart tissue following myocardial infarction, and for mesoangioblasts to treat muscular dystrophy.

Adult stem cells can also be useful as vectors to deliver therapeutic genes. An example is the use of autologous haematopoietic stem cells transduced with the correct form of the ADA gene in the gene therapy for ADA-SCID, an inherited form of severe combined immunodeficiency (SCID)4: this investigational protocol has been successfully tested in Italy in 12 children, and is on the way to registration and market approval.

Though applicability of adult stem cells to novel advanced therapies is progressing rapidly, there are still barriers to a wider involvement of the biopharmaceutical industry in this field: inter alia, the difficulty in defining stem cell-related products clearly enough to get patent protection, as well as in establishing large-scale production technologies and standards. In fact, the whole matter of stem cell-based therapies relates much more to organ transplantation rather than pharmacology; consequently, business players in stem cell-based therapeutics currently include a few smaller independent companies working close with academia, and getting financial support from private charities, while public funding comes essentially from the EU’s Framework Programmes. Limited attention is given to this field by National governments, while a steady support of academic research remains vital to maintain high standards of innovation in stem cell research.

In a report published in 2006, The European Molecular Biology Organisation (EMBO) made a series of recommendations to promote and encourage stem cell research in Europe: the core principles included recognition of its prospective value and the need to integrate it into mainstream biomedical research, the need for support for both adult and embryonic stem cell research, the promotion of communication and professional education, the elaboration of adequate intellectual property and regulatory frameworks, and the issue of harmonised standards for processing and clinical practices.

Two years later, advances of stem cell-based therapies towards the market, and intensification of their investigational clinical applications, are witnessed by the recent initiative of the International Society for Stem Cell Research, that has just issued guidelines for best practices when translating stem cell research into medical practice, and by the evolution of the European regulatory framework to specifically cover this kind of therapies. The novel EU legislation on advanced therapies is due to take effect at the end of 2008, allowing free movement of advanced therapy products within Europe, supporting access to the EU market and helping European companies while protecting patients. The regulation provides for a centralised marketing authorisation procedure and the setup of a novel dedicated Committee within the EMEA, the Committee for Advanced Therapies (CAT), which should meet for the first time in January 2009. In addition, the EMEA will provide small and medium enterprises to have their advanced therapy products certified prior to the formal review required for marketing authorisation. In the meantime, stem cell-based therapies are likely to go through approval on a case-by-case basis: therefore, companies and institutions planning to submit marketing applications need to begin clear dialogue as early as possible.

References

1. Bordignon C, Roncarolo MG: “Therapeutic applications for hematopoietic stem cell gene transfer”, Nat Immunol 2002; 3:318-21.
2. Mills J, “European regulators prepare for advanced therapies”, SCRIP online, December 3, 2008
3. International Society for Stem Cell Research (ISSCR), “Guidelines for the Clinical Translation of Stem Cells”, December 3, 2008 (available online at www.isscr.org)
4. Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C, “Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy”, J Clin Invest. 2007 Aug;117(8): 2233-40