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2. Scientific and medical
project of the Institute of Research in Biotherapy (IRB)
2.1 Brief outline of regenerative medicine
Recent data on stem cells
The development of IRB fits into a very rapid progression in current
knowledge on embryonic stem cells (ES cells) and tissue stem cells.
It is thus possible to obtain human embryonic stem cell lines (Thomson,
et al 1998), to reprogram the genome of an adult cell into the genome
of an embryonic cell by implanting it in an ovocyte (Wilmut, et
al 1997), and to obtain embryonic stem cell lines from these modified
ovocytes (Surani 2001). The understanding of the mechanisms of embryonic
stem cell differentiation into stem cells that are more committed
to a pathway of differentiation and into functional differentiated
cells is progressing very rapidly. It should be possible in the
not too distant future to use these embryonic stem cells to repair
a patient's tissue. A recent example is the repair of neuronal functions
by embryonic stem cells in a mouse model of Parkinson's disease
(Kim, et al 2002).
However, the use of ES cells is source of an ethical problem in
Western countries. It is now possible to import develop ES cell
lines or to develop new ES cell lines from surplus embryos obtained
by in vitro fertilization in France, as well as in Belgium, England,
the Netherlands, and Spain.
A major property of ES cells is their ability to proliferate continuously in vitro and thus to generate very large quantities of differentiated cells of a particular tissue. In animals as in humans, it was not possible to obtain adult stem cell lines until the publication of a recent series of articles (Jiang, et al 2002, D'Ippolito, 2004 #2236, Kogler, 2004 #2244). These teams showed the existence of stem cells in adult blood marrow or cord blood proliferating extensively in vitro, with the ability of multipotential generation of tissues. But these studies have been challenged. On the other hand, the revolutionary data of the Yamanaka Japanese group have now been confirmed and extended by this team and other teams. In mice, only 4 genes (Oct4, Sox2, myc, Klf4) can confer on somatic cells embryonic stem properties, in particular the ability to contribute to generate embryos and viable mice (Okita, et al 2007, Takahashi and Yamanaka 2006). These data have been extended to other species, particularly to human cells. This reprogramming process must be reproducible and secure, particularly the transitory expression of oncogenes must be controlled. But major barriers have been past, opening to get stem cells able of extensive proliferation and tissue generation.
Differentiated cells : an example provided by tumor immunotherapy
Differentiated cells could be also critical for regenerative
medicine. Dendritic cells or T lymphocytes are the most promising
examples. They are produced outside the body to induce anti-tumor
immunity. More than 1000 thousand patients were vaccinated with
dendritic cells (Ridgway 2003). The knowledge of dendritic cell
biology improves very quickly and makes it possible to design new
therapeutic strategies (Banchereau and Palucka 2005). Impressive
tumor regressions were obtained in patients with melanoma refractory
to conventional therapies (Dudley, et al 2005). In this trial, large
numbers of anti-tumor T lymphocytes were produced in vitro and injected
to the patients as drug cells. Other medical fields are actively
progressing: cartilage repair with expanded chondrocytes, pancreas
repair with Langerhans islets, cardiac regeneration with expanded
muscle cell or bone marrow cells.
Now we are faced with a veritable scientific, technological, and
medical challenge, which should offer patients in the coming years
possibilities for repairing a deficient tissue or organ.
References
Banchereau, J. & Palucka, A.K.
(2005) Dendritic cells as therapeutic vaccines against cancer. Nat
Rev Immunol, 5, 296-306.
Dudley, M.E., Wunderlich, J.R., Yang, J.C., Sherry,
R.M., Topalian, S.L., Restifo, N.P., Royal, R.E., Kammula, U., White,
D.E., Mavroukakis, S.A., Rogers, L.J., Gracia, G.J., Jones, S.A.,
Mangiameli, D.P., Pelletier, M.M., Gea-Banacloche, J., Robinson,
M.R., Berman, D.M., Filie, A.C., Abati, A. & Rosenberg, S.A.
(2005) Adoptive cell transfer therapy following non-myeloablative
but lymphodepleting chemotherapy for the treatment of patients with
refractory metastatic melanoma
Cancer immunotherapy: moving beyond current vaccines. J Clin Oncol,
23, 2346-2357.
Jiang, Y., Vaessen, B., Lenvik, T., Blackstad,
M., Reyes, M. & Verfaillie, C.M. (2002) Multipotent progenitor
cells can be isolated from postnatal murine bone marrow, muscle,
and brain. Exp Hematol, 30, 896-904.
Kim, J.H., Auerbach, J.M., Rodriguez-Gomez, J.A.,
Velasco, I., Gavin, D., Lumelsky, N., Lee, S.H., Nguyen, J., Sanchez-Pernaute,
R., Bankiewicz, K. & McKay, R. (2002) Dopamine neurons derived
from embryonic stem cells function in an animal model of Parkinson's
disease. Nature, 418, 50-56.
Okita, K., Ichisaka, T. & Yamanaka, S. (2007)
Generation of germline-competent induced pluripotent stem cells.
Nature.
Ridgway, D. (2003) The first 1000 dendritic cell
vaccinees. Cancer Invest, 21, 873-886.
Surani, M.A. (2001) Reprogramming of genome function
through epigenetic inheritance. Nature, 414, 122-128.
Takahashi, K. & Yamanaka, S. (2006) Induction
of pluripotent stem cells from mouse embryonic and adult fibroblast
cultures by defined factors. Cell, 126, 663-676
Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S.,
Waknitz, M.A., Swiergiel, J.J., Marshall, V.S. & Jones, J.M.
(1998) Embryonic stem cell lines derived from human blastocysts.
Science, 282, 1145-1147.
Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J.
& Campbell, K.H. (1997) Viable offspring derived from fetal
and adult mammalian cells. Nature, 385, 810-813.
2.2 IRB scientific and medical projects
Our
strategy is to develop :
- Basic research, in order to identify
the critical mechanisms to produce cells able to repair in vivo
tissues.
- Pathophysiological driven research, in order
to identify reparative defects and to define properties of stem
and progenitor cells for reducing or eventually curing these defects.
Particular attention should be given to the achievement of long-term
tissue repair, which will require engraftment, survival and integration
of the administered cells while avoiding uncontrolled proliferation
or differentiation of the cells.
- Translational research, in order to reproducibly
generate clinical grade cells, key parameters (culture medium, growth
factors, chemicals, and pharmacological agents) that are necessary
to produce cells need to be monitored under well defined culture
conditions and at a large scale bioreactors.
- Clinical research, to investigate the safety,
efficacy and efficacy of cellular products or drugs phase I-II-III
clinical trials will be performed in a single-center or multi-center
design.
- Securing of intellectual property, licensing,
and cooperation with private companies: to translate new developments
into the clinics, IRB structures will in the design of clinical
trials.
- Mastering production costs : within 5 to 10 years,
a scientific and medical project should lead to a therapeutic application
and possibly to a marketable cellular product or drug. The conception
of the translational research must integrate the parameter cost
from the very beginning. Indeed, specific directions made as early
as during the basic research phase of a project could be critical
for the final cost of the product.
The following scientific and clinical teams at the University Hospital
and Cancer Center in Montpellier have declared their interest in
joining the IRB:
Cancer:
Cancers with the development of targeted therapies :
- Multiple myeloma: Pr B. Klein and Pr JF Rossi (INSERM
U1040)
- Immune system: with the development of immunotherapy
in cancer, autoimmune diseases and infectious diseases.
- Allogenic transplantation in cancer patients with acute myeloid
leukemia. Dr M. Villalba, Dr P. Ceballos and Dr N. Fegueux
(CNRS, IGMM).
-Detection of Rare Circulating Human Cells in cancer and infectious
disease. Dr JP. Vendrell (CHU Montpellier) ).
In vitro fertilization, embryology, pluripotent
stem cells, gamete generation with the obtaining of new
pluripotent stem cell lines and the understanding of the mechanisms
controlling their maintenance, differentiation into gametes as well
the mechanisms involved in in-vitro fertilization of oocytes. Pr
S. Hamamah and Dr J. De Vos (INSERM U1040);
Regenerative medicine
- Diabetes with the graft of insulin producing
cells or stem cells in patients with type 1 diabetes who are poorly
controlled by insulin treatment. Dr S. Dalle, Pr E. Renard, and
Dr A. Wotjuzyscin.
- Hepatic failure with the repair of hepatic tissue
with hepatic stem cells. Dr P. Maurel, Dr M. Daujat, Pr P. Blanc
and Pr F. Navarro (INSERM U1040).
IRB will eventually be able to host up to 8 research
projects which will not be sufficient to cover all fields in the
mandatory deapth necessary for international competiveness. Some
of the outlined medical fields will have be developed outside of
the IRB, but IRB will support these teams and their development
of biotherapy in other Montpellier institutes through collaboration
and providing them open access to IRB technical platforms (associated
teams). All IRB projects have to be managed by both a clinician
and a scientist.
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