Lausanne: Scientists at EPFL have demonstrated a new method
that can be used to greatly improve the safety and efficiency of gene
therapy using the patient’s own stem cells.
Ex vivo gene therapy is a medical
technique in which stem cells are taken from the patient, and their
deficient genes are switched with healthy ones. The stem cells are grown
in the lab and re-inserted into the patient. However, this method often
has health risks, such as leukemia and mutations. The problem is that
most stem cells cannot be grown efficiently with current technologies,
and the resulting cell population in the lab can contain a mix of
healthy and unhealthy cells. Scientists at EPFL have developed a
selection process that can detect the cells that have take up the
healthy genes with great specificity, greatly reducing the risks of ex vivo gene therapy. The method, successfully tested on cells from a skin disease, is published in EMBO Molecular Medicine.
Yann
Barrandon at EPFL and Centre Hospitalier Universitaire Vaudois (CHUV)
led a team of researchers that has developed a safe “clonal strategy”
for ex vivo gene therapy that can be easily performed before
cells are transplanted back into patients. The strategy uses a set of
stringent quality control assays inspired from the protocols used by
biotech companies and regulatory affairs to produce medicinal proteins
through genetically engineered mammalian cells.
The quality
control assays aim to satisfy several selection criteria before the
cells are transplanted back into the patient. Specifically, the
genetically modified stem cells must: show high growth potential;
produce the protein needed to fight the disease; sustain long-term
tissue regeneration in the patient; sustain long-term correction of the
disease; not run the risk of forming tumors; have properly integrated
the new genes into their genome and; not spread across the patient’s
body.
The researchers tested their strategy of criteria and
assays on stem cells from the skin of a 4-year-old child suffering from a
severe condition called dystrophic epidermolysis bullosa, which causes
extremely fragile skin, and can even be lethal. The cells from the child
were isolated, put through the quality control strategy and implanted
in mice to see if they would cause tumors. After more than 100 days, no
tumors were recorded.
The study shows that the safety and efficiency of ex vivo
gene therapy depends on creating a homogeneous (“clonal”) culture of
cells rather than the more widely used mixed populations. This approach
is more demanding, and Barrandon’s lab is actually one of the few in the
world who have successfully created and maintained single-cell stem
cultures. However, the study is expected to open a new chapter in the
use of gene therapy methodologies, making them safer and more efficient
for patients.
The next step for the researchers is to test their
method on actual patients and to develop tools to facilitate the
transfer of the single cell technology to other laboratories. This work
is ongoing in collaboration with EPFL engineers. They are now in the
process of developing a pilot clinical trial. “This is a proof-of
concept study,” says Yann Barrandon. “But the greatest aspect is that
now any clinical lab in the world can take our strategy and adapt it to
the disease that they are targeting.”
This work represents a
collaboration of EPFL with CHUV, the University of Modena and Reggio
Emilia, and Généthon (France). It was supported by CHUV, EPFL, EEC, and
the “Fondation Enfants Papillons”.
Reference
Droz-Georget
Lathion S, Rochat A, Knott G, Recchia A, Martinet D, Benmohammed S,
Grasset N, Zaffalon A, Besuchet Schmutz N, Savioz-Dayer E, Beckmann JS,
Rougemont J, Mavilio F, Barrandon Y. A single epidermal stem cell strategy for safe ex vivo gene therapy. EMBO Molecular Medicine 27 February 2015. DOI 10.15252/emmm.201404353