EMBARGOED: NOT FOR RELEASE UNTIL 2:00 PM U.S. EASTERN TIME THURSDAY, 11 JULY 2013
Science publishes two research articles reporting the results of the team of Luigi Naldini, director of
the San Raffaele Telethon Institute for Gene Therapy, TIGET, in Milan (Italy)
TWO SEVERE GENETIC DISEASES ARE SUCCESSFULLY TREATED WITH
BLOOD STEM CELLS GENE THERAPY USING VECTORS DERIVED FROM HIV
Gene therapy offers real hope of a cure for metachromatic leukodystrophy and Wiskott-Aldrich
syndrome. The six children treated in Milan are all doing fine.
The AIDS virus can be used to treat two severe hereditary diseases. After years of study in the
laboratory to engineer the virus and design the gene therapies, six children from all over the world,
now three years after the treatment, are well and show significant benefits. The announcement
was made in two studies published today in Science* by researchers at the San Raffaele Telethon
Institute for Gene Therapy (TIGET) in Milan, Italy, led by Luigi Naldini, demonstrating that
hematopoietic stem cell gene therapy works against two severe genetic diseases, metachromatic
leukodystrophy and Wiskott-Aldrich syndrome.
“Three years after the start of the clinical trial,” says Naldini, “the results obtained from the first six
patients are very encouraging: the therapy is not only safe, but also effective and able to change
the clinical history of these severe diseases. After 15 years of effort and our successes in the
laboratory, but frustration as well, it’s really exciting to be able to give a concrete solution to the first
patients,” explains the director of TIGET.
At the origin of both diseases is a genetic defect that results in the deficiency of a protein essential
for the organism in the early years of life. In the case of metachromatic leukodystrophy, which
currently lacks any effective treatment, it is the nervous system to be affected: babies with this
disease are apparently healthy at birth, but at some point they begin to gradually lose the cognitive
and motor skills they have acquired, with no possibility of arresting the neurodegenerative process.
Children with Wiskott-Aldrich syndrome, on the other hand, have a faulty immune system that
makes them much more vulnerable than normal to the development of infections, autoimmune
diseases and cancer, as well as having a defect in the platelets which causes frequent bleeding.
After the positive results obtained in the course of many years of study in the laboratory,
researchers at the San Raffaele Telethon Institute in Milan tried to correct the genetic defect that
causes these diseases with gene therapy. The technique consists in withdrawing hematopoietic
stem cells from the bone marrow of the patient and introducing a corrected copy of the gene that is
defective using viral vectors derived from HIV (which began to be developed in 1996, thanks to
Luigi Naldini’s work with Didier Trono and Inder Verma at the Salk Institute, La Jolla, CA). Once reinjected into the body, the treated cells are able to restore the missing protein to key organs.
“In patients with Wiskott-Aldrich syndrome, blood cells are directly affected by the disease and the
corrected stem cells replace the diseased cells creating a properly functioning immune system and
normal platelets. Thanks to gene therapy, the children no longer have to face severe bleeding and
infection. They can run, play and go to school,” explains Alessandro Aiuti, coordinator of the clinical
study on these patients and Head of Research of the Pediatric Clinic at TIGET. “In the case of
metachromatic leukodystrophy, however,” says Alessandra Biffi, who heads the other study, “the
therapeutic mechanism is more sophisticated: the corrected hematopoietic cells reach the brain
through the blood and release the correct protein that is uptaken there by the surrounding nerve
cells. The winning card was to make engineered cells able to produce a quantity of protein much
higher than normal, and thus effectively counteract the neurodegenerative process.” Eugenio
Montini, who coordinated the molecular analysis of patients’ cells, adds, “Until now we have never
seen a way to engineer stem cells using gene therapy that is as extensive and safe as this one.
These results pave the way to the development of new therapies for other more common
diseases.”
Both trials, which involved a team of over 70 people including researchers and clinicians, began in
the spring of 2010, and called for the participation of 16 patients in total, 6 suffering from WiskottAldrich syndrome and 10 from metachromatic leukodystrophy. The results published in Science
refer only to the first 6 patients (three from each study), i.e. those for whom sufficient time has
passed after administration of the therapy to allow scientists to draw the first significant conclusions
regarding its safety and efficacy.
The studies were mainly supported by the Telethon Foundation, an Italian charity with the mission
to promote research and cure for genetic diseases. Additional support was provided by research
grants from the EU, Italian Ministry of Health and the European Leukodystrophy Foundation. Maria
Grazia Roncarolo, scientific director of the San Raffaele Institute and the scientist who led the
preparatory studies of the Wiskott-Aldrich syndrome clinical trial, commented: “The translational
path, from the bench to the bedside has presented obstacles and frustrations, both for scientists
and for parents and children who understandably find it hard to accept science ‘slowness’. But the
results we’re showing today repay us of all the efforts and give us a hope for the future of these
children and for the possible cure of other genetic diseases”.
In 2010, Telethon Foundation and San Raffaele Institute entered into a strategic alliance with
GlaxoSmithKline to develop and commercialize ex vivo stem cell gene therapies developed at
TIGET. Under the terms of the agreement, GSK has an exclusive option to further develop the
treatments for metachromatic leukodystrophy and Wiskott-Aldrich Syndrome reported in these
studies.
Milan, 11 July 2013
*Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy.
A. Biffi*, E. Montini*, L. Lorioli, M. Cesani, F. Fumagalli, T. Plati, C. Baldoli, S. Martino, A. Calabria,
S. Canale, F. Benedicenti, G. Vallanti, L. Biasco, S. Leo, N. Kabbara, G. Zanetti, W. Rizzo, N. AL.
Mehta, M. Cicalese, M. Casiraghi, J. Boelens, U. Del Carro, D. Dow, M. Schmidt, A. Assanelli, V.
Neduva, C. Di Serio, E. Stupka, J. Gardner, C. von Kalle, C. Bordignon, F. Ciceri, A. Rovelli, M.
Roncarolo, A. Aiuti, M. Sessa and L. Naldini. Science, 2013.
*Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott- Aldrich
Syndrome. A. Aiuti, L. Biasco, S. Scaramuzza, F. Ferrua, M. Cicalese, C. Baricordi, F. Dionisio, A.
Calabria, S. Giannelli, M. Castiello, M. Bosticardo, C. Evangelio, A. Assanelli, M. Casiraghi, S. Di
Nunzio, L. Callegaro, C. Benati, P. Rizzardi, D. Pellin, C. Di Serio, M. Schmidt, C. Von Kalle, J.
Gardner, N. Mehta, V. Neduva, D. Dow, A. Galy, R. Miniero, A. Finocchi, A. Metin, P. Banerjee, J.
Orange, S. Galimberti, M. Valsecchi, A. Biffi, E. Montini, A. Villa, F. Ciceri, M. Roncarolo* and L.
Naldini*. Science, 2013.
See the full articles at http://www.sciencexpress.org
For more information on these studies see the Telethon website http://www.telethon.it/en
For information on TIGET see http://www.tiget.it/