INSERM: French teams, and English teams demonstrated the efficacy
of gene therapy treatment for Wiskott-Aldrich Syndrome (WAS). Six
children that were treated and followed for at least 9 months had their
immune system restored and clinical condition improved. This work, which
was published today in the Journal of the American Medical Association (JAMA), was carried out with support from the AFM-Telethon.
Wiskott-Aldrich
syndrome is a rare congenital immune and platelet deficiency which is
X-linked and has an estimated prevalence of 1/250 000. It is caused by
mutations in the gene encoding the WAS protein (WASp) expressed in
hematopoietic cells. This disease, which primarily affects boys, causes
bleeding, severe and recurrent infections, severe eczema and in some
patients autoimmune reactions and the development of cancer. The only
treatment available today is bone marrow transplantation, which requires
a compatible donor and can itself cause serious complications.
The
Phase I / II study, with Genethon as the promoter, was launched in
December 2010 and conducted in Paris and London to treat severely ill
patients without a compatible donor. This study, which is ongoing,
assesses the feasibility and efficacy of gene therapy in this
indication. The article published in JAMA reports the results for the
first six patients, aged 8 months to 16 years, where the monitoring
period allowed assessment of the initial effects of the treatment.
The
treatment involves collected blood stem cells carrying the genetic
anomaly of patients and corrected them in the laboratory by introducing a
healthy WAS gene using a lentiviral vector developed and produced by
Genethon. The corrected cells were reinjected into patients who in
parallel were treated with chemotherapy to suppress their defective stem
cells and autoimmune cells to make room for new corrected cells. After
reinjection, these cells were then differentiated into the various cell
lines that make up the blood (red and white cells, platelets).
To date treated patients showed significant clinical improvement.
Severe eczema and severe infection disappeared in all cases. Arthritis
was eliminated in one patient and another saw major improvement in
vasculitis of the lower limbs and was able to return to normal physical
activity without a wheelchair. However, the rate of corrected platelets
varies from one patient to another.
Fulvio Mavilio, Chief Scientific Officer Genethon: “We
are all very happy and encouraged by the results of this study. It is
the first time that a gene therapy based on genetically modified stem
cells is tested in a multicenter, international clinical trial that
shows a reproducible and robust therapeutic effect in different centers
and different countries. For very rare diseases such as WAS, multicenter
clinical trials are the only effective way of proving the safety and
efficacy of gene therapy and having it rapidly approuved and made
available to all patients. We are following the same approach for other
rare and less rare blood diseases.”
Frédéric Revah, CEO of Genethon, the laboratory of the AFM-Telethon and the trial sponsor, said “These
first results of our clinical trial for the treatment of Wiskott
Aldrich syndrome are very encouraging. They illustrate not only the
ability of Genethon to carry out the upstream research to develop
treatments for these rare and complex diseases, but also to construct
and conduct international clinical trials, to produce these advanced
therapy products, to work with international teams and to manage the
regulatory aspects of the trials in France and abroad. These are skills
that we implement for other international trials of gene therapy for
rare genetic diseases of the immune system, blood, muscle, vision or
liver… We will continue the current study with the objective of
providing treatment for patients.”
Marina Cavazzana: “The
results obtained in this multicenter clinical trial constitute an
important therapeutic advance (overhang) because they concern a complex
pathology which affects almost all of blood cells with dramatic clinical
consequences. After transfer of gene, the patients showed a significant
clinical improvement due to the reexpression of the protein WASp in the
cells of the immune system. The efficiency of the treatment of such a
deficit for which a high level of correction of hematopoietic stem cells
is required, indicates that it is from now on justifiable to hope to
treat other complex genetic diseases as those affecting red blood cells.”
Professor Thrasher says: “This
is a very powerful example of how gene therapy can offer highly
effective treatment for patients with complex and serious genetic
disease. It also excitingly demonstrates the potential for treatment of a
large number of other diseases for which existing therapies are either
unsatisfactory or unavailable.”