Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT01410825 |
Other study ID # |
CHB-P00000148 |
Secondary ID |
|
Status |
Active, not recruiting |
Phase |
Phase 1/Phase 2
|
First received |
|
Last updated |
|
Start date |
July 2011 |
Est. completion date |
August 2024 |
Study information
Verified date |
June 2024 |
Source |
Boston Children's Hospital |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The Wiskott-Aldrich Syndrome (WAS) is an inherited disorder that results in defects of the
blood and bone marrow. It affects boys because the genetic mistake is carried on the X
chromosome. Normal people have blood cells called platelets that stop bleeding when blood
vessels are damaged. Boys with WAS have low numbers of platelets that do not function
correctly. Boys with WAS are thus at risk for severe life-threatening bleeding. A normal
immune system is made of special blood cells called white blood cells, which protect against
infection and also fight certain types of cancer. In WAS, these white blood cells don't work
as well as they should, making these boys very susceptible to infections and to a form of
blood cancer known as lymphoma. The abnormal white blood cells of patients with WAS also
cause diseases such as eczema and arthritis. Although WAS can be mild, severe forms need
treatment as early as possible to prevent life-threatening complications due to bleeding,
infection and blood cancer.
Over the past decade, investigators have developed new treatments based on the investigators
knowledge of the defective gene causing WAS. The investigators can now use genes as a type of
medicine that will correct the problem in the patient's own bone marrow. The investigators
call this process gene transfer. The procedure is very similar to a normal bone marrow
transplant, in that the old marrow is killed off using chemotherapy, but is different because
the patient's own bone marrow is given back after it is treated by gene transfer. This
approach can be used even if the patient does not have any matched donors available and will
avoid problems such as GVHD and rejection. The investigators wish to test whether this
approach is safe and whether gene transfer will lead to the development of a healthy immune
and blood system.
Description:
Wiskott-Aldrich syndrome (WAS) (OMIM 301000) is a rare X-linked immunodeficiency caused by
mutations in a single gene, WAS, mapping to Xp11.22-Xp11.3 and coding for the Wiskott-Aldrich
Syndrome Protein (WASP) 1. WASP is a critical regulator of actin signaling with expression
limited to hematopoietic cells, and thus is required for multiple functions including T cell
activation, dendritic cell migration and podosome formation, and B cell terminal development
and function. WAS is characterized by microthrombocytopenia, recurrent infections, eczema and
associated with a high incidence of auto-immunity and of lymphoid malignancies. Classic or
severe WAS, is generally observed in patients with nonsense mutations or insertions/deletions
resulting in frameshift or splice-site mutations or missense mutations and resulting in
unstable protein 2. With few exceptions, WASP-negative patients have classical disease.
Affected patients have a severely reduced life expectancy.
Currently, the only curative option for WAS patients is hematopoietic stem cell
transplantation (HSCT). This treatment is most successful when an HLA-identical sibling or
matched unrelated donor is available and results in correction of microthrombocytopenia and
immune dysfunction, even when stable mixed chimerism occurs. However, even patients
undergoing matched HSCT can suffer from considerable morbidity and mortality due to graft
versus host disease (GVHD) and many patients lack an HLA-identical donor. The outcome of
mismatched related HSCT is consistently poor with survival of approximately 50%. Gene
transfer is an attractive alternative treatment for WAS. Successful gene transfer using
autologous gene-corrected HSC would overcome clinical complications linked to GVHD and its
treatment. Furthermore, in contrast to allogeneic HSCT, gene transfer would not be limited by
the availability of compatible donors. Several lines of evidence indicate that partial
reconstitution with gene corrected cells may be sufficient to ameliorate the disease.
We propose here a Pilot and Feasibility study of ex vivo gene transfer using a lentiviral
vector (LV) to transduce autologous bone marrow derived CD34+ HSC. Cells will be infused into
patients conditioned with cytoreductive chemotherapy. Our collaborating investigators in
Europe have developed a LV encoding the human WAS cDNA under control of the WAS promoter and
pseudotyped with the Vesicular Stomatitis Virus glycoprotein (VSVg) envelope. This
w1.6_hWASP_WPRE (VSVg) LV (abbreviated as w1.6W) has been shown to be efficacious in both in
vitro and in vivo preclinical models. Safety including cellular toxicity, insertional
mutagenesis and tumor formation has been studied by a number of methods including: 1) a
sensitive in vitro transformation assay, 2) toxicity studies in transduced human CD34+ cells,
3) examination of the insertional pattern in transduced murine cells, and 4) long-term
observation and secondary transplant studies in mice. In the United States, we plan to enroll
5 boys with classic WAS who lack a matched related or unrelated donor. Parallel studies (not
under our Investigational New Drug application) using the same LV produced in the same
facility, Genethon, will be conducted in London, UK (5 subjects) and Paris, France (5
subjects). The primary objective will be to demonstrate feasibility and safety. The secondary
objective will be to assess therapeutic efficacy.