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Pilot and Feasibility Study of Hematopoietic Stem Cell Gene Transfer for the Wiskott-Aldrich Syndrome

Phase 1/Phase 2
1 Month
35 Years
Open (Enrolling)
Wiskott-Aldrich Syndrome

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Trial Information

Pilot and Feasibility Study of Hematopoietic Stem Cell Gene Transfer for the Wiskott-Aldrich Syndrome

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 micro-thrombocytopenia, 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 Feasibilty 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 pre-clinical 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.

Inclusion Criteria:

1. Confirmed molecular diagnosis by DNA sequencing and either

1. absence of the WAS protein by flow cytometry OR

2. clinical score 3-5

2. Age 1 months to 35 years

3. For subjects < 5 years of age:

1. Lack of HLA-genotypically identical bone marrow donor.

2. Lack of a 9/10 or 10/10 molecularly HLA-matched unrelated donor after 3 months
of searching.

3. Lack of a 6/6 molecularly HLA-matched cord blood donor of adequate cell number
after 3 months of searching

4. For subjects 5 years of age or older:

a.Lack of HLA-genotypically identical bone marrow donor.

5. Subjects who have undergone allogeneic transplant previously must additionally have:

1. Failure defined as <5% donor T cell engraftment and

2. Contraindication to re-use of the same donor due to severe GVHD or

6. Parental/guardian/patient signed informed consent

7. Willingness to return for follow-up during the 5 year study period.

8. Adequate organ function and performance status

1. Performance status ≥50% (Lansky play for age <16 years, Karnofsky for age ≥16

2. Left ventricular ejection fraction >40% or shortening fraction >25%

3. Bilirubin ≤ 2.0 mg/dL

4. Measured creatinine clearance or GFR by nuclear medicine study ≥40 ml/min/1.73

5. DLCO (corrected for hemoglobin), FEV1, FVC >50% of predicted; if age < 7 years,
then oxygen saturation >92% on room air

Exclusion Criteria:

1. Contraindication to bone marrow harvest, or to administration of conditioning

2. Known positive HIV serology or HIV nucleic acid testing.

3. Other uncontrolled infection.

4. Active malignancy other than EBV lymphoproliferative disease.

5. Known myelodysplasia of the bone marrow or abnormal bone marrow cytogenetics

6. Congenital cardiac disease with congestive heart failure

7. Oxygen dependence at baseline

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety of infusion of transduced cells

Outcome Description:

Safety of infusion of transduced cells as rescue of hematopoiesis after conditioning (hematopoietic recovery as assessed by absolute neutrophil count (ANC) above 0.5 x 109 /l for three consecutive days, achieved within 6 weeks following infusion).

Outcome Time Frame:

5 Years

Safety Issue:


Principal Investigator

Sung-Yun Pai, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Hospital Boston


United States: Food and Drug Administration

Study ID:




Start Date:

July 2011

Completion Date:

Related Keywords:

  • Wiskott-Aldrich Syndrome
  • WAS
  • Wiskott
  • Gene Transfer
  • Gene Therapy
  • Wiskott-Aldrich Syndrome



Children's Hospital BostonBoston, Massachusetts  02115