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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01410825
Recruitment Status : Active, not recruiting
First Posted : August 5, 2011
Last Update Posted : January 23, 2020
Information provided by (Responsible Party):
David Williams, Boston Children's Hospital

Tracking Information
First Submitted Date  ICMJE August 4, 2011
First Posted Date  ICMJE August 5, 2011
Last Update Posted Date January 23, 2020
Study Start Date  ICMJE July 2011
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 4, 2011)
  • Safety of infusion of transduced cells [ Time Frame: 5 Years ]
    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).
  • Engraftment of genetically corrected T cells [ Time Frame: 5 Years ]
    Engraftment of genetically corrected T cells in peripheral blood (as assessed by evidence of vector sequences in >1% of CD3+ T cells) at 6 months.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Pilot and Feasibility Study of Hematopoietic Stem Cell Gene Transfer for the Wiskott-Aldrich Syndrome
Official Title  ICMJE Pilot and Feasibility Study of Hematopoietic Stem Cell Gene Transfer for the Wiskott-Aldrich Syndrome
Brief 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.

Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Wiskott-Aldrich Syndrome
Intervention  ICMJE Biological: Retrovirus-mediated gene transfer
Two procedures: 1) Bone marrow harvest from the patient's posterior iliac crests or collection of peripheral blood stem cells via apheresis procedure. 2) One time infusion of patient's transduced bone marrow cells.
Study Arms  ICMJE Experimental: Gene transfer
Open label single arm study
Intervention: Biological: Retrovirus-mediated gene transfer
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 4, 2011)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2023
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 3 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 non-availability.
  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 years)
    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 m2
    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 medication.
  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
  8. Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful study completion. This may include but is not limited to:

    • Severe deterioration of clinical condition after collection of cells but before infusion of transduced cells
    • Documented refusal or inability of the family to return for scheduled visits
    • Other concerns about unwillingness or inability to comply with protocol requirements
    • Unforeseen rare circumstances such as sudden loss of legal guardianship
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 3 Months to 35 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01410825
Other Study ID Numbers  ICMJE CHB-P00000148
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party David Williams, Boston Children's Hospital
Study Sponsor  ICMJE David Williams
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sung-Yun Pai, M.D. Boston Children's Hospital
PRS Account Boston Children's Hospital
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP