Wiskott-Aldrich syndrome (WAS) is a rare congenital disease affecting 1 in 500,000 live births. Mutations in the Wiskott-Aldrich Syndrome protein (WASp) result in immune cells with significantly reduced capacity for host defense. As a result, Wiskott-Aldrich Syndrome patients have substantially shortened life expectancies, succumbing at young ages to fatal hematologic malignancies and herpes virus infections. Current therapeutic options for Wiskott-Aldrich Syndrome are suboptimal. Hematopoietic stem cell transplantation (HSCT) carries a failure rate of approximately 30% and is only an option for a subset of Wiskott-Aldrich Syndrome patients. Data suggest that transplantation needs to be performed prior to age 5 and only when a suitably matched donor is available. Milder forms of Wiskott-Aldrich Syndrome do exist, however, these have a median event-free survival of 9 years, typically resulting in diagnosis later in childhood, often too late for transplantation. Other therapeutic options, including antibody replacement therapy and prophylactic antibiotics, are limited and of minimal therapeutic utility. Host defense against viral infection and malignancy requires natural killer (NK) cells, which can innately recognize and kill affected cells. In the absence of the actin branching protein WASp, natural killer cells do not properly form immunologic synapses with target cells, which limits their cytotoxic function. In vitro studies, however, have shown that interleukin (IL)-2 can restore function to WASp-deficient natural killer cells by inducing WAVE2, an alternative actin-branching protein. A Phase 1 clinical trial was recently opened to determine the safety and tolerability of Interleukin-2 in Wiskott-Aldrich Syndrome. The grant application will allow support for conducting and completing this trial, evaluating the restoration of natural killer cell function an cytoskeletal dynamics as secondary endpoints.
The Specific Aims of the study are: 1) To determine if Interleukin-2 is safely tolerated in Wiskott-Aldrich Syndrome using doses expected to increase natural killer cell function and 2) To determine if Interleukin-2 administration restors natural killer cell function in Wiskott-Aldrich Syndrome patients.

Public Health Relevance

PROJECT NARATIVE Wiskott-Aldrich syndrome (WAS) is a devastating fatal rare pediatric disease affecting 1 in 500,000 births. We have identified a novel therapeutic strategy in WAS (the first in over 30 years), which could address the most substantive problems affecting patients. Specifically, we found interleukin (IL)-2 can directly circumvent the molecular defect in WAS and restore deficient immune functions in WAS patient cells. We opened a phase-I trial of IL-2 in WAS (NCT00774358) and enrolled 3 WAS subjects. IL-2 was safely tolerated thus far and restored certain immune functions. We aim to complete this study and build upon it to provide much needed innovation in WAS and fulfill the mission of the Orphan Products Research Project program.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01FD004091-02
Application #
8729420
Study Section
Special Emphasis Panel (ZFD1)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104