Interleukin-2 Treatment for Wiskott-Aldrich Syndrome (WAS)

Reinstituting Natural Killer Cell Cytotoxicity and Cytoskeletal Dynamics in Wiskott-Aldrich Syndrome With IL-2 Therapy

Funding Source--FDA OOPD. Orphan Product Grant Number--1R01FD004091-01A1 Context: Wiskott-Aldrich syndrome (WAS) is a fatal, devastating disease with ill-defined treatment modalities, which affects young boys. Classic WAS is characterized by a clinical triad of thrombocytopenia, eczema and severe, recurrent infections. Despite diagnostic and therapeutic advances most WAS patients die at less than 12 years of age due to infections, hemorrhage, malignancy or complications from treatments. WAS patients suffer from herpesvirus infections as a result of poor Natural Killer (NK) cell function (cytotoxicity). In the laboratory, the investigators have seen correction of WAS Natural Killer Cell (NK) function after treatment with Interleukin-2 (IL-2). Objectives: Initiate a prospective clinical trial by treating WAS subjects with IL-2 and using safety as the primary endpoint. Restoration of NK cell cytotoxicity and effects on cytoskeletal dynamics are secondary endpoints. The investigators will also observe patient clinical status (eczema, infections, use of treatment dose antibiotics, food allergies, etc). Study Design/Setting/Participants: This is a prospective clinical trial treating 9 WAS subjects in the Clinical Translational Research Center (CTRC) with IL-2. Intervention: The investigators propose to subcutaneously administer 0.5 Million Units (MU)/m2 of IL-2 daily to WAS subjects for 5 days. Research treatment will be repeated 2 and 4 months later. Inter-patient dose escalation will be employed to 1 MU/m2 and/or 2 MU/m2 based on safety as the primary endpoint. Study Measures: The investigators will observe safety and tolerability measures and perform assays on subject blood samples prior to and after research treatment to observe improvement in NK cell function.

The Wiskott-Aldrich syndrome (WAS) is a fatal genetic disease of the immune system that results from a mutation of the WAS protein (WASp) gene. Immune cells that carry this mutation have a decreased ability to reorganize filamentous actin (F-actin) after activation. As a result there are a number of defective immunologic functions, some of which result in deficient host defense. The investigators have identified a pervasive deficit in natural killer (NK) cell cytotoxicity in WAS patients. WAS patients suffer from conditions that are hallmarks of NK cell deficiencies. These include severe herpesvirus infections and B cell malignancies. Our lab and others have also found that exposure of WAS subject NK cells to IL-2 in vitro restores NK cell function and allows for normal F-actin reorganization. Thus, the investigators propose a proof of principal clinical trial to treat WAS subjects with IL-2 to determine safety and efficacy of IL-2 in this population and if NK cell function is restored ex vivo. If IL-2 can circumvent a defective WASp to restore NK cell function, the investigators will propose a larger NIH funded efficacy trial of IL-2 in WAS. The investigators will also use the in vivo treatment of WAS subjects to forward our mechanistic studies of how IL-2 may facilitate F-actin reorganization in the absence of WASp function.

We propose to subcutaneously administer 0.5 MU/m2 of IL-2 daily to WAS subjects for 5 days. Research treatment will be repeated 2 and 4 months later. Inter-patient dose escalation will be employed to 1 MU/m2 and/or 2 MU/m2 based on safety as the primary endpoint.

We propose to subcutaneously administer 0.5 MU/m2 of IL-2 daily to WAS subjects for 5 days. Research treatment will be repeated 2 and 4 months later. Inter-patient dose escalation will be employed to 1 MU/m2 and/or 2 MU/m2 based on safety as the primary endpoint.

Inclusion Criteria: Age: Subjects age greater than 24 months Weight: Subjects greater than 12.5 kilograms Disease status: WAS classified as Grade 1-4 Informed Consent: Written informed consent of the subject (if an adult) or parental permission, and assent of the child subject provided justification is made for the inclusion of children in the study Exclusion Criteria: Prior or planned hematopoetic transplant WAS classified as currently Grade 5 (Malignancy or autoimmune disease including the following: Crohn's disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous pemphigoid . Not included here are: Hepatitis C virus induced vasculitis, alopecia areata and systemic lupus erythematosus.) Known previous reaction to IL-2 Subjects taking immunosuppressive medications that might alter study results Subjects taking nephrotoxic, cytotoxic, cardiotoxic, or hepatotoxic medications (including medications for hypertension) Subjects currently taking systemic corticosteroids (not included here: topical and inhaled corticosteroids) Subjects taking Interferon alpha Use of any other investigational agent in the last 30 days Women of childbearing potential not using contraception method(s), as well as women who are breastfeeding Subjects with abnormal cardiac, hepatic and CNS function

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