Lentiviral Gene Transfer for Treatment of Children Older Than 2 Years of Age With X-Linked Severe Combined Immunodeficiency

This study will evaluate the safety and effectiveness of lentiviral gene transfer treatment
at restoring immune function to participants with X-linked severe combined immunodeficiency
(XSCID) who are 2 to 40 years of age, and have significant impairment of immunity. XSCID is a
severe genetic condition of the immune system.

Participants in this study will be treated at the National Institutes of Health (NIH)
Clinical Center.

Before the gene transfer treatment, a participant's own CD34+ hematopoietic stem cells (HSCs)
will have been or will be collected from the participant's blood or bone marrow. When the
participant has the required number of HSCs harvested, then the participant's HSCs will be
grown in tissue culture and exposed to the lentiviral gene transfer vector containing the
corrective gene (VSV-G pseudotyped CL20-4i-EF1α-hγc-OPT). These gene corrected HSCs will be
administered by intravenous (IV) infusion to the participant. To increase engraftment of the
corrected HSCs, participants will receive a chemotherapy drug called busulfan on 2 days
before the gene transfer treatment. Participants will also receive palifermin, which helps
prevent mucositis, which is the main side effect from the busulfan.

After the gene transfer treatment, participants will be monitored to see if the treatment is
safe and whether their immune system improves. Participants will be followed at frequent
intervals for the first 2 years, and less frequently thereafter so that the effectiveness in
restoration of immune function and the safety of the treatment can be evaluated. Additional
safety follow-up may occur through Year 15.

Inclusion Criteria:

- A proven mutation in the common gamma chain gene as defined by direct sequencing of
patient DNA

- Human leukocyte antigen (HLA) typing of the patient will have been performed before
enrollment

- No available HLA matched sibling donor as determined before enrollment.

- Must be between 2 and 40 years of age and weigh 10 kg

- If previously transplanted, must be 18 months post-hematopoietic stem cell transplant
(HSCT)

- Expected survival of at least 120 days.

- Documented to be negative for HIV infection by genome polymerase chain reaction (PCR)

- The patient must be judged by the primary evaluating physician to have a suitable
family and social situation consistent with ability to comply with protocol procedures
and the long-term follow-up requirements.

- Medical lab data (historical) of severe B cell dysfunction (low or absent
immunoglobulin G [IgG] levels, failed immune response to vaccines); OR demonstrated
requirement for intravenous gamma globulin (IVIG) (significant drop over 3 to 6 weeks
between peak and trough IgG levels).

- Must be willing to have blood and tissue samples stored. IN ADDITION, patients must
satisfy the following Laboratory Criteria AND Clinical Criteria:

- Laboratory Criteria: (at least 1 must be present)

- CD4+ lymphocytes: absolute number less than or equal to 50% of the lower limit of
normal (LLN)

- CD4+CD45RA+ lymphocytes: absolute number less than or equal to 50% of the LLN OR
T-cell receptor excision circles (TRECs) less than or equal to 5% of normal for
age.

- Memory B Cells: absolute number less than or equal to 50% of LLN

- Serum immunoglobulin M (IgM) less than normal for age

- Natural killer (NK) cells: absolute number less than or equal to 50% of LLN

- Lymphocyte proliferative response to each of 2 mitogens, phytohemagglutinin (PHA)
and concanavalin A (ConA), is less than or equal to 25% compared with a normal
control.

- Molecular spectratype analysis- absent or very oligoclonal (1-3 dominant peaks)
in greater than or equal to 6 of the 24 Vbeta T-cell receptor families.

- Clinical Criteria: (at least 1 must be present)

- i. Infections (not including molluscum, warts or mucocutaneous candidiasis; see vii
and viii below): 3 significant new or chronic active infections during the 2 years
preceding evaluation for enrollment, with each infection accounting for one criteria.
Infections are defined as an objective sign of infection (fever greater than 38.3^0C
[101^0F] or neutrophilia or pain/redness/swelling or radiologic/ultrasound imaging
evidence or typical lesion or histology or new severe diarrhea or cough with sputum
production). In addition to one or more of these signs/symptoms of possible infection,
there also must be at least 1 of the following criteria as evidence of the attending
physician's "intent to treat" a significant infection (a. and b.) or objective
evidence for a specific pathogen causing the infection (c.)

- a. Treatment (not prophylaxis) with systemic antibacterial, antifungal or
antiviral antibiotics 14 days OR

- b. Hospitalization of any duration for infection OR

- c. Isolation of a bacteria, fungus, or virus from biopsy, skin lesion, blood,
nasal washing, bronchoscopy, cerebrospinal fluid or stool likely to be an
etiologic agent of infection

- ii. Chronic pulmonary disease as defined by:

- a. Bronchiectasis by x-ray computerized tomography OR

- b. Pulmonary function test (PFT) evidence for restrictive or obstructive disease
that is 60% of Predicted for Age OR

- c. Pulse oximetry 94% in room air (if patient is too young to comply with
performance of pulmonary function tests [PFTs]).

- iii. Gastrointestinal enteropathy:

- a. Diarrhea-watery stools 3 times per day (of at least 3 months duration that is
not a result of infection as defined in criterion number i. above) OR

- b. Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will
only be performed if medically indicated) OR

- c. Other evidence of enteropathy or bacterial overgrowth syndrome: including
malabsorption of fat soluble vitamin(s), abnormal D-xylose absorption, abnormal
hydrogen breath test, evidence of protein losing enteropathy (for example
increasingly high or frequent dosing of intravenous gamma globulin supplement
required to maintain blood IgG level).

- iv. Poor nutrition: Requires gastrostomy tube (G-tube) or intravenous feeding
supplement to maintain weight or nutrition.

- v. Auto- or allo-immunity: Examples must include objective physical findings that
include, but are not limited to any one of alopecia, severe rashes, uveitis, joint
pain with redness or swelling or limitation of movement that is not a result of
infection, lupus-like lesions, and granulomas (Does not include auto- or allo-immune
enteropathy which is criterion iii). Where possible and appropriate, diagnosis will be
supported by histopathology or other diagnostic modality.

- vi. Failure to grow in height: 3rd percentile for age

- vii. Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum
consists of 10 lesions or there are two or more lesions at each of two or more widely
separated anatomic sites; or there are 3 warts at different anatomic sites at the same
time; or the patient has both molluscum and warts)

- viii. Mucocutaneous candidiasis (chronic oral thrush or candida esophagitis or candida
intertriginous infection or candida nail infections; must be culture positive to
satisfy this criterion)

- ix. Hypogammaglobulinemia: requires regular IgG supplementation

Exclusion Criteria:

- Any current or pre-existing hematologic malignancy

- Current treatment with any chemotherapeutic agent (becomes eligible if not on
treatment for at least 3 months)

- Documented HIV-1 infection

- Documented active Hepatitis B infection

- Childhood malignancy (occurring before 18 years of age) in the patient or a first
degree relative, or previously diagnosed known genotype of the subject conferring a
predisposition to cancer (no DNA or other testing for cancer predisposition genes will
be performed as part of the screen for this protocol)