Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector

Severe combined immunodeficiencies (SCID) are a heterogeneous group of inherited disorders
characterized by a profound reduction or absence of T lymphocyte function. They arise from a
variety of molecular defects which affect lymphocyte development and function. The most
common form of SCID is an X-linked form (SCID-X1) which accounts for 40-50% of all cases.
SCID-X1 is caused by defects in the common cytokine receptor chain, which was originally
identified as a component of the high affinity interleukin-2 receptor (IL-2RG), but is now
known to be an essential component of the IL-4, -7, -9 -15, and -21 cytokine receptor
complexes. Classic SCID-X1 has an extremely poor prognosis without treatment. Death usually
occurs in the first year of life from infectious complications unless definitive treatment
can be administered. Until the recent advent of somatic gene therapy, hematopoietic stem cell
transplantation (HSCT) offered the only curative option for patients with any form of SCID.
If a genotypically matched sibling donor is available, HSCT is a highly successful procedure.
However a genotypically matched family donor is only available for approximately 30% of
patients. For the remaining individuals, alternative donor transplants, principally from
matched unrelated or haploidentical parental donors have been performed. These approaches are
still problematic with toxicity from ablative therapy, graft-versus-host disease and
incomplete lymphoid reconstitution. Recent gene transfer trials have documented the efficacy
of gene transfer in this disease, albeit with toxicity related to insertional mutagenesis. A
new generation of self-inactivating (SIN) vectors has been developed which lack all
enhancer-promoter elements of the LTR U3 region and are also devoid of all gammaretroviral
coding regions. A SIN vector expressing the IL-2RG gene, pSRS11.EFS.IL2RG.pre* has been
developed and has shown a reduction in mutagenic potential compared to LTR configuration in
non-clinical studies. The current study is a phase I/II trial of somatic gene therapy for
patients with SCID-X1.

Inclusion Criteria:

1. Diagnosis of SCID-X1 based on immunophenotype (<200 CD3+ autologous T cells, and
confirmed by DNA sequencing)

AND

2. Lack an HLA identical (A, B, C, DR, DQ) related donor

AND either one of the following:

1. Patients in good clinical condition who do not have a readily available HLA identical
(A,B,C,DR,DQ) unrelated donor (readily available defined as: a donor confirmed within 6
weeks of searching, with ability to transplant within 3 months of diagnosis).

2. Patients with an active, therapy-resistant infection or other medical conditions that
significantly increase the risk of allogeneic transplant. Examples of "therapy-resistant
infections that significantly increase the risk of allogeneic transplant" include but are
not limited to:

1. interstitial pneumonia due to adenovirus or parainfluenzae virus.

2. protracted diarrhea requiring total parenteral nutrition.

3. disseminated BCG infection.

4. virus-induced lymphoproliferative disease.

5. any active opportunistic infection (eg, due to Pneumocystis jiroveci,
cytomegalovirus,cryptosporidium) that does not improve on medical management.

6. active and progressive pulmonary disease requiring mechanic ventilation. Inclusion of
patients with disease-related organ dysfunction is justified by the known poor outcome
with standard treatment and the potential life-saving nature of the treatment
proposed. Patients who are on high-dose steroids or other immunosuppressive agents
will also be considered eligible, because use of these drugs is common in patients
with SCID and maternal T cell engraftment or who present with severe interstitial lung
disease. Use of immunosuppressive drugs does not affect efficacy of hematopoietic cell
transplantation, and therefore should not affect efficacy of gene transfer.

Exclusion Criteria:

1. No available molecular diagnosis confirming SCID-X1.

2. Patients who have an available HLA-identical related donor.

3. Diagnosis of active malignant disease other than EBV-associated lymphoproliferative
disease

4. Patients with evidence of infection with HIV-1

5. Previous gene transfer

6. Major (life-threatening) congenital anomalies. Examples of "major (life-threatening)
congenital anomalies" include, but are not limited to: unrepaired cyanotic heart
disease, hypoplastic lungs, anencephaly or other major CNS malformations, other severe
non-repairable malformations of the gastrointestinal or genitourinary tracts that
significantly impair organ function.

7. Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate
collection and/or infusion of transduced cells or indicate patient's inability to
follow the protocol. These may include for example clinical ineligibility to receive
anesthesia, severe deterioration of clinical condition of the patient after collection
of bone marrow but before infusion of transduced cells, or documented refusal or
inability of the family to return for scheduled visits. There may be other unforeseen
rare circumstances that would result in exclusion of the patient, such as sudden loss
of legal guardianship.

Although the presentation of the disease may be variable in type, the severity of the
immunodeficiency is uniform. The gene transfer protocol will be instituted in the place of
haploidentical transplant for those patients who do not have a matched family donor or in
whom an unrelated donor transplant is not indicated for the reasons specified above. Apart
from the gene transfer protocol, the patients will not undergo additional procedures that
would not form part of an equivalent haploidentical transplantation regimen, and will not
receive conditioning chemotherapy.