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

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Brief Title

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

Official Title

Multi-institutional Phase I/II Trial Evaluating the Treatment of SCID-X1 Patients With Retrovirus-mediated Gene Transfer

Brief Summary

      Researchers are working on ways to treat SCID patients who don't have a matched brother or
      sister. One of the goals is to avoid the problems that happen with stem cell transplant from
      parents and unrelated people, such as repeat transplants, incomplete cure of the immune
      system, exposure to chemotherapy, and graft versus host disease.

      The idea behind gene transfer is to replace the broken gene by putting a piece of genetic
      material (DNA) that has the normal gene into the child's cells. Gene transfer can only be
      done if we know which gene is missing or broken in the patient. For SCID-X1, gene transfer
      has been done in the laboratory and in two previous clinical trials by inserting the normal
      gene into stem cells from bone marrow. The bone marrow is the "factory" inside the bones that
      creates blood and immune cells. So fixing the gene in the bone marrow stem cells should fix
      the immune problem, without giving chemotherapy and without risk of graft versus host
      disease, because the child's own cells are used, rather than another person's. Out of the 20
      subjects enrolled in the two previous trials, 18 are alive with better immune systems after
      gene transfer. Two of the surviving subjects received gene corrected cells over 10 years ago.

      Gene transfer is still research for two reasons. One is that not enough children have been
      studied to tell if the procedure is consistently successful. Of the 20 children enrolled in
      the previous two trials, one child did not have correction of the immune system, and died of
      complications after undergoing stem cell transplant. The second important reason why gene
      transfer is research is that we are still learning about the side effects of gene transfer
      and how to do gene transfer safely. In the last two trials, 5 children have experienced a
      serious side effect. These children developed leukemia related to the gene transfer itself.
      Leukemia is a cancer of the white blood cells, a condition where a few white blood cells grow
      out of control. Of these children, 4 of the 5 have received chemotherapy (medication to treat
      cancer) and are currently in remission (no leukemia can be found by sensitive testing),
      whereas one died of gene transfer-related leukemia.

Detailed Description

      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.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

CD3 cell count post transfusion

Secondary Outcome

 Molecular characterization of gene transfer.


Severe Combined Immunodeficiency


Gene transfer

Study Arms / Comparison Groups

 Gene Transfer
Description:  open label single arm study


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

April 2010

Completion Date

March 2023

Primary Completion Date

March 2022

Eligibility Criteria

        Inclusion Criteria:

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


          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

          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.




N/A - N/A

Accepts Healthy Volunteers



Jennifer Whangbo, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party


Study Sponsor

David Williams


 Boston Children's Hospital

Study Sponsor

Jennifer Whangbo, MD, Principal Investigator, Boston Children's Hospital

Verification Date

April 2021