Gene Therapy for Bubble Boy Disease
Trial Summary
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. However, since the trial involves gene therapy and conditioning with busulfan, it's important to discuss your current medications with the trial team to ensure there are no interactions.
What data supports the effectiveness of the treatment Lentiviral Gene Transfer for Bubble Boy Disease?
Gene therapy has shown positive outcomes in treating various genetic diseases, including primary immunodeficiencies like SCID (Severe Combined Immunodeficiency), by restoring the immune system in children. Lentiviral vectors, which are used in this treatment, have been improved to safely and effectively deliver therapeutic genes, offering hope for lasting correction of immune deficiencies.12345
How is Lentiviral Gene Transfer treatment different from other treatments for Bubble Boy Disease?
Lentiviral Gene Transfer is unique because it uses a virus to deliver a healthy gene into the patient's cells, which can integrate into both dividing and non-dividing cells, providing a long-term solution. This is different from other treatments that may not offer permanent genetic correction or may not work effectively in non-dividing cells.46789
What is the purpose of this trial?
This is a Phase I/II non-randomized clinical trial of ex vivo hematopoietic stem cell (HSC) gene transfer treatment for X-linked severe combined immunodeficiency (XSCID, also known as SCID-X1) using a self-inactivating lentiviral vector incorporating additional features to improve safety and performance. The study will treat 35 patients with XSCID who are between 2 and 50 years of age and who have clinically significant impairment of immunity. Patients will receive a total busulfan dose of approximately 6 mg/kg/body weight (target busulfan Area Under Curve is 4500 min\*micromol/L/day) delivered as 3mg/kg body weight on day 1 and dose adjusted on day 2 (if busulfan AUC result is available) to achieve the target dose, to condition their bone marrow, and this will be followed by a single infusion of autologous transduced CD34+HSC. Patients will then be followed to evaluate engraftment, expansion, and function of gene corrected lymphocytes that arise from the transplant; to evaluate improvement in laboratory measures of immune function; to evaluate any clinical benefit that accrues from the treatment; and to evaluate the safety of this treatment. The primary endpoint of the study with respect to these outcomes will be at 2 years, though data relevant to these measures will be collected at intervals throughout the study and during the longer follow-up period of at least 15 years recommended by the Food and Drug Administration (FDA) Guidance "Long Term Follow-Up After Administration of Human Gene Therapy Products" https://www.fda.gov/media/113768/download for patientsparticipating in gene transfer clinical trials.XSCID results from defects in the IL2RGgene encoding the common gamma chain (yc) shared by receptors for Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. At birth XSCID patients generally lack or have a severe deficiency of T-lymphocytes and NK cells, while their B- lymphocytes are normal in number but are severely deficient in function, failing to make essential antibodies. The severe deficiency form of XSCID is fatal in infancy without intervention to restore some level of immune function. The best current therapy is a T-lymphocyte-depleted bone marrow transplant from an HLA tissue typing matched sibling, and with this type of donor it is not required to administer chemotherapy or radiation conditioning of the patient's marrow to achieve excellent engraftment and immune correction of an XSCID patient. However, the great majority of patients with XSCID lack a matched sibling donor, and in these patients the standard of care is to perform a transplant of T- lymphocyte depleted bone marrow from a parent. This type of transplant is called haploidentical because in general a parent will be only half- matched by HLA tissue typing to the affected child. Whether or not any conditioning is used, haploidentical transplant for XSCID has a significantly poorer prognosis than a matched sibling donor transplant. Following haploidentical transplant, XSCID patients are observed to achieve a wide range of partial immune reconstitution and that reconstitution can wane over time in some patients. That subset of XSCID patients who either fail to engraft, fail to achieve adequate immune reconstitution, or lose immune function over time suffer from recurrent viral, bacterial and fungal infections, problems with allo- or autoimmunity, impaired pulmonary function and/or significant growth failure.We propose to offer gene transfer treatment to XSCID patients\^3 \>= 2 years of age who have clinically significant defects of immunity despite prior haploidentical hematopoietic stem cell transplant, and who lack an HLA-matched sibling donor. Our current gene transfer treatment protocol can be regarded as a salvage/rescue protocol.Prior successful retroviral gene transfer treatment instead of bone marrow transplant (BMT) in Paris and London for 20 infants with XSCID has provided proof of principle for efficacy. However, a major safety concern is the occurrence of 5 cases of leukemia at 3-5 years after treatment triggered in part by vector insertional mutagenesis activation of LMO2 and other DNA regulatory genes by the strong enhancer present in the long-terminal repeat (LTR) of the Moloney Leukemia Virus (MLV)- based vector.Furthermore, previous studies of gene transfer treatment of older XSCID patients with MLV- based vectors demonstrated the additional problem of failure of adequate expansion of gene corrected T- lymphocytes to the very high levels seen in infants. To reduce or eliminate this leukemia risk, and possibly enhance performance sufficiently to achieve benefit in older XSCID patients, we have generated a lentivector with improved safety and performance features. We have generated a self-inactivating (SIN) lentiviral vector that is devoid of all viral transcription elements; that contains a short form of the human elongation factor 1a (EF1a) internal promoter to expres......
Research Team
Suk S De Ravin, M.D.
Principal Investigator
National Institute of Allergy and Infectious Diseases (NIAID)
Eligibility Criteria
This trial is for children and adults aged 2 to 40 with X-linked severe combined immunodeficiency (XSCID) who lack a matched sibling bone marrow donor, may have had an unsuccessful half-matched transplant, and show significant immune impairment. Participants must weigh at least 10 kg, be HIV negative, have documented B cell dysfunction or need for IVIG therapy, and be able to comply with the study's long-term follow-up.Inclusion Criteria
Timeline
Screening
Participants are screened for eligibility to participate in the trial
Conditioning
Patients receive a total busulfan dose to condition their bone marrow, followed by an infusion of autologous transduced CD34+HSC
Gene Transfer Treatment
Patients receive a single infusion of the transduced cells and are monitored for safety and efficacy
Follow-up
Participants are monitored for engraftment, expansion, and function of gene-corrected lymphocytes, as well as safety and clinical benefit
Long-term Follow-up
Long-term safety and efficacy evaluation as recommended by FDA Guidance for gene transfer treatment studies
Treatment Details
Interventions
- Lentiviral Gene Transfer
Lentiviral Gene Transfer is already approved in United States for the following indications:
- X-linked severe combined immunodeficiency (XSCID)
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Who Is Running the Clinical Trial?
National Institute of Allergy and Infectious Diseases (NIAID)
Lead Sponsor