Gene Therapy for X Linked Severe Combined Immunodeficiency

Overview

A safety and efficacy clinical study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells in ten children with genetic diagnosed X-SCID(severe combined immune deficiency ).The ten children will be followed for 3-5 years and be evaluated by clinical characteristics, vector marking (vector copy number per cell) in blood and bone marrow cells, immune reconstitution vector insertion-site patterns and so on.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: May 1, 2023

Interventions

  • Device: Lentiviral Vector Gene Therapy
    • Lentiviral vector to transfer IL2RG complementary DNA to patients’bone marrow stem cells

Arms, Groups and Cohorts

  • Experimental: Experimental Group
    • a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells in ten children with genetic diagnosed X-SCID(severe combined immune deficiency).

Clinical Trial Outcome Measures

Primary Measures

  • 1-year survival rate 1-year survival rate
    • Time Frame: one year after gene therapy of last recruited patient
    • 1-year survival rate of 10 recruited patients
  • 3-year survival rate
    • Time Frame: three years after gene therapy of last recruited patient
    • 3-year survival rate of 10 recruited patients
  • 5-year survival rate
    • Time Frame: five years after gene therapy of last recruited patient
    • 5-year survival rate of 10 recruited patients

Secondary Measures

  • Growth velocity after gene therapy,weight in kilograms, height in meters
    • Time Frame: through study completion, an average of 2 year
    • Body weight and height of patients will be assessed prior to (month 0) and post gene therapy,weight in kilograms, height in meters
  • Vector marking (vector copy number per cell) in blood and bone marrow cells
    • Time Frame: through study completion, an average of 1 year
    • vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors.
  • Absolute numbers of peripheral-blood immune-cell subsets
    • Time Frame: through study completion, an average of 1 year
    • Absolute numbers of peripheral-blood immune-cell subsets,as determined by means of standard flow cytometry
  • Quantity of DNA T-cell-receptor excision circles (TRECs) in peripheral-blood mononuclear cells
    • Time Frame: through study completion, an average of 1 year
    • Quantity of DNA T-cell-receptor excision circles (TRECs) in peripheral-blood ,as determined by means of quantitative polymerase chain reaction (PCR)
  • Serum immunoglobulins levels
    • Time Frame: through study completion, an average of 2 year
    • Serum immunoglobulins levels will be reported IgM(immunoglobulin M) in mg/dL Serum immunoglobulins levels will be reported IgM in mg/dL
  • Number of patients without intravenous immune globulin supplementation
    • Time Frame: through study completion, an average of 2 year
    • Number of patients without intravenous immune globulin supplementation after gene therapy
  • Number of patients who has a response to vaccines
    • Time Frame: through study completion, an average of 2 year
    • Number of patients who has a response to vaccines after gene therapy
  • Number of patients who recovers from previous infection(virus and bacteria)
    • Time Frame: through study completion, an average of 2 year
    • Number of patients who recovers from previous infection(virus and bacteria)after gene therapy

Participating in This Clinical Trial

Inclusion Criteria

1. X-SCID patients diagnosed by IL2RG single gene mutation 2. No HLA(human leukocyte antigen) matching donor 3. Hematopoietic stem cell transplantation failed and the time from transplantation was more than 18 months 4. Severe and persistent refractory infections 5. Life expectancy of > : 4 months 6. HIV PCR in peripheral blood was negative 7. the children and their families signed informed consent and were willing to enter the clinical trial and complete follow-up Exclusion Criteria:

1. The patient has diagnosed with hematological malignant diseases 2. Received chemotherapy within 3 months 3. HIV infection or HBV(hepatitis B virus) infection 4. The patient or his first-degree relative has developed a malignant tumor within the age of 18 or has been diagnosed with malignant tumor prone genes 5. Although the patient with X-SCID was diagnosed as IL2RG single gene mutation , the clinical phenotype was not severe, so they could continue to wait for the donor search; 6. Patients whose family members have no intention to continue the follow-up treatment in any link

Gender Eligibility: Male

Minimum Age: N/A

Maximum Age: 18 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Children’s Hospital of Chongqing Medical University
  • Provider of Information About this Clinical Study
    • Principal Investigator: mingfeng hu, Resident physician – Children’s Hospital of Chongqing Medical University
  • Overall Official(s)
    • Xiaodong Zhao, PHD, Study Director, Assistant President of Children’s Hospital of Chongqing Medical University
  • Overall Contact(s)
    • Xiaodong Zhao, PHD, 18623070626, zhaoxd530@aliyun.com

References

Mamcarz E, Zhou S, Lockey T, Abdelsamed H, Cross SJ, Kang G, Ma Z, Condori J, Dowdy J, Triplett B, Li C, Maron G, Aldave Becerra JC, Church JA, Dokmeci E, Love JT, da Matta Ain AC, van der Watt H, Tang X, Janssen W, Ryu BY, De Ravin SS, Weiss MJ, Youngblood B, Long-Boyle JR, Gottschalk S, Meagher MM, Malech HL, Puck JM, Cowan MJ, Sorrentino BP. Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1. N Engl J Med. 2019 Apr 18;380(16):1525-1534. doi: 10.1056/NEJMoa1815408.

Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debré M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana-Calvo M. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2010 Jul 22;363(4):355-64. doi: 10.1056/NEJMoa1000164.

De Ravin SS, Wu X, Moir S, Anaya-O'Brien S, Kwatemaa N, Littel P, Theobald N, Choi U, Su L, Marquesen M, Hilligoss D, Lee J, Buckner CM, Zarember KA, O'Connor G, McVicar D, Kuhns D, Throm RE, Zhou S, Notarangelo LD, Hanson IC, Cowan MJ, Kang E, Hadigan C, Meagher M, Gray JT, Sorrentino BP, Malech HL, Kardava L. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016 Apr 20;8(335):335ra57. doi: 10.1126/scitranslmed.aad8856. Erratum in: Sci Transl Med. 2016 Jun 1;8(341):341er5.

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