Severe combined immunodeficiencies (SCID) are a heterogeneous group of fatal inherited disorders characterized by a profound reduction or absence of T lymphocyte function. The most common form of SCID is an X-linked form (SCID-X1) caused by defects in the common cytokine receptor ? chain (?c or IL-2RG). 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. In the 20-25% of cases when a genotypically matched sibling donor is available, HSCT is a highly successful procedure. For the remaining individuals, alternative donor transplants, principally from matched unrelated (MUD) or haploidentical parental donors have been problematic due to toxicity from ablative therapy, graft-versus-host disease and incomplete lymphoid reconstitution. Recent gene transfer trials have documented efficacy, albeit with toxicity related to insertional mutagenesis. We have developed a next generation self-inactivating (SIN) vector expressing the IL-2RG gene controlled by an internal cellular promoter, pSRS11.EFS.IL2RG.pre* and have shown this vector to have reduced mutagenic potential compared to LTR configuration in non-clinical studies. We hypothesize that this vector will have similar efficacy to the vector used in the past trial but without insertional mutagenesis. The current study is a phase l/ll trial of somatic gene therapy for patients with SCID-X1. Inclusion criteria include patients with a definitive diagnosis of SCIDX1 in whom HLA-matched family donors are unavailable and who are either patients >3.5 months old and lack an HLA identical (A,B,C,DR,DQ) unrelated donor OR patients of any age with an active, therapy-resistant infection or other medical conditions that significantly increase the risk of allogeneic transplant. Primary endpoints include immunological reconstitution defined as absolute CD3 cells of >300/?l and PHA stimulation index >15 at 6 months post infusion and the incidence of life-threatening adverse reactions related to the gene transfer procedure. We will also perform detailed immune reconstitution and insertion site analysis studies.

Public Health Relevance

(provided by applicant): Gene therapy holds great promise for cure of many diseases, including cancer, HIV, blood disorders, and others. Gene therapy for severe combined immunodeficiency has been one of few documented successes but has had significant complications due to development of leukemia in 5 of 20 patients. This study will prove whether a safer gene therapy design will be effective without causing leukemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI087628-03
Application #
8318573
Study Section
Special Emphasis Panel (ZAI1-BDP-I (M3))
Program Officer
Johnson, David R
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$977,629
Indirect Cost
$103,445
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Williams, David A; Thrasher, Adrian J (2014) Concise review: lessons learned from clinical trials of gene therapy in monogenic immunodeficiency diseases. Stem Cells Transl Med 3:636-42
Williams, David A (2014) Curing genetic disease with gene therapy. Trans Am Clin Climatol Assoc 125:122-8; discussion 128-9
Hacein-Bey-Abina, Salima; Pai, Sung-Yun; Gaspar, H Bobby et al. (2014) A modified ?-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 371:1407-17
Kohn, Lisa A; Seet, Christopher S; Scholes, Jessica et al. (2014) Human lymphoid development in the absence of common ?-chain receptor signaling. J Immunol 192:5050-8