Autologous hematopoietic stem cell gene therapy in RAG-deficient severe combined immunodeficiency: pre-phase study

Severe combined immunodeficiency (SCID) is the most severe form of inherited
primary immunodeficiency (PID). SCID due to RAG deficiency has an invariably
fatal prognosis if untreated. The only currently available potentially curative
treatment is allogeneic stem cell transplantation. Recently, successful
application of (lentiviral) codon-optimized SIN vector mediated gene therapy in
mouse models for RAG1 and RAG2-deficient SCID has been demonstrated. A phase
1/2 clinical trial is planned that will investigate safety and efficacy (i.e.
engraftment and sustained reconstitution of humoral and cellular immunity) of
gene therapy using lentiviral SIN vector encoding codon-optimized human RAG1
transduced autologous hematopoietic stem cells (HSC) in RAG1-deficient patients
without a HLA-matched donor. A similar approach is currently under development
for patients with RAG2-deficient SCID.

The purpose of this study is to evaluate the feasibility and efficiency of
transducing freshly obtained CD34+ HSC from either mobilized peripheral blood
or bone marrow of healthy donors using lentiviral SIN vectors encoding
codon-optimized human RAG1 or RAG2 cDNA.

Test runs in the LUMC clean room facility of lentiviral vector transduction
procedures on fresh HSC material obtained from mobilized peripheral blood or
bone marrow of healthy donors.

No potential subject benefit or risk from participation in this study. Burden
consists of the collection of an extra 20 ml of bone marrow or a lengthening of
the stem cell collection apheresis duration during procedures that are part of
standard donor care.