PHASE I/II CLINICAL TRIAL OF AUTOLOGOUS HEMATOPOIETIC STEM CELL GENE THERAPY FOR RAG1-DEFICIENT SEVERE COMBINED IMMUNODEFICIENCY

Severe combined immunodeficiency (SCID) is a genetically heterogeneous
life-threatening disease characterized by severely impaired T cell development
with or without impaired NK and B cell development or function depending on the
genetic defect. Mutations in recombination activating genes 1 and 2 (RAG1 and
RAG2) represent about 20% of all types of SCID. SCID is a paediatric emergency
since it leads to severe and recurrent infections often in combination with
protracted diarrhoea and failure to thrive. When left untreated, it is usually
fatal within the first year of life. Currently, the only curative treatment
option for RAG deficient SCID is allogeneic hematopoietic stem cell
transplantation (HSCT). Despite improvements in HSCT in recent years, this
treatment is associated with serious potential complications like
graft-versus-host disease which results in an unfavourable outcome,
particularly in patients who lack a human leukocyte antigen (HLA)-matched
donor. In recent years, gene therapy based on transplantation of autologous
gene-corrected hematopoietic stem cells (HSC) has evolved as an effective and
safe therapeutic option for X-linked and ADA-deficient forms of SCID. We have
recently demonstrated that gene therapy using lentiviral self-inactivating
(SIN) vectors expressing codon-optimized human RAG1 in a mouse model for
RAG1-deficient SCID effectively restores T and B cell development and function.
In this phase I/II explorative intervention study feasibility, safety and
efficacy of gene therapy using gene corrected autologous CD34+-selected
mobilized peripheral blood or bone marrow cells will be investigated in
patients with RAG1-deficient SCID with an indication for allogeneic HSCT but
lacking a HLA-matched donor.

This study has been transitioned to CTIS with ID 2023-510204-50-00 check the CTIS register for the current data.

Primary: The main objectives of the study are to demonstrate feasibility and
safety of gene corrected autologous CD34+-selected hematopoietic stem cell
therapy using a lentiviral SIN vector encoding codon-optimized human RAG1 cDNA
in patients with RAG1-deficient SCID.

Secondary: To demonstrate efficacy of this therapeutic intervention based on a)
T and B cell reconstitution at one year after infusion of the investigational
medicinal product, b) persistence of gene marking in myeloid and lymphoid cell
lineages in blood and marrow, and c) recovery from failure-to-thrive and/or
serious/invasive infections

This study is a prospective, non-randomized, explorative open label,
multicenter phase I/II intervention study designed to treat children up to 24
months of age with RAG1-deficient SCID with an indication for allogeneic
hematopoietic stem cell transplantation but lacking a HLA-matched donor. The
study involves infusion of autologous CD34+ cells transduced with the
pCCL.MND.coRAG1.wrpe lentiviral vector (hereafter called RAG1 LV CD34+ cells)
in ten patients with RAG1-deficient SCID.

Patients will receive a single infusion of autologous CD34+ hematopoietic stem
cells transduced with the pCCL.MND.coRAG1.wrpe lentiviral vector (RAG1 LV CD34+
cells).

The study focuses on feasibility, safety and efficacy of gene therapy using
corrected autologous HSC in RAG1-deficient SCID patients. Based on results from
other gene transfer studies and our own experience, the infusion of cultured
and gene altered autologous blood progenitors does not appear to be associated
with any significant transfusion reactions and is expected to be less toxic to
what can be expected in allogeneic SCT, the current standard of care. The risk
and side effects associated with the use of chemotherapy conditioning prior to
infusion of the autologous gene-corrected cells is similar or even less
compared to the setting of allogeneic HSCT since less intensive conditioning
will be used. The significant risk of graft versus host disease (GvHD)
associated with standard allogeneic HSCT (20-25%) will be eliminated in this
study with autologous cells. The expected duration of hospital admission, the
frequency of blood sampling and the expected visits to the outpatient clinic
after discharge are similar to the standard post HSCT procedures. Within the
first year after infusion of the RAG1 LV CD34+ cells, two bone marrow
aspirations will be performed under general anesthesia to assess engraftment of
the infused IMP. When possible, these procedures will be combined with routine
procedures, e.g. removal of a central venous access. Insertional mutagenesis
remains a finite risk of gene therapy treatment using integrating vectors.
However, recent work has shown that next generation vectors, particularly SIN
vectors as used in this study, significantly reduce the incidence of
insertional mutagenesis and so far, no malignant transformation has been
reported in recent clinical trials including more than 100 patients using these
SIN vectors. Even lentiviral-based gene therapy includes a potential risk for
insertion mutagenesis. In contrast to the first-generation retroviral vectors,
the occurrence of insertional mutagenesis when using SIN lentiviral vectors (>
250 patients), including the lentiviral vector versions used in our study, has
so far been limited to a single case. Of note, the concerned a patient with a
completely different underlying disease compared to our study. The expected
benefit of successful gene therapy involves restoration of humoral and cellular
immunity without concomitant risk of GvHD, and as a consequence improved
quality of life.