We propose a novel regulatory T (Treg) cell therapy to treat IPEX syndrome, a rare autoimmune monogenic
disease. IPEX is a life-threatening disease caused by loss-of-function FOXP3 mutations leading to dysfunctional
Treg cells. The only current curative treatment for IPEX is allogeneic hematopoietic stem cell transplantation
(allo-HSCT), which is only available to a minority of patients. The proposed product, CD4LVFOXP3 consists of
autologous CD4+ T cells that have undergone lentiviral vector (LV)-mediated gene transfer of wild-type human
FOXP3 leading to persistent high FOXP3 expression and acquisition of Treg cell phenotype and function.
CD4LVFOXP3 were granted Orphan Drug designation in October, 2020. Based on the etiology of IPEX, our
hypothesis is that the administration of autologous CD4+ T cells converted into CD4LVFOXP3 Treg-like cells
by LV-mediated FOXP3 gene transfer, will reduce the immune dysregulation and the autoimmune
manifestations. CD4LVFOXP3 is functionally equivalent to Treg cells and therefore, offer a novel cell therapy
approach that circumvents the requirement for generalized immune suppression (IS) and could improve the
clinical status of participants. This First-Time-in-Human (FTiH) Phase 1 clinical trial will test the feasibility of the
manufacturing and the safety of the administration of CD4LVFOXP3 (Aim 1) in minimum of 20 up to 36 evaluable
human participants with IPEX, who meet eligibility criteria. The secondary objective is to evaluate the impact of
the CD4LVFOXP3 infusion on clinical manifestations. The dosing rationale has been developed with a conservative
approach based on initial cell doses used in previous clinical trials with Treg cells of different origins. CD4LVFOXP3
also express membrane NGFR (CD271) encoded within the same LV construct that contains the FOXP3 gene.
allowing ex vivo purification and traceability enabling further studies of CD4LVFOXP3survival, phenotypic stability
and functional characteristics. Thus, during this clinical trial, we will perform exploratory studies to build
knowledge on the CD4LVFOXP3 pharmacokinetics (PK) (Aim2) and pharmacodynamics (PD) (Aim 3) by monitoring
the immune phenotype and function of patient immune cells. The possibility to provide functional autologous
Treg-like cells is expected to be of benefit to all eligible IPEX patients. CD4LVFOXP3 could: 1. improve control of
clinical manifestations resulting in the reduction of IS and related side effects, and 2. diminish the need for allo-
HSCT, or allow patients to be transplanted in a more stable clinical condition, resulting in improved allo-HSCT
outcomes. Successful completion of this clinical trial in patients with IPEX using CD4LVFOXP3 Treg-like cells as a
functional replacement for FOXP3 mutated Treg cells, addresses a significant unmet medical need while also
providing proof of safety and preliminary indications of benefit in controlling autoimmune disease manifestations.
As such, data from this trial could lead to expanded application of autologous CD4LVFOXP3 to other Tregopathies
and/or other more common autoimmune disorders, such as inflammatory bowel disease (IBD), type 1 diabetes
(T1D), cytopenia and atopic dermatitis, all of which have overlapping disease manifestations in IPEX patients.