A First-in-human Clinical Trial Using a Gene Therapy With Patient's Own Stem Cells to Treat Early Type 1 Diabetes

Purpose:

The purpose of the trial is to assess the safety profile of the study treatment and to evaluate its efficacy in terms of improvement in key diabetes management parameters, including insulin requirements and β-cell function, and immunological parameters, in patients with T1D at recent onset / diagnosis and with residual β-cell function.

Rationale:

The study treatment consists of an autologous CD34+-enriched population that contains HSPCs transduced ex vivo with a third generation VSV-G pseudotyped LVV encoding the hPD-L1 cDNA. The drug product (DP) is composed of genetically modified autologous CD34+ HSPCs formulated in cryopreservation medium, transferred to the final container closure, and cryopreserved.

The mechanism of action is based on the ability of the PD-L1-expressing HSPCs to exert immunoregulatory properties activity and ablate suppress the autoimmune reaction induced by auto-reactive T lymphocytes, by homing to the site of inflammation, i.e., the pancreas.

PD-L1 is the ligand for the PD-1 receptor, expressed primarily on activated T cells. Crosslinking of PD-L1 and PD-1 inhibits T cell activation and favours their exhaustion/apoptosis and in mice deficient in PD-L1/PD-1 develop accelerated diabetes. HSPCs have been extensively used as an effective therapeutic approach in haematological malignancies and have demonstrated to be safe in human subjects.

Immunologically based clinical trials performed thus far have failed to cure T1D, in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4+ T cells, which destroy β cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in PD-L1, an important immune checkpoint, in the T1D non-obese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. The Investigators therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro.

The Investigators therefore hypothesized that targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D or slow the progression of β-cell destruction.