ESPE Yearbook of Paediatric Endocrinology

Cell 2024; 187(22):6152-6164.e18. PMID: 39326417

Brief summary: This is a preliminary analysis of a first-in-human phase I clinical trial assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for T1D treatment. In the first treated patient, this approach resulted in tolerable safety and promising restoration of exogenous-insulin independent glycemic control at 1-year follow-up.

Human induced pluripotent stem cells (iPSCs) show remarkable potential as an unlimited cell source for cellular replacement therapies such as islet transplantation, due to their ability to self-renew and differentiate into functional cell types (1).

In this study, a novel approach was tested, consisting in the use of chemically induced pluripotent stem cells (CiPSCs), generated using small-molecule chemicals as reprogramming factors, for the creation of islet-like cells (CiPSC-islets). Additionally, a new transplantation strategy for CiPSC-islets was implemented, involving an extrahepatic site.

The reported results are from the first treated patient, a 25-year-old woman with 11-year diabetes duration and challenging diabetes management. Patient-derived iPSCs were generated from adipose-derived mesenchymal stromal cells isolated from the patient’s adipose tissue using a chemical reprogramming strategy, obtaining patient-specific CiPSCs, which were differentiated into CiPSC-islets. The latter were injected underneath the abdominal anterior rectus sheath of the patient, a location which allowed monitoring though ultrasound and magnetic resonance imaging.

Remarkably, the patient achieved sustained insulin independence starting 75 days post-transplantation. Time-in-target glycemic range increased from baseline 43% to 96% by month 4 post-transplantation, accompanied by a decrease and normalization in HbA1c. Thereafter, the patient showed stable glycemic control, and after 12 months, all study endpoints were met without any safety concerns.

This study reports encouraging clinical outcomes in the first patient, and there is considerable interest in the forthcoming results from the 2 additional patients who have received the same treatment. These findings support continue clinical research in this area and represent meaningful progress toward broader application of the evaluated techniques.

Reference: 1. Cerneckis J, Cai H, Shi Y. Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. Signal Transduct Target Ther. 2024;9(1):112.