Japanese Phase 1 Trial Supports Medium-Term Safety of iPSC-Derived Neural Stem/Progenitor Cell Therapy for Spinal Cord Injury

A Phase 1 study by Keio University reported no tumor formation, graft-related adverse events, or unexpected neurological deterioration after iPSC-derived neural stem/progenitor cells were transplanted into four patients with subacute complete cervical spinal cord injuries, with follow-up lasting two to four years. Two participants improved from AIS grade A to grades C and D by Week 52, but the small, open-label study was designed primarily to assess safety and could not establish whether the transplantation caused the neurological improvements. Jiji Press reported that the research team plans to begin another investigator-initiated clinical trial as early as 2027.

iPSC neural stem cell transplantation

• ▪The four patients received the cell transplants during the subacute stage of spinal cord injury, within four weeks of their injuries.
• ▪A Keio University research team reported an acceptable safety profile for iPSC-derived neural stem/progenitor cell transplantation in four patients with subacute complete cervical spinal cord injuries during two to four years of follow-up.
• ▪The Keio University research team transplanted approximately two million iPSC-derived neural stem/progenitor cells into each of four participants enrolled after screening conducted between December 2021 and November 2023.
• ▪The Keio University research team plans to launch an investigator-initiated clinical trial as early as 2027 to bring the stem cell treatment into practical use.

Spinal cord injury treatment

• ▪More than 20 million people globally live with disabilities related to spinal cord injuries, which cause irreversible disruption of neural connectivity.
• ▪Current standard care for spinal cord injuries, including surgical decompression, stabilization, and rehabilitation, cannot reconstruct damaged neural circuits.

Preclinical efficacy mechanisms

• ▪Transplanted neural stem/progenitor cells in animal models differentiated into neurons, astrocytes, and oligodendrocyte-lineage cells, contributing to remyelination and attenuation of spinal atrophy.
• ▪Transplanted cells in preclinical models secreted neurotrophic and angiogenic factors, including hepatocyte growth factor, brain-derived neurotrophic factor, and vascular endothelial growth factor.
• ▪Preclinical studies in rodent and nonhuman primate models showed that transplanted human induced pluripotent stem cell-derived neural stem/progenitor cells promoted functional motor recovery.

Phase 1 trial design

• ▪The phase 1 trial enrolled four male participants aged 26 to 66 years with cervical spinal cord injuries and a neurological level of injury between C4 and C6.
• ▪The phase 1 trial protocol required participants to have an American Spinal Injury Association Impairment Scale grade A status, which was reconfirmed on the day of transplantation.
• ▪The phase 1 clinical study was a 52-week, open-label, single-arm, first-in-human interventional trial designed primarily to evaluate the safety of intramedullary transplantation of human induced pluripotent stem cell-derived neural stem/progenitor cells.

Cell manufacturing quality control

• ▪The integration-free human induced pluripotent stem cell line YZWJs513, derived from umbilical-cord blood cells of a healthy donor homozygous for common Japanese HLA haplotypes, served as the starting material.
• ▪The stem cells were exposed to a gamma-secretase inhibitor for 24 hours to suppress Notch signaling before transplantation, and the culture supernatant was removed prior to injection.

Safety outcomes adverse events

• ▪All four participants experienced hypomagnesemia, considered probably related to tacrolimus, and urinary tract infections, considered possibly related because an effect of the immunosuppressant could not be excluded.
• ▪A total of 84 adverse events were recorded across all participants during the 52-week study period, with one participant developing transient, asymptomatic hyperkalemia.
• ▪Two participants improved from AIS grade A to grades C and D by Week 52, but the researchers cautioned that the small, uncontrolled study could not determine whether the improvements were caused by the transplantation.
• ▪No major safety issues, including tumor formation, were observed in any of the four patients two to four years after the transplantation surgery.