Preclinical study of novel human allogeneic adipose tissue-derived mesenchymal stem cell sheets toward a first-in-human clinical trial for myopic chorioretinal atrophy

Mesenchymal stem cells may have neuroprotective and tissue regenerative capabilities and the potential to rescue retinal degeneration in chorioretinal diseases including myopic chorioretinal atrophy. Transplantation of human (allogeneic) adipose tissue-derived mesenchymal stem cell (adMSC) suspensions has been clinically conducted to treat retinal degenerative diseases. However, serious side effects including proliferative vitreoretinopathy and epiretinal membrane formation have been reported. PharmaBio Corporation fabricated novel adMSC sheets with a Bruch's membrane-like structure using our original method, potentially overcoming these problems. We evaluated the characteristics of newly developed adMSC sheets named PAL-222 and assessed their safety and efficacy in rats with congenital retinal degeneration (RCS rats) to obtain the proof-of-concept for the first-in-human clinical trial for myopic chorioretinal atrophy.

We confirmed the efficacy and safety of PAL-222 and are currently conducting a clinical trial to treat myopic chorioretinal atrophy. Transplantation of these novel adMSC sheets may be a promising therapy for myopic chorioretinal atrophy.

We measured the viability of cells obtained from PAL-222, examined cell surface antigens by flow cytometry, measured the vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) secretory ability, examined the expression of types I and IV collagen and elastin by immunostaining. We performed a transwell in vitro migration assay to evaluate durability and similarity to retinal pigment epithelium (RPE) and checked in vitro tumorigenicity. In an in vivo experiment, we transplanted PAL-222 into the subretinal space of RCS rats and evaluated the safety and efficacy.

Viability of cells obtained from PAL-222 was 88.1%. The rate of positive markers such as CD90, CD73, CD105 and CD44 exceeded 90%; that of the negative markers such as CD34, CD11b, CD19, CD45 and HLA-DR was less than 2%. PAL-222 secreted significant amounts of VEGF and PEDF and expressed types I and IV collagen and elastin. The migration assay showed that PAL-222 preserved the sheet structure without cell migration. No chromosomal aberration or colony formation was observed in in vitro tumorigenicity tests. PAL-222 transplantation suppressed the progression of retinal degeneration by preserving the outer nuclear layer without negative changes in RCS rats, suggesting a retinoprotective effect. Conclusions: We confirmed the efficacy and safety of PAL-222 and are currently conducting a clinical trial to treat myopic chorioretinal atrophy. Transplantation of these novel adMSC sheets may be a promising therapy for myopic chorioretinal atrophy.

ClinicalTrials.gov, Identifier: NCT05658237. URL: https://classic. Clinicaltrials: gov/ct2/show/NCT05658237 .