Management of retinitis pigmentosa by Wharton’s jelly derived mesenchymal stem cells: preliminary clinical results

Abstract

Purpose: The aim of this study is to determine if umbilical cord Wharton's jelly derived mesenchymal stem cells implanted in sub-tenon space have beneficial effects on visual functions in retinitis pigmentosa patients by reactivating the degenerated photoreceptors in dormant phase. Material and methods:This prospective, open-label, phase-3 clinical trial was conducted between April of 2019 and October of 2019 at Ankara University Faculty of Medicine, Department of Ophthalmology. 32 RP patients (34 eyes) were included in the study. The patients were followed for 6 months after the Wharton's jelly derived mesenchymal stem cell administration, and evaluated with consecutive examinations. All patients underwent a complete routine ophthalmic examination, and best corrected visual acuity, optical coherens tomography angiography, visual field, multifocal and full-field electroretinography were performed. The quantitative results were obtained from a comparison of the pre-injection and final examination (6th month) values.Results: The mean best corrected visual acuity was 70.5 letters prior to Wharton's jelly derived mesenchymal stem cell application and 80.6 letters at the 6th month (p = 0.01). The mean visual field median deviation value was 27.3 dB before the treatment and 24.7 dB at the 6th month (p = 0.01). The mean outer retinal thickness was 100.3 μm before the treatment and 119.1 μm at 6th month (p = 0.01). In the multifocal electroretinography results, P1 amplitudes improved in ring1 from 24.8 to 39.8 nv/deg2 (p = 0.01), in ring2 from 6.8 to 13.6 nv/deg2 (p = 0.01), and in ring3 from 3.1 to 5.7 nv/deg2 (p = 0.02). P1 implicit times improved in ring1 from 44.2 to 32.4 ms (p = 0.01), in ring2 from 45.2 to 33.2 ms (p = 0.02), and in ring3 from 41.9 to 32.4 ms (p = 0.01). The mean amplitude improved in 16 Tds from 2.4 to 5.0 nv/deg2 (p = 0.01) and in 32 Tds from 2.4 to 4.8 nv/deg2 (p = 0.01) in the full-field flicker electroretinography results. Full field flicker electroretinography mean implicit time also improved in 16 Tds from 43.3 to 37.9 ms (p = 0.01). No ocular or systemic adverse events related to the two types of surgical methods and/or Wharton's jelly derived mesenchymal stem cells itself were observed during the follow-up period.Conclusion: RP is a genetic disorder that can result in blindness with outer retinal degeneration. Regardless of the type of genetic mutation, sub-tenon Wharton's jelly derived mesenchymal stem cell administration appears to be an effective and safe option. There are no serious adverse events or ophthalmic / systemic side effects for 6 months follow-up. Although the long-term adverse effects are still unknown, as an extraocular approach, subtenon implantation of the stem cells seems to be a reasonable way to avoid the devastating side effects of intravitreal/submacular injection. Further studies that include long-term follow-up are needed to determine the duration of efficacy and the frequency of application.

Management of retinitis pigmentosa by Wharton’s jelly-derived mesenchymal stem cells: prospective analysis of 1-year results

“…Structural measurements, such as EZW and ORT, and functional measurements such as BCVA, FPDI, and ERG responses can indicate photoreceptor reactivation (Tables 3, 4, and 5). Statistically significant improvements in these parameters show that the paracrine trophic effects of WJ-MSCs still persist during the first year similar to the results at 6th month [46]. Dormant phase reactivation and statistically significant increases were detected in 19 of 34 eyes (55.9%) according to visual field and EZW parameters.…”

“…Stem cell-based paracrine trophic therapies can be effective for a large number of patients regardless of the genetic inheritance [ 24 – 45 ]. For this purpose, stem cell research has increased in recent years, e.g., our previous study with Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) in the treatment of RP patients [ 46 ].…”

Embryonic stem cell microenvironment enhances proliferation of human retinal pigment epithelium cells by activating the PI3K signaling pathway

“…Additionally, even young cells are doomed to perish when introduced into an old organ without a youthful niche [44,45]. Though the recent study demonstrated that sub-tenon WJ-MSCs administration was effective on reactivating the degenerated photoreceptors in dormant phase [13], the long-term effects may be weakened with the gradual aging of WJ-MSCs in vivo, and the senescenceassociated secretory phenotype secreted by senescent WJ-MSCs may even produce adverse effects. Therefore, the idea of providing endogenous or transplanted stem and progenitor cells with better microenvironments is being pursued by many researchers in the eld of regenerative medicine.…”

“…Differentiated ESCs and tissue-speci c adult stem cells yield much weaker results than ESCs [22,25,44]. Administration of sub-tenon WJ-MSCs could stop the progression of retinal degeneration and rescue photoreceptors in the dormant phase with the paracrine effects of WJ-MSCs [13]. Interactions between cells involve multi-directional signaling.…”

“…In addition, lipofuscin and melanosomes undergoing signi cant age-related changes will in uence phototoxicity and detract from the normal functioning of the RPE and hinder the bene ts of RPE transplantation [9]. Researchers have successfully attempted to promote RPE cells proliferation and functional recovery by mesenchymal stem cells [10][11][12], such as umbilical cord Wharton's jelly derived mesenchymal stem cells (WJ-MSCs) [13]. But the inevitable immune rejection by allogeneic cells cannot be ignored.…”