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.

Trial registration: SHGM56733164. Redistered 28 January 2019 https://shgm.saglik.gov.tr/organ-ve-doku-nakli-koordinatorlugu/56733164/203 E.507.

Keywords: Retinitis pigmentosa; Stem cell; Subtenon space; Umbilical cord stem cell; Wharton’s jelly derived mesenchymal stem cell.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

a Obtaining mesenchymal stem cells from umbilical cord Wharton’s jelly, morphological appearance and final injectable product. b Flow cytometric analysis of WJ-MSC

Fig. 2

a, b Visual field changes in the WJ-MSC treatment (Table 1, patient no. 1: right eye). a: before the application, b: 6 months later after the application

Fig. 3

a, b Visual field changes in the WJ-MSC treatment (Table 1, patient no. 2: left eye). a: before the application, b: 6 months later after the application

Fig. 4

a, b Outer retinal thickness changes in the WJ-MSC treatment (Table 1, patient no. 1: right eye). a: before the application, b: 6 monts later after the application. (In order for the assessment to be meaningful, the threshold scan value should be 5 and above. Reference: OCTA device user manual)

Fig. 5

a, b Outer retinal thickness changes in the WJ-MSC treatment (Table 1, patient no. 4: left eye): a: before the application, b: 6 months later after the application

Fig. 6

a, b mfERG improvement in the WJ-MSC Treatment (Table 1, patient no. 18: left eye). a: before the application, b: 6 months later after the application

Fig. 7

Full-field flicker ERG improvement during the follow-up (6 months) after the WJ-MSC applecation (Table 1, patient no. 11: right eye)

Fig. 8

a-c Ultrasonographyic view of WJ-MSC implantation into the deep subretinal space within the extraocular muscle conus; a: before the application (Table 1, patient no. 1), b: injection via 25 G sharp-tip needle (Table 1, patient no. 1), c: placement via 20 G curved subtenon canulla with pre-placed suture to prevent the leakage (Table 1, patient no. 4)

Fig. 9

Regression of recalsitrant cyctoid macular edema after the WJ-MSC application (Table 1, patient no.16: left eye)

Fig. 10

Releasing of epiretinal membrane contraction after the WJ-MSC application (Table 1, patient no.26: left eye)

Fig. 11

Dissapear of lipofuscin deposits after the WJ-MSC application (Table 1, patient no.26: left eye)