Intravitreal autologous mesenchymal stem cell transplantation: a non-randomized phase I clinical trial in patients with retinitis pigmentosa

Abstract

Background: Retinitis pigmentosa (RP) is a progressive inherited retinal disease with great interest for finding effective treatment modalities. Stem cell-based therapy is one of the promising candidates. We aimed to investigate the safety, feasibility, and short-term efficacy of intravitreal injection of bone marrow-derived mesenchymal stem cells (BM-MSCs) in participants with advanced stage RP.

Methods: This non-randomized phase I clinical trial enrolled 14 participants, categorized into three groups based on a single dose intravitreal BM-MSC injection of 1 × 10⁶, 5 × 10⁶, or 1 × 10⁷ cells. We evaluated signs of inflammation and other adverse events (AEs). We also assessed the best corrected visual acuity (BCVA), visual field (VF), central subfield thickness (CST), and subjective experiences.

Results: During the 12-month period, we noticed several mild and transient AEs. Interestingly, we found statistically significant improvements in the BCVA compared to baseline, although they returned to the baseline at 12 months. The VF and CST were stable, indicating no remarkable disease progression. We followed 12 participants beyond the study period, ranging from 1.5 to 7 years, and observed one severe but manageable AE at year 3.

Conclusion: Intravitreal injection of BM-MSCs appears to be safe and potentially effective. All adverse events during the 12-month period required observation without any intervention. For the long-term follow-up, only one participant needed surgical treatment for a serious adverse event and the vision was restored. An enrollment of larger number of participants with less advanced RP and long-term follow-up is required to evaluate the safety and efficacy of this intervention.

Trial registration: ClinicalTrials.gov, NCT01531348 . Registered on February 10, 2012.

Keywords: Inherited retinal diseases; Mesenchymal stem cell; Phase I clinical trial; Retinitis pigmentosa (RP); Stem cell therapy.

Fig. 1

The transparent reporting of evaluations with non-randomized design (TREND) flow diagram. The TREND flow diagram describes the number of study participants during trial enrollment, allocation, follow-up, and discontinuation of intervention of the intravitreal injection of autologous bone marrow-derived mesenchymal stem cells

Fig. 2

Characteristics of bone marrow-derived mesenchymal stem cells (BM-MSCs). Representative flow cytometry histogram of mesenchymal stem cell (MSC) characteristics assessed by positive expression of CD73, CD90, and CD105 and negative expression of CD34, CD45, and HLA-DR surface markers. Cell viability was assessed by the expression of the 7-amino-actinomycin D (7-AAD). Dashed lines represent the unstained control

Fig. 3

The cell numbers and flare values after the intravitreal injection of BM-MSCs. The cells and flare were evaluated daily for the first week, weekly for the first month, then monthly for the next 12 months. The graphs show the comparison of cells (a) and flare (b) in the study eyes among groups (blue, red, and green lines represent groups 1, 2, and 3, respectively). The comparison between the fellow eye (gray line) and study eye in each group (c and d for cells and flare of group 1, N = 7; e and f for group 2, N = 3; and g and h for group 3, N = 4). Error bars indicate the SD of cells and flare value in each group

Fig. 4

Subjective complain during the study. The subjective complain for the safety (a) and efficacy (b) of autologous intravitreal injection of BM-MSCs during the 12-month follow-up

Fig. 5

Retinal appearances during the study period. A1 Fundus montages demonstrate generalized pigmentary changes with heavy bone spicules and macular involvement. A2 and A3 images, representing months 6 and 12, respectively, show similar appearances. B1 Fundus autofluorescence images describe the central hyper-autofluorescence surrounding the island of hypo-autofluorescence in the macula, where autofluorescence indicates the presence of normal retinal pigment epithelium (RPE). B2 and B3 images represent months 6 and 12, respectively, with no remarkable changes. C1, C2, C3 The optical coherence tomography indicates central subfield thickness at baseline, month 6, and month 12, respectively. The study eye and fellow eye show similar appearances. Images were retrieved from a study participant in group 1

Fig. 6

Adverse events in the study participants receiving intravitreal injection of BM-MSCs. a Slit-lamp biomicroscopy of a study participant with posterior synechiae (indicated by arrows). b After treatment with the cycloplegic agent, the posterior synechiae were released, leaving some residual pigments adhered on the lens surface (indicated by the arrow). c Optical coherence tomography imaging in a study participant at baseline and d at month 3 with mild cystoid macular edema (indicated by the arrow). e The ultra-widefield retinal imaging shows choroidal detachment (indicated by arrows) at the superotemporal periphery. f Ultrasound imaging demonstrates double-peak reflectivity (indicated by arrows) with anechoic suprachoroidal space

Fig. 7

Ultra-widefield retinal image and histopathological finding of a participant with a severe adverse event. a The ultra-widefield retinal image displays the margin of retinectomy upon removing the fibrous membrane along the vitreous base temporal periphery (indicated by arrows). b Histopathological section of the membrane shows osseous metaplasia or heterotopic ossification (hematoxylin and eosin (HE) staining, magnification × 40)

Fig. 8

Best corrected visual acuity (BCVA) after the intravitreal BM-MSC injection. The changes in visual acuity (logMAR) of each month were normalized to the baseline. a The comparison of the BCVA in the study eye among groups (blue, red, and green lines indicate groups 1, 2, and 3, respectively). The comparison of the BCVA between the study eye (gray line) and fellow eye of groups 1 (b), 2 (c), and 3 (d). Data represent mean of study participants from each group; group 1: N = 7, group 2: N = 3, and group 3: N = 4 (except for M12: N = 3). Error bars indicate the SD of cells and flare value in each group. Asterisks indicate the statistical significance at P value < 0.05