Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings

Abstract

Purpose: Because human bone marrow (BM) CD34+ stem cells home into damaged tissue and may play an important role in tissue repair, this pilot clinical trial explored the safety and feasibility of intravitreal autologous CD34+ BM cells as potential therapy for ischemic or degenerative retinal conditions.

Methods: This prospective study enrolled six subjects (six eyes) with irreversible vision loss from retinal vascular occlusion, hereditary or nonexudative age-related macular degeneration, or retinitis pigmentosa. CD34+ cells were isolated under Good Manufacturing Practice conditions from the mononuclear cellular fraction of the BM aspirate using a CliniMACs magnetic cell sorter. After intravitreal CD34+ cell injection, serial ophthalmic examinations, microperimetry/perimetry, fluorescein angiography, electroretinography (ERG), optical coherence tomography (OCT), and adaptive optics OCT were performed during the 6-month follow-up.

Results: A mean of 3.4 million (range, 1-7 million) CD34+ cells were isolated and injected per eye. The therapy was well tolerated with no intraocular inflammation or hyperproliferation. Best-corrected visual acuity and full-field ERG showed no worsening after 6 months. Clinical examination also showed no worsening during follow-up except among age-related macular degeneration subjects in whom mild progression of geographic atrophy was noted in both the study eye and contralateral eye at 6-month follow-up, concurrent with some possible decline on multifocal ERG and microperimetry. Cellular in vivo imaging using adaptive optics OCT showed changes suggestive of new cellular incorporation into the macula of the hereditary macular degeneration study eye.

Conclusions: Intravitreal autologous BM CD34+ cell therapy appears feasible and well tolerated in eyes with ischemic or degenerative retinal conditions and merits further exploration. (ClinicalTrials.gov number, NCT01736059.).

Keywords: OCT; retinal degeneration; retinal imaging; retinal vein occlusion; stem cells.

Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Figures

Figure 1

Serial fundus photographs and fluorescein angiograms of subject 1 with a history of combined central retinal artery and vein occlusion diagnosed 9 months prior to study enrollment. (A) Fundus photograph of the right eye taken at time of enrollment showing persistent extensive retinal hemorrhages especially temporally with some retinal venous congestion. (B) Fundus photography of the study eye taken 3 months following intravitreal CD34+ cell injection showing marked resolution of retinal hemorrhages compared to enrollment. (C) Fluorescein angiogram of the study eye at enrollment showing an area temporal to the macula with microaneurysmal and telangiectatic retinal vascular changes with some patches of retinal ischemia. Patches of blocked fluorescence from retinal hemorrhages are also noted along with two small patches of fluorescein pooling from small focal areas of pigment epithelial detachment. (D) Fluorescein angiogram of the study eye taken 3 months following CD34+ cell therapy shows partial resolution of the microaneurysmal and telangiectatic retinal vascular changes and blocked fluorescence from the retinal hemorrhages noted at enrollment. The changes are more noteworthy inferior to the two small areas of fluorescein pooling from pigment epithelial detachment that remain unchanged.

Figure 2

Serial Goldmann perimetry of the study eye of subject 5 with advanced retinitis pigmentosa. (A) Baseline perimetry. (B) Perimetry at 1 month following intravitreal CD34+ cell therapy showing improved sensitivity in the nasal visual field to III4e stimulus (blue). (C) Perimetry at final follow-up at 6 months following enrollment shows sustained improvement in nasal visual field noted at 1-month follow-up perimetry.

Figure 3

Fluorescein angiogram and microperimetry of the study eye of subject 4 with age-related macular degeneration showing mild extrafoveal enlargement of geographic atrophy during the study follow-up period with corresponding area of worsening macular function on microperimetry. (A) Late transit fluorescein angiogram of the study left eye at baseline showing patches of geographic atrophy involving the fovea. (B) Corresponding macular sensitivity map on microperimetry of the left eye at baseline. (C) Late transit fluorescein angiogram of the study left eye at 6-month study follow-up showing some enlargement of geographic atrophy temporal to the fovea. (D) Corresponding macular sensitivity map on microperimetry of the left eye at 6-month study follow-up showing an increase in scotoma temporally. Color coding of macular sensitivity map: green, normal function; red/orange, decreased function; black, absolute scotoma.

Figure 4

Full-field photopic electroretinogram of subject 2 with Stargardt's disease at baseline (A), 1 month (B), and 6 months (C) following intravitreal CD34+ cell injection in the left eye (left eye recording is depicted in the right recording panel) showing an increase in the b-wave and flicker signal amplitude in the study eye at 6-month follow-up visit relative to the untreated contralateral eye and baseline recordings. The rectangular boxes within the recording represent the age-matched normal b-wave and flicker amplitude range for each recording, as follows: normal mean flicker amplitude ± SD 106 ± 32 μV; normal mean b-wave amplitude 128 ± 46 μV.

Figure 5

Adaptive optics optical coherence tomography (AO-OCT) imaging of the central macula of the study eye of subject with Stargardt's disease. Left: B-scan cross-sectional images of the central macula at study enrollment showing the irregular hyperreflective retinal pigment epithelial layer with overlying photoreceptor inner segment–outer segment layer not well visualized. Middle: Cross-sectional B-scan images of the central macula 1 month after intravitreal CD34+ cell injection showing new multiple hyperreflective (white) deposits within the retinal layers. Right: Cross-sectional B-scan image taken 6 months after CD34+ cell injection showing less prominent hyperreflective deposits within the retinal layers and a hint of an increase in hyperreflectivity of the irregular retinal pigment epithelial layer centrally under the fovea. GCL, ganglion cell layer; RPE, retinal pigment epithelium.