Intravitreal autologous bone marrow-derived mononuclear cell transplantation: a feasibility report

Introduction

In the era of intravitreal injections of drugs such as triamcinolone acetonide, pegabtanib, ranibizumab and bevacizumab for treatment of retinal oedema and neovascularization, one of the next challenges in the therapy of retinal diseases concerns the regeneration of damaged or destroyed retinal vasculature and retinal cells. Such vasculo-regenerative and retino-regenerative therapies might be useful for a whole array of diseases, such as inherited retinal dystrophies, which afflict about one in 3500 individuals, optic nerve diseases such as the glaucomas, macular disorders such as geographic atrophy in age-related macular degeneration, and panretinal disorders such as advanced diabetic retinopathy with occlusion of the retinal capillaries. Recent experimental studies and animal models have reported bone marrow-derived stem cells applied intravitreally as potentially beneficial in terms of achieving such goals (Otani et al. 2002, 2004; Smith 2004; Meyer et al. 2005; Harris et al. 2006). It was recently demonstrated that mouse or human adult bone marrow-derived stem cells containing endothelial precursors can stabilize and rescue retinal blood vessels in experimental retinal dystrophies, and that this effect is accompanied by an additional neurotrophic rescue effect (Otani et al. 2004). Given these pioneering investigations, the present report aims to demonstrate the clinical feasibility of intravitreal application of autologous bone marrow-derived mononuclear cells in a patient.

Case report

A 43-year-old pseudophakic patient had previously undergone pars plana vitrectomy with panretinal endolaser coagulation and intravitreal silicone oil endotamponade for removal of vitreous haemorrhage, vitreoretinal tractions and epiretinal membranes resulting from proliferative diabetic retinopathy. One year after surgery, the subject's visual acuity (VA) was defective light projection caused by marked atrophy of the retina and optic nerve, with the retinal arteries mostly occluded. The retina was completely attached. The electroretinogram was abolished. Intraocular pressure (IOP) was within the normal range. There were no signs of neovascularization of the retina or iris. Under local anaesthesia, 100 ml of bone marrow was harvested and mononuclear cells were separated from the aspirate via Ficoll density gradient sedimentation. All preparation procedures were carried out according to the current European Union Guidelines for Good Manufacturing Practice and under the corresponding manufacturing licence (Cytonet Hannover GmbH, Hanover, Germany). Extensive sterility control of the incoming bone marrow harvest and the final product was carried out and demonstrated the absence of microbial contamination. One day after the bone marrow harvesting, a 0.5-ml cell suspension was transsclerally injected into the centre of the vitreous cavity through the pars plana region under topical anaesthesia. This 0.5-ml suspension contained 180 million bone marrow-derived mononuclear cells and 0.5 million CD34-positive cells, with viability of 94% as shown by trypan blue dye examination, and a haematocrit of 2%. Prior to the injection, an anterior chamber aspiration was carried out through a paracentesis. The patient was fully informed about the experimental nature of the treatment attempt and had signed informed consent.

On postoperative day 1, a cluster of the injected cells was observed on the retinal surface in the inferior fundus periphery. The anterior chamber was completely filled with silicone oil, which was transcorneally released under topical anaesthesia. Within the first 2 weeks of the injection, IOP increased to ≤ 35 mmHg, and irregularly formed medium-to- large cells appeared in the anterior chamber. At 4 weeks after the procedure, the anterior chamber was free of cells and flare, IOP was within the normal range without antiglaucomatous medication, and the cell cluster on the retinal surface had mostly dissolved. Visual acuity was light perception and defective light projection.

Conclusions

This report suggests that an intravitreal injection of autologous bone marrow-derived cells into the vitreous cavity is technically feasible. In view of the potential clinical indications for intravitreal autologous bone marrow-derived mononuclear cell transplantations, the present attempt may serve to warrant further clinical trials.

Acknowledgement

L. Arseniev is concomitantly an employee of Cytonet Hannover GmbH, Hanover, Germany, which produces bone marrow cells according to German drug law.