Improvement of ischaemic macular oedema after intravitreal injection of autologous bone marrow-derived haematopoietic stem cells.

Abstract

No proven treatment exists for decreased vision due to macular oedema associated with ischaemic diabetic maculopathy or ischaemic central retinal vein occlusion (CRVO). Clinical trials are being conducted by our research group on the safety and efficacy of intravitreal injection of autologous bone marrow-derived stem cells (auto-BMSC) for the treatment of retinal vascular diseases with ischaemic maculopathy [severe capillary non-perfusion, as per Early Treatment Diabetic Retinopathy Study (ETDRS) criteria] (NCT01518842). Recently, we published data regarding the safety and efficacy of intravitreal injection of auto-BMHSC in patients with retinal dystrophy (Siqueira et al. 2011), and reported resolution of macular oedema after intravitreal injection of auto-BMHSC in a patient with retinitis pigmentosa (Siqueira et al. 2013). Two patients with macular oedema associated with macular ischaemia [due to diabetic retinopathy in one patient and ischaemic central retinal vein occlusion (CRVO) in the other patient] were treated with intravitreal injection of 0.1 ml of a cell suspension containing 2.0 × 104 autologous bone marrow-derived haematopoietic stem cells (CD34 +; auto-BMHSC). In both patients, the treated eye demonstrated improved best-corrected ETDRS visual acuity (20/800 to 20/100 and 20/200 to 20/100), reduced central subfield thickness on spectral domain optical coherence tomography (383–285 μm and 612–302 μm), improved macular sensitivity on microperimetry (increase in bivariate contour ellipse area) and imp-roved multifocal electroretinography amplitude density with a follow-up varying from one to 12 weeks after treatment (Fig. 1). To our knowledge, and based on a Medline database search, this is the first report of intravitreal injection of auto-BMHSC for the treatment of macular oedema associated with macular ischaemia secondary to diabetic retinopathy and ischaemic CRVO. The mechanisms by which auto-BMHSC may be associated with functional and structural improvements in retinal diseases are unclear, but several stem cell paracrine effects may be important (Siqueira et al. 2010). For example, it has been demonstrated that, when stimulated by pro-inflammatory agents such as tumour necrosis factor, bone marrow mesenchymal stem cells release anti-inflammatory paracrine factors, exerting modulation of local inflammation, which could improve vascular permeability (Li et al. 2009). In addition, bone marrow-derived haematopoietic stem cells injected intravitreally have been shown to exert trophic rescue effects in animal models of retinal light damage, retinal ischaemia and diabetic retinopathy (Zhang & Wang 2010). The current report describes decreased macular oedema and improved retinal function in an eye with macular oedema associated with ischaemic diabetic maculopathy and in an eye with ischaemic CRVO after intravitreal injection of auto-BMHSC. The modest visual acuity improvement after macular oedema resolution is consistent with the small improvements observed on microperimetry and multifocal ERG, indicating that functional deficits are, at least in part, due to retinal abnormalities other than macular oedema, such as degeneration of photoreceptors and/or inner retinal cells. The increase in bivariate contour ellipse area (BCEA) in both patients may be explained by the improvement and re-establishment of additional parafoveal fixation sites; these patients may have alternated fixation between these fixation sites, as the central foveal function did not recover completely after treatment (probably due to loss of foveal neurons secondary to severe ischaemia). Clinical trials further investigating the safety and efficacy of intravitreal auto-BMHSC are ongoing, and the results of these trials will facilitate an understanding of the potential role of auto-BMHSC for ischaemic retinopathy.