Stem cells may replace some lost retinal neurons
Two ischemic retinopathies, ie, diabetic retinopathy and retinal vein occlusion, are the most frequently occurring such diseases worldwide. Anti-VEGF therapies are the first-line treatments by blocking the VEGF pathways to improve retinal ischemia and hypoxia.
Age-related macular degeneration (AMD) affects an estimated
200 million people, and inherited retinal dystrophies result from 110 culprit genetic defects. No currently available treatment can stop progression of or reverse these diseases.
Investigators are evaluating how cell therapy can counteract these diseases. Fernanda Soubhia Liedtke, MD, from Unioftal–Ophthalmology and Eye Plastic, São José do Rio Preto, São Paulo, Brazil; and Idiberto José Zotarelli Filho, MD, from Associação Brasileira de Nutrologia/Brazilian Association of Nutrology, Catanduva, São Paulo, and the College of Palliative Medicine of Sri Lanka, Colombo, Sri Lanka, undertook a systematic review to determine the main clinical findings when bone marrow stem cells were used to treat ischemic retinopathy and AMD.1
Investigators conducted a literature search from March to June 2022 using the keywords: eye diseases, ischemic retinopathies, age-related macular degeneration, cellular therapy and bone marrow stem cell. The quality of evidence in the studies was classified as high, moderate, low or very low, according to risk of evidence bias, sample size, clarity of comparisons, precision and consistency in the effects of the analyses.
Researchers explained adult bone marrow contains hematopoietic stem cells (HSCs) that can be divided into lineage-positive and lineage-negative subpopulations, according to potential to differentiate and form blood elements.2 The latter contains progenitor cells, including those capable of becoming vascular endothelial cells.3 These cells can respond to a variety of signaling molecules and reach sites of angiogenesis in the ischemic peripheral vasculature, myocardium, or areas of induced ocular injury.
The investigators identified 235 articles involving retinitis pigmentosa, macular degeneration, and bone marrow stem cell therapy. Of these, 51 were evaluated; 28 studies were ultimately included in the review. No significant risk of bias was identified between the small sample size studies.
AMD. This disease is characterised in the early stages by changes in retinal pigment epithelium and the presence of drusen. AMD does not cause substantial visual impairment in most patients until the central or extensive forms of atrophy occur, ie, geographic or formation of choroidal neovascularisation, subretinal exudation, and macular fibrous scar with marked visual loss.
Prevalence increases with age. Ferris et al4 reported 1.6% of AMD was diagnosed in patients aged 52 to 64 and 27.9% in patients over age 75 years. The dry, atrophic, geographic or nonneovascular form occurring in 79% of patients evolves slowly. When a choroidal neovascular membrane and/or disciform scar is present, the wet exudative, disciform, or neovascular form occurs in 15.3% of AMD cases.5-9 Wet AMD is responsible for about 80% of legal blindness.10-12
No effective therapy is available for dry AMD. For the 10% with wet AMD, laser photocoagulation therapy, photodynamic therapy with verteporfin, and intravitreal antiangiogenics achieve visual stabilisation in about 67% of eyes despite high costs.4-6 Drs Liedtke and Zotarelli believe prevention is the best strategy, since AMD reduces patients’ ability to perform daily activities and is associated with a high risk of depression and social dependence.8
Ischemic retinopathies. These diseases are characterised by absent blood supply to the inner retina, resulting in visual loss. The most serious of these is retinal arterial occlusion. Arteriolar/capillary occlusion occurs in severe stages of diabetic retinopathy and retinal venous occlusion. In advanced disease, retinal ischemia includes the macular region. Visual loss is irreversible. Available treatments can only reduce complications from choroidal neovascularisation. Functional improvement is impossible.13,14
The investigators cited studies by Jonas et al15,16 who treated a patient with retinal vascular occlusion sequelae with intravitreal injection of stem cells. The authors reported the treatment was feasible and safe in humans. However, the preparation and application of intravitreal cells from the stroma-medullary fraction must be standardised.16-19
Otani et al20 injected Lin-HSCs into rats and found the cells activated astrocytes and participated in the development of angiogenesis in neonatal/adult rats with injury-induced neovascularisation. The authors also reported bone marrow-derived stem cells (Lin-HSCs) injected intravitreally 2 weeks post-natally prevented retinal vascular degeneration seen in mouse models of retinal degeneration (type rd1 and rd 10). Those authors found vascular rescue was correlated with neuronal rescue. The inner nuclear layer appeared almost normal and the outer nuclear layer containing the photoreceptors was significantly preserved with salvage of cells containing predominantly cones. In an electroretinographic study, rats responded to treatment and controls did not.21 Analysis of treated and untreated eyes showed increased expression of apoptotic genes. The findings demonstrated neurotrophic effects correlated with vasculature preservation.21
Chiou et al22 who isolated and cultured bone marrow-derived stem cells with differentiation potential reported that after 2 and 4 weeks of culture in hepatocyte induction media, stem cells differentiated into cartilage, bone, adipocytes and hepatocyte-like cells. These cells differentiated and demonstrated plasticity in differentiating into retinal cells and photoreceptor lineages.
Banin et al23 studied embryonic stem cells to treat retinal degenerative diseases, the potential to differentiate into retinal cells, and survival and integration after transplantation. The cells did differentiate into retinal cells and the subretinal medium for placing the cells offered the best results compared to the intravitreal and subretinal medium in rats. Crucially, teratoma did not develop in any samples.
Meyer et al24,25 found that intravitreally injected embryonic stem cells were incorporated into the retinal layers, underwent differentiation, and assumed the morphologic appearance of retinal neurons. Samples treated with stem cells showed greater cell survival, especially photoreceptors. The authors concluded that stem cells can protect retinal cells from degeneration and can replace some lost retinal neurons.
Das et al26 highlighted the rationale of using this therapeutic modality as an alternative with possibilities to increase the survival of degenerated cells and the repositioning of damaged cells.
Finally, Minamino et al27 showed that bone marrow-derived stem cells can differentiate into retinal cells. A new option for the intravitreal injection of stem cells previously applied retinal laser photocoagulation. In the group undergoing photocoagulation, stem cells survived longer and showed greater specificity for binding to retinal cells.
Drs Liedtke and Zotarelli concluded intravitreal injection of bone marrow-derived stem cells in a patient with retinal vascular occlusion sequelae was safe and feasible for use in humans without signs of infection, inflammation or intraocular tumor formation. Neurotrophic treatment effects were correlated with vasculature preservation, suggesting that bone marrow-derived stem cells can treat retinal degenerations and vasculopathy that currently lack effective treatment.
Fernanda Soubhia Liedtke | E: firstname.lastname@example.org
Fernanda Liedtke, MD, MsC, PhD, is president of Unioftal-Ophthalmology and Eye Plastic, Sao Jose do Rio Preto, Sao Paulo, Brazil.
Idiberto José Zotarelli Filho | E: email@example.com
Zotarelli Filho, MD, PhD, is a professor and scientific coordinator at the Brazilian Association of Nutrology.