Intravitreal cell therapy as protection from degenerations
Stem cells may replace some lost retinal neurons
Investigators are evaluating how cell therapy can counteract retinal diseases. Image credit: ©vipman4 – stock.adobe.com
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.
Search results
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
Results of cell therapy
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: drafernandaliedtke@unioftal.com.br
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: m.zotarelli@gmail.com
Zotarelli Filho, MD, PhD, is a professor and scientific coordinator at the Brazilian Association of Nutrology.
Fernanda Soubhia Liedtke, PhD, MsC; and Idiberto José Zotarelli Filho, PhD
References
1. Daher ID, Perez Moura MI, Saad Murad AC, et al. Major clinical findings of cellular therapy for intravitreal use in ischemic retinopathy and macular degeneration: a systematic review. MedNext 2022; doi:https://doi.org/10.54448/mdnt22311
2. Acland GM. et al. 2001. Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet. 28:92-95.
3. Frasson M. et al. 1999. Retinitis pigmentosa: rod photoreceptor rescue by a calcium-channel blocker in the rd mouse. Nat. Med. 5:1183-1187.
4. Treatment of Age-related Macular Degeneration with Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfirin.Arch Ophthalmol.1999;117:1329-1345.
5. Verterporfin in Photodynamic Therapy Study Group.Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verterporfin 2-year results of randomized clinical trial incluing lesions with occult but no classic neovascularization-VIP report.Am J Ophthalmol 2001:131:542-560.
6. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results. Ophthalmol Clin North Am. 2006 Sep;19(3):361-72.
7. Landa G, Amde W, Doshi V, Ali A, McGevna L, Gentile RC, Muldoon TO, Walsh JB, Rosen RB. Comparative Study of Intravitreal Bevacizumab (Avastin) versus Ranibizumab (Lucentis) in the Treatment of Neovascular Age-Related Macular Degeneration. Ophthalmologica. 2009 Jul 8;223(6):370- 375.
8. Mitchell P, Korobelnik JF, Lanzetta P, Holz FG, Pruente C, Schmidt- Erfurth UM, Tano Y, Wolf S. Ranibizumab (Lucentis) in neovascular agerelated macular degeneration: evidence from clinical trials. Br J Ophthalmol. 2009 May 20.
9. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. [Comment on: Arch Ophthalmol 1994 112:874- 5]
10. Rudkin AK, Lee AW, Chen CS. Central retinal artery occlusion: timing and mode of presentation. Eur J Neurol. 2009 Jun;16(6):674-7. Epub 2009 Apr 3
11. Augsburger JJ, Magargal LE: Visual prognosis following treatment of acute central retinal artery obstruction. Br J Ophthalmol 1980 Dec; 64(12): 913-7
12. Brown G: Retinal arterial occlusive disease. In: Guyer DR, ed. Retina-Vitreous-Macula. Vol. 1. WB Saunders; 1999: 271-85.
13. Chang PC, Chen WS, Lin HY, Lee HM, Chen SJ. Combined central retinal artery and vein occlusion in a patient with systemic lupus erythematosus and anti-phospholipid syndrome. Lupus. 2010 Feb;19(2):206-9. Epub 2009 Oct 30.
14. Nagy V, Takacs L, Steiber Z, Pfliegler G, Berta A. Thrombophilic screening in retinal artery occlusion patients. Clin Ophthalmol. 2008 Sep;2(3):557-61.
15. Jonas JB, Witzens-Harig M, Arseniev L, Ho AD. Intravitreal autologous bone marrow-derived mononuclear cell transplantation: a feasibility report. Acta Ophthalmol Scand. 2007 Sep 26.
16. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina 2004:S3-S19.
17. Siqueira RC, Voltarelli JC, Messias AM, Jorge R. Possible mechanisms of retinal function recovery with the use of cell therapy with bone marrow-derived stem cells. Arquivos brasileiros de oftalmologia. Sep-Oct 2010;73(5):474-479.
18. Siqueira RC, Messias A, Voltarelli JC, Scott IU, Jorge R. Intravitreal injection of autologous bone marrow-derived mononuclear cells for hereditary retinal dystrophy: a phase I trial. Retina. Jun 2011;31(6):1207-1214.
19. Siqueira RC, Messias A, Voltarelli JC, Messias K, Arcieri RS, Jorge R. Resolution of macular edema associated with retinitis pigmentosa after intravitreal use of autologous BM-derived hematopoietic stem cell transplantation. Bone marrow transplantation. Apr 2013;48(4):612-613.
20. L.Otani, A. et al. 2002. Bone marrow-derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis. Nat. Med. 8:1004- 1010.
21. Otani A, Dorrel MI,Kinder K,Moreno SK,Nusinowitz S, Banin E,. Heckenlively J, Friedlander M Clin. Invest. 2004, 114:765-774.
22. Kalka, C. et al. 2000. Vascular endothelial growth factor (165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ. Res. 86:1198-1202.
23. Banin E, Obolensky A, Idelson M, Hemo I, Reinhardtz E, Pikarsky E, Ben- Hur T, Reubinoff B. Retinal Incorporation and Differentiation of Neural Precursors Derived from Human Embryonic Stem Cells. Stem Cells. 2005 Aug 25; [Epub ahead of print]
24. Meyer JS, Katz ML, Maruniak JA, Kirk MD. Embryonic stem cell-derived neural progenitors incorporate into degenerating retina and enhance survival of host photoreceptors. Stem Cells. 2005 Aug 25; [Epub ahead of print].
25. Meyer JS, Katz ML, Kirk MD. Stem cells for retinal degenerative disorders. Ann N Y Acad Sci. 2005 May;1049:135-45.
26. Das AM, Zhao X, Ahmad I. Stem cell therapy for retinal degeneration: retinal neurons from heterologous sources. Semin Ophthalmol. 2005 Jan- Mar;20(1):3-10.
27. Minamino K, Adachi Y, Yamada H, Higuchi A, Suzuki Y, Iwasaki M, Nakano K, Koike Y, Mukaide H, Kiriyama N, Shigematsu A, Matsumura M, Ikehara SLong-term survival of bone marrow-derived retinal nerve cells in the retina. Neuroreport. 2005 Aug 22;16(12):1255-9.
