MSCs in treatment Retinal Diseases

The retina contains millions of light-sensitive cells (rods and cones) and other nerve cells that receive and organize visual information, retina sends this information to your brain through your optic nerve, enabling you to see [1]. Retinal diseases are diverse, but most can affect any part of the retina [2]. Retinal diseases can affect any part of your retina, a thin layer of tissue on the inside back wall of your eye [1]. Treatment is available for some retinal diseases. Depending on your condition, treatment goals may be to stop or slow the disease and preserve, improve, or restore your vision. Untreated, some retinal diseases can cause severe vision loss or blindness [3].

The treatment of several retinal diseases has been the subject of extensive research on Mesenchymal Stem Cells (MSCs). The therapeutic potential of MSCs lies in its ability to differentiate into multiple lineages and secretome enriched with immunomodulatory, anti-angiogenic, and neurotrophic factors. Several studies have reported the role of MSCs in repair and regeneration of the damaged retina, where the secreted factors from MSCs prevent retinal degeneration, improve retinal morphology and function. [3] Based on some promising results obtained from preclinical studies, several clinical trials have been initiated to explore the potential benefits of MSCs in the treatment of retinal diseases.

Retinal Disease characteristics

Retinal diseases vary widely, but most of them cause visual symptoms. Common retinal diseases such as diabetic retinopathy (DR), retinal tear (RT), macular degeneration (AMD), retinal detachment (RDs) [4]. Retinopathy can affect any part of the retina, including the macula, the central part of the retina. Many retinal diseases cause symptoms that affect vision, and many patients can become blind or have poor vision if not treated [3]. There are many causes of retinal diseases that can be influenced by age, environmental factors, and family [5]. However, the most common symptoms include Usher syndrome, Stargardt disease and retinitis pigmentosa, various types of eye damage, diabetes and high blood pressure or certain types of retinal damage, such as retinitis. Because of cytomegalovirus, occurring after infection [6].

The current goal in treating diseases that cause corneal damage is to stop or slow the progression of the disease and restore vision [3]. Including invasive surgeries and the use of drugs for treatment and recovery after surgery [4].

However, sometimes the disease does not have a positive outcome and causes side effects and in some disease groups, such as macular degeneration, it may not be cured [5]. Cell therapy using mesenchymal stem cells (MSCs) is a recent approach that has surprising effects on retinal diseases [3].

Mesenchymal stem cells (MSCs) and their potential in treating retinal diseases

Researchers successfully isolated mesenchymal stem cells (MSCs) from various tissue sources, such as bone marrow, adipose tissue, dental pulp, umbilical cord blood, and amniotic membrane. They considered these cells as promising candidates for therapy to regenerate and repair degenerated retinal cells in several retinal degenerative disorders [7]. The important reasons for considering MSCs as a suitable option for treatment of retinal disorders are, first, the paracrine signaling through secretion of neurotrophic factors for repair of neuro-retinal cells, second, MSCs possess immunomodulatory properties that can dampen the pro-inflammatory microenvironment common to the retinal degenerative diseases and third, their ability to secrete anti-angiogenic factors to inhibit the pro-angiogenesis involved in the etiology of certain ocular diseases [8]. Several cell therapy approaches were aimed at augmenting endogenous retinal regeneration by retinal pigment epithelium (RPE) cells and mϋller glial cells, as well as cell replacement therapy through mesenchymal stem cells [3].

In addition, paracrine neuroprotective factors of mesenchymal stem cell have also been mentioned to provide potential for retinal repair and regeneration characterized by exosome secretion and mitochondria transfer into host cells. The secretome of bone marrow derived mesenchymal stem cells (BMSCs) contain an array of neurotrophic factors (NTFs) such as ciliary neurotrophic factor (CNTF), BDNF, glial cell derived neurotrophic factor (GDNF), platelet derived growth factor (PDGF), nerve growth factor (NGF), neurotrophin-3, 4/5 (NT-3, 4/5) [9], insulin-like growth factor 1 (IGF1), basic Fibroblast growth factor (FGF2), PEDF and erythropoietin (EPO) [10]. The signaling pathways activated by the NTFs, such as P13K/AKT, P13K/IAP, PLC/IP3/PKC, MAPK/ERK and JAK/STAT3 have a neuroprotective effect on the neuro-retinal cells [11].

As BMSC, Ezquer et al found that intravitreal administration of murine ADSCs resulted in a significant increase in intraocular levels of NGF, FGF2 and GDNF, prevented RGC loss and reduced oxidative stress in the retina in a diabetic mouse model [3]. In addition, the injected cells also differentiated into RGCs, astrocytes and pericyte in vivo [12]. Further, conditioned media from human ADSCs protected RPE and photoreceptor cells from oxidative stress mediated cell death and inhibited retinal damage in vitro and in vivo [13].

Mead et al [13] found that human dental pulp derived mesenchymal stem cells (DPSCs) secreted higher levels of PDGF, NGF and prostaglandin E2 receptor (PGE2R) than human BMSCs and ADSCs [13]. Further, DPSCs transplantation resulted in significantly high number of brain specific transcription factor 3a (Brn3a) positive RGCs, increased retinal nerve fibre layer thickness and improved RGC function in an open-angle glaucomatous preclinical model [14].

Clinical trials

In a case report of SCOTS (Stem cell ophthalmology treatment study) clinical trial [3], a patient suffering from autoimmune optic neuropathy prone to relapse, underwent a vitrectomy and intra-optic injection of autologous BMSCs in the right eye along with retrobulbar, sub-tenon and intravitreal injection of the same cells in the left eye. Significant improvement in visual acuity and visual field was observed 3 months and 6 months after the treatment [15]. In another SCOTS trial, a patient suffering from idiopathic optic neuropathy resulting in significant loss of central vision for approximately 5 years received retrobulbar, sub-tenon and intravitreal injection of autologous BMSCs in the right eye. They performed vitrectomy and intra-optic nerve injection of the same cells on the left eye, followed by intravenous infusion. The enhancement of visual acuity in both eyes remained stable when examined 12 months post-operation [16].

Weiss and Levy conducted a SCOTS clinical trial in 17 patients suffering from bilateral vision loss because of progressive RP with autologous BMSCs transplantation. A 6 months followup found an improvement in visual acuity in 11 out of 17 patients (64.7%), 8 patients (35.3%) exhibited stability in their condition and none experienced vision loss. This study also found that the ability of the eyes to respond to cell therapy was irrespective of the duration of the disease [17].

However, Satarian et al [18] reported that intravitreal injection of autologous BMSCs in three patients suffering from advanced RP, resulted in an improvement in visual acuity in only two of the patients, whereas the third patient developed severe and progressive adverse effects.

In a clinical trial involving 12 AMD patients, Limoli et al administered autologous adipocytes along with ADSCs obtained from stromal vascular fraction (SVF) and platelet rich plasma (PRP) between choroid and sclera and found a significant improvement in retinal functionality as observed by increased electroretinogram (ERG) values [19]

In the next phase of the trial, ADSCs along with PRP was administered in suprachoroidal space of 36 eyes involving 25 AMD patients. Six months follow up showed that 19 out of 36 (52.78%) eyes exhibited better vision, 14 eyes (38.89%) showed no change in functionality, and the condition of three eyes (8.33%) worsened. Patients with greater retinal thickness before the treatment showed greater improvement in vision. This suggests that a high number of residual cells can interact with paracrine factors secreted by ADSCs and chorioretinal cell membrane receptors, leading to an enhancement in vision quality [19].

Oner et al tested the safety and efficacy of subretinal implantation of ADSCs in 11 patients suffering from end-stage RP and found neither improvement nor adverse effects in most of the patients. However, five patients in the study group experienced ocular complication and one patient suffered from CNV [20].

In another phase II study, Oner et al found an improvement in visual acuity, visual field and multifocal electroretinography (mf-ERG) readings after suprachoroidal ADSCs implantation in patients with dry AMD (4 patients) and Stargardt’s macular dystrophy (SMD, 4 patients). During the 6 months follow up, no ocular or systemic complications were observed in these patients [21].

Although MSCs possess the ability to secrete a repertoire of NTFs, modulate inflammation and angiogenesis, regenerate pericyte, and donate mitochondria, they have limited therapeutic outcomes because of poor cell survivability and self-renewal post-transplantation [22]. The source of MSCs and the age of the donor affect the differentiation and paracrine effects of MSCs. For example, ADSCs were secret VEGF, unlike BMSCs [23].

Thus, MSCs from different sources have potential benefits to treat retinal disorders, as observed in several preclinical studies and human clinical trials [3], but more research is still needed on safety and optimization for each patient’s condition with different retinal diseases.

References

[1] Yanoff M, et al., eds. Ophthalmology. 5th ed. Mosby Elsevier; 2019. https://www.clinicalkey.com. Accessed Feb. 10, 2020.

[2] Retinal Diseases – Overview. https://www.mayoclinic.org/diseases-conditions/retinal-diseases/symptoms-causes/

[3] ADAK, Sanjucta, et al. A review on mesenchymal stem cells for treatment of retinal diseases. Stem cell reviews and reports, 2021, 1-20.

[4] Complex retinal detachment: Proliferative vitreoretinopathy and giant retinal tears. American Society of Retina Specialists. https://www.asrs.org/patients/retinal-diseases/34/complex-retinal-detachment. Accessed Feb. 10, 2020.

[5] American Academy of Ophthalmology. Multiple pages reviewed. Retina (https://www.aao.org/eye-health/anatomy/retina-103). Accessed 3/18/2023.

[6] Retinal disease. https://my.clevelandclinic.org/health/diseases/24853-retinal-diseases

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[13] SUGITANI, Sou, et al. The potential neuroprotective effect of human adipose stem cells conditioned medium against light-induced retinal damage. Experimental Eye Research, 2013, 116: 254-264.

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[16] WEISS, Jeffrey N.; LEVY, Steven; MALKIN, Alexis. Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a preliminary report. Neural regeneration research, 2015, 10.6: 982.

[17] WEISS, Jeffrey N.; LEVY, Steven; BENES, Susan C. Stem Cell Ophthalmology Treatment Study: bone marrow derived stem cells in the treatment of non-arteritic ischemic optic neuropathy (NAION). Stem Cell Investigation, 2017, 4.

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[19] LIMOLI, Paolo Giuseppe, et al. Preliminary study on electrophysiological changes after cellular autograft in age-related macular degeneration. Medicine, 2014, 93.29.

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[21] ONER, Ayse, et al. Suprachoroidal adipose tissue-derived mesenchymal stem cell implantation in patients with dry-type age-related macular degeneration and Stargardt’s macular dystrophy: 6-month follow-up results of a phase 2 study. Cellular reprogramming, 2018, 20.6: 329-336.

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