Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

Producción CientíficaABSTRACT: The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice. Sources include human fetal retinal stem cells, allogenic cadaveric human cells, adult hippocampal neural stem cells, human CNS stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), human pluripotent stem cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). Of these, RPCs, PSCs and MSCs have already entered early-stage clinical trials since they can all differentiate into RPE, photoreceptors or ganglion cells, and have demonstrated safety, while showing some indicators of efficacy. Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long-term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical translation of cell-based therapy, including (1) the ability to enrich for specific retinal subtypes; (2) cell survival; (3) cell delivery, which may need to incorporate a scaffold to induce correct cell polarization, which increases the size of the retinotomy in surgery and, therefore, the chance of severe complications; (4) the need to induce a localized retinal detachment to perform the subretinal placement of the transplanted cell; (5) the evaluation of the risk of tumor formation caused by the undifferentiated stem cells and prolific progenitor cells. Despite these challenges, stem/progenitor cells represent the most promising strategy for retinal and optic nerve disease treatment in the near future, and therapeutics assisted by gene techniques, neuroprotective compounds and artificial devices can be applied to fulfil clinical needs

Intravitreal stem cell paracrine properties as a potential neuroprotective therapy for retinal photoreceptor neurodegenerative diseases

Producción CientíficaAbstract: Retinal degenerations are the leading causes of irreversible visual loss worldwide. Many pathologies included under this umbrella involve progressive degeneration and ultimate loss of the photoreceptor cells, with age-related macular degeneration and inherited and ischemic retinal diseases the most relevant. These diseases greatly impact patients’ daily lives, with accompanying marked social and economic consequences. However, the currently available treatments only delay the onset or slow progression of visual impairment, and there are no cures for these photoreceptor diseases. Therefore, new therapeutic strategies are being investigated, such as gene therapy, optogenetics, cell replacement, or cell-based neuroprotection. Specifically, stem cells can secrete neurotrophic, immunomodulatory, and anti-angiogenic factors that potentially protect and preserve retinal cells from neurodegeneration. Further, neuroprotection can be used in different types of retinal degenerative diseases and at different disease stages, unlike other potential therapies. This review summarizes stem cell-based paracrine neuroprotective strategies for photoreceptor degeneration, which are under study in clinical trials, and the latest preclinical studies. Effective retinal neuroprotection could be the next frontier in photoreceptor diseases, and the development of novel neuroprotective strategies will address the unmet therapeutic needs

Pathophysiology of age-related macular degeneration: implications for treatment

Producción CientíficaABSTRACT: Age-related macular degeneration (AMD) is a complex, multifactorial, progressive retinal disease that affects millions of people worldwide and has become the leading cause of visual impairment in developed countries. The disease etiopathogenesis is not understood fully, although many triggers and processes that lead to dysfunction and degeneration of the retinal pigment epithelium (RPE) have already been identified. Thus, the lack of cellular control of oxidative stress, altered proteostasis, dysfunction of lipid homeostasis, and mitochondrial dysfunction form an internal feedback loop that causes the RPE to fail and allows accumulation of Abnormal misfolded proteins and abnormal lipids that will form drusen. An inadequate antioxidant response, deficits in autophagy mechanisms, and dysregulation of the extracellular matrix (ECM) help to increase the deposition of abnormal drusen material over time. The drusen then act as inflammatory centers that trigger chronic inflammation of the subretinal space in which microglia and recruited macrophages are also involved, and where the complement system is a key component. Choriocapillaris degeneration and nutritional influences are also classic elements recognized in the AMD pathophysiology. The genetic component of the disease is embodied in the recognition of the described risk or protective polymorphisms of some complement and ECM related genes (mainly CFH and ARMS2/HTRA1). Thus, carriers of the risk haplotype at ARMS2/HTRA1 have a higher risk of developing late AMD at a younger age. Finally, gut microbiota and epigenetics may play a role in modulating the progression to advanced AMD with the presence of local inflammatory conditions. Because of multiple implicated processes, different complex combinations of treatments will probably be the best option to obtain the best visual results; they in turn will differ depending on the type and spectrum of disease affecting individual patients or the disease stage in each patient at a specific moment. This will undoubtedly lead to personalized medicine for control and hopefully find a future cure. This necessitates the continued unraveling of all the processes involved in the pathogenesis of AMD that must be understood to devise the combinations of treatments for different concurrent or subsequent problems

Modifiable determinants of satisfaction with intravitreal treatment in patients with neovascular age-related macular degeneration

Producción CientíficaABSTRACT. BACKGROUND: The success of intravitreal treatment for neovascular age-related macular degeneration (nAMD) depends on maximal adherence to treatment, which in turn requires patient satisfaction. OBJECTIVE The aim of this study was to assess the factors associated with nAMD patient satisfaction to implement actions to improve treatment experiences and increase adherence. DESIGN This was a prospective, observational, analytical, cross-sectional study. SUBJECTS Our study included 100 consecutive nAMD patients under intravitreal treatment for at least 1 year. METHODS Patients completed the Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) and the EuroQol Visual Analog Scale (EQ VAS). A logistic regression was estimated to model the low values of the satisfaction score (MacTSQ < 50). RESULTS The mean age of patients was 82.1 ± 7.8 years and 62% were female. Males (p = 0.002) and patients who improved their visual acuity (p = 0.004) were more satisfied, while patients who received a higher number of injections (p = 0.036) and treatment in both eyes (p = 0.001) were less satisfied. Higher health-related quality of life was related to higher satisfaction. The sensitivity and specificity of the predictive model were 75.8% and 76.1%, respectively. Factors independently associated with low satisfaction were female sex (odds ratio [OR] 6.84), going to the clinic alone (OR 8.51), longer duration of treatment (OR 0.62), receiving treatment in both eyes (OR 3.54), and suffering a decline in visual acuity (OR 3.30). The questionnaire revealed patients’ needs for more information and injection points closer to their homes. CONCLUSIONS Well-defined areas for improvement were identified, i.e. to improve the information offered to each patient, to incorporate new long-acting drugs, and to establish locations for injection services in peripheral areas.This research was supported by a grant from Gerencia Regional de Salud de Castilla-León (GRS 2111/A/19). Agustín Mayo-Iscar has been partially supported by the Spanish Ministerio de Economía y Competitividad (grant MTM2017-86061-C2-1-P) and by Consejería de Educación de la Junta de Castilla y León and FEDER (grants VA005P17 and VA002G18

Impact of COVID-19 confinement on quality of life of patients with age-related macular degeneration: a two-wave panel study

Producción CientíficaABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. Intravitreal injections of antiangiogenic agents (anti-VEGF) can stop vision loss in the neovascular form of the disease (nAMD). The aim of this study was to assess the general healthrelated quality of life (HRQoL) in a cohort of patients with nAMD treated with intravitreal anti-VEGF injections and to detesrmine to what extent their HRQoL was affected by COVID-19. This was an observational, analytical, and longitudinal study performed with a two-wave panel survey. Clinical outcomes, HRQoL, and tangible support were evaluated. In the final survey, changes in living conditions and medical visits due to the COVID-19 pandemic were also examined. Of the 102 patients initially interviewed in the before-COVID survey, 24 were lost after 30 months of follow-up. In the initial assessment, the mean health index was 0.73 0.2. The EQ VAS score worsened at the final survey (p = 0.048). Patients needing treatment in both eyes (p = 0.007) and with lower levels of bilateral visual acuity (p = 0.018) reported an increase in social support at the final survey. In conclusion, patients perceived a worsening in HRQoL after confinement. However, patients enjoyed good social support that improved in the after-COVID survey.This research was supported by a grant from Gerencia Regional de Salud de Castilla- León (GRS 2111/A/19). Agustín Mayo-Iscar has been partially supported by Spanish Ministerio de Economía y Competitividad, grant MTM2017-86061-C2-1-P, and by Consejería de Educación de la Junta de Castilla y León and FEDER, grants VA005P17 and VA002G18

Reliability of colour perimetry to assess macular pigment optical density in age-related macular degeneration

Producción CientíficaABSTRACT: BACKGROUND: The aim of this study was to determine the intra-session repeatability and inter-examiner reproducibility of the colour perimetry technique when assessing in vivo macular pigment optical density in age-related macular degeneration patients. METHODS: Age-related macular degeneration patients were classified into four groups: early age-related macular degeneration, intermediate age-related macular degeneration, atrophic age-related macular degeneration and neovascular age-related macular degeneration after undergoing fundus photography (TRC 50DX type IA) and spectral-domain optical coherence tomography analysis (Topcon 3D-2000). Central fixation was confirmed in all patients using the MP-1 microperimeter (Nidek, Padua, Italy). To analyse repeatability, one examiner obtained three consecutive macular pigment optical density measures with MonCV3 device (Metrovision, Perenchies, France). To study agreement between two observers, a second examiner performed another macular pigment optical density measurement in random order. Within-subject standard deviation, coefficient of variation, and intraclass correlation coefficient data were obtained. RESULTS: Fifty two (32 females and 20 males) consecutive age-related macular degeneration patients having a mean age of 71.5 ± 8.2 years were recruited. Six had early age-related macular degeneration, 25 had intermediate age-related macular degeneration, 10 had atrophic age-related macular degeneration and 11 had neovascular age-related macular degeneration. For repeatability, coefficient of variation values ranged from 22.3% (neovascular age-related macular degeneration) to 41.0% (atrophic age-related macular degeneration) and intraclass correlation coefficient values from 0.52 (intermediate age-related macular degeneration) to 0.79 (neovascular age-related macular degeneration). For agreement between two examiners, coefficient of variation values ranged from 20.1% (intermediate age-related macular degeneration) to 37.8% (neovascular age-related macular degeneration) and intraclass correlation coefficient values from 0.61 (neovascular age-related macular degeneration) to 0.80 (atrophic age-related macular degeneration). CONCLUSION: The reliability (intra-session repeatability and inter-examiner reproducibility) of colour perimetry technique to assess macular pigment optical density in age-related macular degeneration patients is only moderate. Thus, it cannot be recommended to be performed when evaluating and monitoring age-related macular degeneration patients in the daily clinic

A new manual retinal thickness measurement protocol to evaluate high myopia patients

Producción CientíficaPurpose: To validate a manual measurement protocol for quantifying retinal thickness (RT) using an optical coherence tomography (OCT) device in pathologic myopia patients. Methods: The macular Cross Hair protocol of Stratus OCT3 (Carl Zeiss Meditec, Inc., Dublin, Calif., USA) was applied and manual RT gauging was performed using the caliper tool. Foveal and paramacular RT, located at 1 and 2 mm distances from the fovea in both vertical and horizontal scans, were measured. Three consecutive RT measurements were taken to assess measurement reliability. The within-subject coefficient of variation (CVw) and intraclass correlation coefficients (ICC) were calculated to validate the manual method. Results: The mean axial length of the 29 eyes assessed was 28.28 ± 2.72 mm and the mean spherical refraction was -13.61 ± 6.68 diopters. CVw ranged from 0.86 to 8.73% and ICC varied from 0.81 to 0.98. Conclusion: A manual RT measurement protocol could reliably be used in the daily clinic for assessing pathologic myopic patients when OCT software segmentation fails

Descriptive study of a cohort of 488 patients with inherited retinal dystrophies

Producción CientíficaABSTRACT. PURPOSE: To analyze the distribution of inherited retinal diseases (IRDs), describe the clinical characteristics of patients, and determine the percentages of patients with genetic diagnosis in the Castilla y Leon region of Spain. METHODS: All patients with an IRD seen in the two major referral units of Castilla y Leon during a 20-year period were included. The ages at symptom onset, diagnosis, and the last visit; sex; family history; history of consanguinity; type of inheritance; status of the fundus and electroretinogram findings; lens and macular status, visual acuity; and visual field data were recorded. Patients were divided into those with retinitis pigmentosa (RP) and all others. Gene mutations were gathered when available. RESULTS: Four hundred eighty-eight patients with IRDs were studied: 216 (44.26%) with RP of which 34 (15.74%) had syndromic diseases, and 272 had other conditions being 161 (59,19%) macular dystrophies. The mean delay in diagnosis was 6–16.2 years respectively. For the RP group the mean age at the last visit was 47.96±17,26; mean age of cataract surgery was 48.30 ± 12.01 years; and the foveal area was preserved in 74 (35.07%) patients, atrophic in 101 (47.87%), and edematous in 36 (17.06%). A genetic study had been performed in 58 (26.85%) of patients with RP and 71 (26,1%) of the rest, being indeterminate in 17 (29.31%) out of RP group and 20 (28.16%) out of the others. CONCLUSION: Clinical characteristics are comparable to other published series. There is a significant delay in diagnosis. The number of patients with IRDs and available genetic diagnosis, thus being possible candidates for undergoing personalized treatments including gene therapy in our region is low and must be improved

Development and evaluation of a head-mounted display system based on stereoscopic images and depth algorithms for patients with visual impairment.

Abstract: In this work, we developed a wearable system using a commercial stereoscopic head-mounted display. We compared depth first-then contour (df-tc) and contour first-then depth (cf-td) algorithms in terms of images processed per second rate versus the window size and sweep values. Likewise, we performed a comparison of several edge detection methods in the same terms. The developed technical aid was clinically tested. We evaluated the preferred walking speed and the walking speed with and without the devices during three test circuits. For comparative analysis of anxiety levels, we recorded patients’ heart rate data before, during and after the test. The system has proven its potential for enhancing the patients’ mobility and reducing the level of anxiety related to movement activities

Matrix metalloproteinases in age-related macular degeneration (AMD)

Producción CientíficaAge-related macular degeneration (AMD) is a complex, multifactorial and progressive retinal disease affecting millions of people worldwide. In developed countries, it is the leading cause of vision loss and legal blindness among the elderly. Although the pathogenesis of AMD is still barely understood, recent studies have reported that disorders in the regulation of the extracellular matrix (ECM) play an important role in its etiopathogenesis. The dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). The present review focuses on the crucial processes that occur at the level of the Bruch’s membrane, with special emphasis on MMPs, TIMPs, and the polymorphisms associated with increased susceptibility to AMD development. A systematic literature search was performed, covering the years 1990–2020, using the following keywords: AMD, extracellular matrix, Bruch’s membrane, MMPs, TIMPs, and MMPs polymorphisms in AMD. In both early and advanced AMD, the pathological dynamic changes of ECM structural components are caused by the dysfunction of specific regulators and by the influence of other regulatory systems connected with both genetic and environmental factors. Better insight into the pathological role of MMP/TIMP complexes may lead to the development of new strategies for AMD treatment and prevention