Publications by authors named "M Valeria Canto-Soler"

26 Publications

HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease.

J Clin Invest 2021 Jun;131(12)

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Therapies targeting VEGF have proven only modestly effective for the treatment of proliferative sickle cell retinopathy (PSR), the leading cause of blindness in patients with sickle cell disease. Here, we shift our attention upstream from the genes that promote retinal neovascularization (NV) to the transcription factors that regulate their expression. We demonstrated increased expression of HIF-1α and HIF-2α in the ischemic inner retina of PSR eyes. Although both HIFs participated in promoting VEGF expression by hypoxic retinal Müller cells, HIF-1 alone was sufficient to promote retinal NV in mice, suggesting that therapies targeting only HIF-2 would not be adequate to prevent PSR. Nonetheless, administration of a HIF-2-specific inhibitor currently in clinical trials (PT2385) inhibited NV in the oxygen-induced retinopathy (OIR) mouse model. To unravel these discordant observations, we examined the expression of HIFs in OIR mice and demonstrated rapid but transient accumulation of HIF-1α but delayed and sustained accumulation of HIF-2α; simultaneous expression of HIF-1α and HIF-2α was not observed. Staggered HIF expression was corroborated in hypoxic adult mouse retinal explants but not in human retinal organoids, suggesting that this phenomenon may be unique to mice. Using pharmacological inhibition or an in vivo nanoparticle-mediated RNAi approach, we demonstrated that inhibiting either HIF was effective for preventing NV in OIR mice. Collectively, these results explain why inhibition of either HIF-1α or HIF-2α is equally effective for preventing retinal NV in mice but suggest that therapies targeting both HIFs will be necessary to prevent NV in patients with PSR.
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http://dx.doi.org/10.1172/JCI139202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203455PMC
June 2021

Immunologic Rejection of Transplanted Retinal Pigmented Epithelium: Mechanisms and Strategies for Prevention.

Front Immunol 2021 12;12:621007. Epub 2021 May 12.

CellSight Ocular Stem Cell and Regeneration Research Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, CO, United States.

Replacement of dysfunctional retinal pigmented epithelium (RPE) with grafts derived from stem cells has the potential to improve vision for patients with retinal disorders. In fact, the potential is such that a great number of groups are attempting to realize this therapy through individual strategies with a variety of stem cell products, hosts, immunomodulatory regimen, and techniques to assess the success of their design. Comparing the findings of different investigators is complicated by a number of factors. The immune response varies greatly between xenogeneic and allogeneic transplantation. A unique immunologic environment is created in the subretinal space, the target of RPE grafts. Both functional assessment and imaging techniques used to evaluate transplants are susceptible to erroneous conclusions. Lastly, the pharmacologic regimens used in RPE transplant trials are as numerous and variable as the trials themselves, making it difficult to determine useful results. This review will discuss the causes of these complicating factors, digest the strategies and results from clinical and preclinical studies, and suggest places for improvement in the design of future transplants and investigations.
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http://dx.doi.org/10.3389/fimmu.2021.621007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153373PMC
June 2021

Retinal stem cell transplantation: Balancing safety and potential.

Prog Retin Eye Res 2020 03 5;75:100779. Epub 2019 Sep 5.

National Eye Institute, National Institutes of Health, Bethesda, MD, 90892, USA.

Stem cell transplantation holds great promise as a potential treatment for currently incurable retinal degenerative diseases that cause poor vision and blindness. Recently, safety data have emerged from several Phase I/II clinical trials of retinal stem cell transplantation. These clinical trials, usually run in partnership with academic institutions, are based on sound preclinical studies and are focused on patient safety. However, reports of serious adverse events arising from cell therapy in other poorly regulated centers have now emerged in the lay and scientific press. While progress in stem cell research for blindness has been greeted with great enthusiasm by patients, scientists, doctors and industry alike, these adverse events have raised concerns about the safety of retinal stem cell transplantation and whether patients are truly protected from undue harm. The aim of this review is to summarize and appraise the safety of human retinal stem cell transplantation in the context of its potential to be developed into an effective treatment for retinal degenerative diseases.
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http://dx.doi.org/10.1016/j.preteyeres.2019.100779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056514PMC
March 2020

Author Correction: Retinal progenitor cells release extracellular vesicles containing developmental transcription factors, microRNA and membrane proteins.

Sci Rep 2018 Oct 22;8(1):15801. Epub 2018 Oct 22.

Department of Biological Sciences, Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY, 10468, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-32118-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197281PMC
October 2018

A unique telomere DNA expansion phenotype in human retinal rod photoreceptors associated with aging and disease.

Brain Pathol 2019 01 23;29(1):45-52. Epub 2018 May 23.

Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.

We have identified a discrete, focal telomere DNA expansion phenotype in the photoreceptor cell layer of normal, non-neoplastic human retinas. This phenotype is similar to that observed in a subset of human cancers, including a large fraction of tumors of the central nervous system, which maintain their telomeres via the non-telomerase-mediated alternative lengthening of telomeres (ALT) mechanism. We observed that these large, ultra-bright telomere DNA foci are restricted to the rod photoreceptors and are not observed in other cell types. Additionally, focus-positive rod cells are dispersed homogeneously throughout the posterior retinal photoreceptor cell layer and appear to be human-specific. We examined 108 normal human retinas obtained at autopsy from a wide range of ages. These large, ultra-bright telomere DNA foci were not observed in infants before 6 months of age; however, the prevalence of focus-positive rod cells dramatically increased throughout life. To investigate associations between this phenotype and retinal pathology, we assessed adult glaucoma (N = 29) and diabetic retinopathy (N = 38) cases. Focus-positive rod cells were prominent in these diseases. When compared to the normal group, after adjusting for age, logistic regression modeling revealed significantly increased odds of falling in the high category of focus-positive rod cells for glaucoma and diabetic retinopathy. In summary, we have identified a dramatic telomere alteration associated with aging and diseases affecting the retina.
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http://dx.doi.org/10.1111/bpa.12618DOI Listing
January 2019
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