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Taiwan Journal of Ophthalmology 2023Congenital aniridia is a rare genetic eye disorder characterized by the complete or partial absence of the iris from birth. Various theories and animal models have been... (Review)
Review
Congenital aniridia is a rare genetic eye disorder characterized by the complete or partial absence of the iris from birth. Various theories and animal models have been proposed to understand and explain the pathogenesis of aniridia. In the majority of cases, aniridia is caused by a mutation in the gene, which affects multiple structures within the eye. Treating these ocular complications is challenging and carries a high risk of side effects. However, emerging approaches for the treatment of aniridia-associated keratopathy, iris abnormalities, cataract abnormalities, and foveal hypoplasia show promise for improved outcomes. Genetic counseling plays a very important role to make informed choices. We also provide an overview of the newer diagnostic and therapeutic approaches such as next generation sequencing, gene therapy, silencing, and miRNA modulation.
PubMed: 38249501
DOI: 10.4103/tjo.TJO-D-23-00140 -
The Ocular Surface Jul 2023The inaugural Aniridia North America (ANA) Symposium was held on the first weekend in November 2021 in Charlottesville, VA, at the University of Virginia. The purpose of... (Review)
Review
The inaugural Aniridia North America (ANA) Symposium was held on the first weekend in November 2021 in Charlottesville, VA, at the University of Virginia. The purpose of this meeting was to bring together an international group of scientists, physicians, patient advocacy groups, and individuals with aniridia to discuss recent advances in knowledge about aniridia and other congenital eye diseases and the development of potential treatments for congenital eye disorders using personalized medicine. Leaders in several areas of eye research and clinical treatment provided a broad perspective on new research advances that impact an understanding of the causes of the damage to the eye associated with aniridia and the development of novel treatments for this and related disorders. Here we summarize the research discussed at the symposium.
Topics: Humans; PAX6 Transcription Factor; Aniridia; North America
PubMed: 37247841
DOI: 10.1016/j.jtos.2023.05.010 -
Journal of Clinical Medicine Sep 2023Childhood glaucoma is one of the most common causes of corneal opacity in childhood and is associated with various pathological corneal changes, including corneal...
BACKGROUND
Childhood glaucoma is one of the most common causes of corneal opacity in childhood and is associated with various pathological corneal changes, including corneal enlargement, corneal clouding, and edema. Congenital glaucoma (CG) may cause a decrease in vision outcomes due to corneal opacity or clouding, which is often associated with stimulus deprivation amblyopia. Therefore, to create a balance between preventing amblyopia and sustaining corneal clearance, patients with CG can be managed with early penetrating corneal transplantation surgery along with advanced glaucoma management.
AIM
To investigate the graft survival rate and factors affecting graft survival in patients with congenital glaucoma who underwent penetrating keratoplasty (PKP).
STUDY DESIGN
Cross-sectional.
MATERIALS AND METHODS
Patients with congenital glaucoma who underwent PKP were retrospectively evaluated. The associations between age, corneal diameter, presence of ocular comorbidities, concurrent ocular surgeries with corneal graft, and visual outcomes were assessed.
RESULTS
Among the 30 eyes enrolled in the study, 6 (20%) had aniridia, 6 (20%) had Axenfeld-Rieger syndrome, and 18 (60%) were diagnosed with primary congenital glaucoma. Graft survival rates were 66.6% and 63.33% at 12 and 24 months, respectively. At the end of the follow-up, the overall graft survival rate was 60%. Statistical significance was observed between patient age at the time of surgery and graft failure ( = 0.02). Graft failure was associated with a younger patient age. Functional vision was achieved in 53.3% of patients.
CONCLUSIONS
The management of congenital glaucoma and its corneal complications is a delicate issue that requires great effort. PKP in congenital glaucoma was moderately successful in the present study. To provide functional vision, PKP could be the treatment of choice.
PubMed: 37834920
DOI: 10.3390/jcm12196276 -
Biology Dec 2023Limbal stem cell deficiency (LSCD) is a pathologic condition caused by the dysfunction and destruction of stem cells, stem cell precursors and limbal cell niche in the... (Review)
Review
Limbal stem cell deficiency (LSCD) is a pathologic condition caused by the dysfunction and destruction of stem cells, stem cell precursors and limbal cell niche in the corneal epithelium, leading to severe conjunctivalization of the cornea. Etiologies for LSCD span from congenital (aniridia), traumatic (chemical or thermal injuries), autoimmune (Stevens-Johnson syndrome) and iatrogenic disease to contact lens (CL) wear. Of these, CL wear is the least understood and is often a subclinical cause of LSCD. Even with recent advances in LSCD research, limitations persist in establishing the pathogenesis and treatment guidelines for CL-induced LSCD. A literature search was conducted to include original articles containing patients with CL-induced LSCD. This review will critically discuss the complex pathophysiology behind CL-induced LSCD, the underlying risk factors and epidemiology of the disease as well as methods to obtain a diagnosis. Various treatment options will be reviewed based on proposed treatment strategies.
PubMed: 38132316
DOI: 10.3390/biology12121490 -
PLoS Biology Oct 2023The transparent corneal epithelium in the eye is maintained through the homeostasis regulated by limbal stem cells (LSCs), while the nontransparent epidermis relies on...
The transparent corneal epithelium in the eye is maintained through the homeostasis regulated by limbal stem cells (LSCs), while the nontransparent epidermis relies on epidermal keratinocytes for renewal. Despite their cellular similarities, the precise cell fates of these two types of epithelial stem cells, which give rise to functionally distinct epithelia, remain unknown. We performed a multi-omics analysis of human LSCs from the cornea and keratinocytes from the epidermis and characterized their molecular signatures, highlighting their similarities and differences. Through gene regulatory network analyses, we identified shared and cell type-specific transcription factors (TFs) that define specific cell fates and established their regulatory hierarchy. Single-cell RNA-seq (scRNA-seq) analyses of the cornea and the epidermis confirmed these shared and cell type-specific TFs. Notably, the shared and LSC-specific TFs can cooperatively target genes associated with corneal opacity. Importantly, we discovered that FOSL2, a direct PAX6 target gene, is a novel candidate associated with corneal opacity, and it regulates genes implicated in corneal diseases. By characterizing molecular signatures, our study unveils the regulatory circuitry governing the LSC fate and its association with corneal opacity.
Topics: Humans; Limbus Corneae; Cornea; Epithelium, Corneal; Transcription Factors; Cell Differentiation; Corneal Opacity
PubMed: 37856539
DOI: 10.1371/journal.pbio.3002336 -
Frontiers in Physiology 2023Long-duration spaceflight can have adverse effects on human health. One of the most common ocular conditions experienced by astronauts is dry eye disease (DED). Symptoms... (Review)
Review
Long-duration spaceflight can have adverse effects on human health. One of the most common ocular conditions experienced by astronauts is dry eye disease (DED). Symptoms of DED include feelings of eye irritation, eye strain, foreign body sensation and blurred vision. Over 30% of International Space Station expedition crew members reported irritation and foreign body sensation. We reviewed the current literature on the prevalence and mechanisms of DED in astronauts and its potential implications for long-duration spaceflight, including the influence of environmental factors, such as microgravity and fluid shift on tear film physiology in space. DED has negative effects on astronaut performance, which is why there is a need for further research into the pathophysiology and countermeasures. As an in-flight countermeasure, neurostimulation seems to be among the most promising options.
PubMed: 37929210
DOI: 10.3389/fphys.2023.1281327 -
Medical Hypothesis, Discovery &... 2023The most accurate method of intraocular lens (IOL) power calculation in cataract surgery has not been determined, and further studies are needed to reach a consensus....
BACKGROUND
The most accurate method of intraocular lens (IOL) power calculation in cataract surgery has not been determined, and further studies are needed to reach a consensus. The aim of this study was to assess publications related to IOL power calculation formulas, mapping their yearly trends, most productive authors, top publishing countries and institutions, and areas of specialization for IOL power formulas.
METHODS
We conducted a comprehensive analysis of research articles published on the topic of IOL power calculation formulas. Using PubMed, we employed appropriate search terms and filtered the results for the period of January 1, 1946, to June 28, 2023. Data were analyzed using CiteSpace, VOSviewer, and Microsoft Excel programs. The visual representations of the collected data through the use of figures was provided to demonstrate the aspects of IOL power calculation research.
RESULTS
We retrieved 5475 documents in the initial search. Analysis of these documents revealed an increase in the number of publications, from one publication in 1946 to 201 publications in 2023. The top three countries contributing to these publications were the United States, China, and Japan, collectively accounting for over 27% of the total articles. However, the two institutions with the highest contributions were located in the United Kingdom and Hungary, neither of which was among the top 10 countries in overall contributions. Overall 15 326 authors contributed to publications pertaining to IOL power calculation formulas. Among these authors, the most prolific contributors included Achim Langenbucher from Saarland University (Germany), Giacomo Savini from G.B. Bietti Foundation I.R.C.C.S. (Italy), and Kenneth J Hoffer from the University of California (United States). Saarland University emerged as the most productive institution, contributing equally to two distinct departments: the Dr. Rolf M. Schwiete Center for Limbal Stem Cell Research and Congenital Aniridia, as well as the Department of Experimental Ophthalmology. The School of Physical Science at the Open University in the United Kingdom engaged in partnership with various institutions including Eye & Laser Clinic Castrop Rauxel in Germany and Johannes Kepler University Linz in Austria. Among the top 10 keywords found in the publications were "cataract", "cataract surgery", and "intraocular lens".
CONCLUSIONS
This study represents the first scientometric analysis of publications related to IOL power calculation formulas. The study offers valuable insights into the geographic distribution, contributing authors, and emphasis of research on the IOL power calculation formulas. Further cooperation is essential to pinpoint the most suitable formula and to address gaps in our current understanding.
PubMed: 38476575
DOI: 10.51329/mehdiophthal1477 -
Ophthalmology and Therapy Aug 2023Aniridia is a rare congenital vision-loss disease caused by heterozygous variants in the PAX6 gene. There is no vision-saving therapy, but one exciting approach is to...
INTRODUCTION
Aniridia is a rare congenital vision-loss disease caused by heterozygous variants in the PAX6 gene. There is no vision-saving therapy, but one exciting approach is to use CRISPR/Cas9 to permanently correct the causal genomic variants. Preclinical studies to develop such a therapy in animal models face the challenge of showing efficacy when binding human DNA. Thus, we hypothesized that a CRISPR gene therapy can be developed and optimized in humanized mouse embryonic stem cells (ESCs) that will be able to distinguish between an aniridia patient variant and nonvariant chromosome and lay the foundation for human therapy.
METHODS
To answer the challenge of binding human DNA, we proposed the "CRISPR Humanized Minimally Mouse Models" (CHuMMMs) strategy. Thus, we minimally humanized Pax6 exon 9, the location of the most common aniridia variant c.718C > T. We generated and characterized a nonvariant CHuMMMs mouse, and a CHuMMMs cell-based disease model, in which we tested five CRISPR enzymes for therapeutic efficacy. We then delivered the therapy via lipid nanoparticles (LNPs) to alter a second variant in ex vivo cortical primary neurons.
RESULTS
We successfully established a nonvariant CHuMMMs mouse and three novel CHuMMMs aniridia cell lines. We showed that humanization did not disrupt Pax6 function in vivo, as the mouse showed no ocular phenotype. We developed and optimized a CRISPR therapeutic strategy for aniridia in the in vitro system, and found that the base editor, ABE8e, had the highest correction of the patient variant at 76.8%. In the ex vivo system, the LNP-encapsulated ABE8e ribonucleoprotein (RNP) complex altered the second patient variant and rescued 24.8% Pax6 protein expression.
CONCLUSION
We demonstrated the usefulness of the CHuMMMs approach, and showed the first genomic editing by ABE8e encapsulated as an LNP-RNP. Furthermore, we laid the foundation for translation of the proposed CRISPR therapy to preclinical mouse studies and eventually patients with aniridia.
PubMed: 37210469
DOI: 10.1007/s40123-023-00729-6 -
Survey of Ophthalmology 2023Congenital aniridia is a rare, panocular disorder with a main phenotypic characteristic of a partial or complete absence of the iris existing alongside other ocular...
Congenital aniridia is a rare, panocular disorder with a main phenotypic characteristic of a partial or complete absence of the iris existing alongside other ocular morbidities such as cataract, keratopathy, optic nerve and foveal hypoplasia, and nystagmus. The iris abnormality, however, often leads to symptoms such as photophobia, glare, and decreased visual acuity, as well as cosmetic dissatisfaction. Current management options for the iris deficit include colored iris contact lenses, corneal tattooing, and tinted contact lenses. Symptoms arising from small iris defects can be resolved with surgical management using micro-tying suture techniques such as McCannel or Siepser. Currently, larger iris defects can be treated with artificial iris implants. New prosthetic options range from colored intraocular lenses to flexible custom-made silicone iris implants. With a range of therapeutic options available and given the challenges of multiple comorbidities in aniridia, we evaluate the literature relating to the use of artificial iris implants in congenital aniridia, with a focus on the different surgical implantation techniques, the clinical outcomes achieved, complications occurred, and risk of bias of the studies included.
Topics: Humans; Visual Acuity; Aniridia; Iris; Lenses, Intraocular; Prosthesis Implantation; Vision Disorders
PubMed: 36379301
DOI: 10.1016/j.survophthal.2022.11.001