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The British Journal of Ophthalmology May 2024The purpose of this study was to develop a concept for predicting the effects of both discrete intraocular lens (IOL) power steps (PS) and power labelling tolerances...
PURPOSE
The purpose of this study was to develop a concept for predicting the effects of both discrete intraocular lens (IOL) power steps (PS) and power labelling tolerances (LT) on the uncertainty of the refractive outcome (REFU).
DESIGN
Retrospective non-randomised cross-sectional Monte Carlo simulation study.
METHODS
We evaluated a dataset containing 16 669 IOLMaster 700 preoperative biometric measurements. The PS and the delivery range of two modern IOLs (Bausch and Lomb enVista and Alcon SA60AT) were considered for this Monte Carlo simulation. The uncertainties from PS or LT were assumed to be normally distributed according to ±½ the IOL PS or the ISO 11979 LT. REFU was recorded and analysed for all simulations.
RESULTS
With both lenses the REFU from discrete PS ranged from 0.11 to 0.12 dpt. Due to the larger PS for low/high power lenses with the enVista/SA60AT, REFU is more dominant in initially myopic/hyperopic eyes. REFU from LT ranged from 0.18 to 0.19 dpt for both lenses. Since LT increases stepwise with IOL power, REFU is more prevalent in initially hyperopic eyes requiring high IOL power values, and for lenses with a wide delivery range towards higher powers.
CONCLUSIONS
Since surgeons and patients are typically aware of the effect of discrete PS on REFU, these might be tolerated in cataract surgery. However, REFU resulting from LT is inevitable while the true measured IOL power is not reported on the package, leading to background noise in postoperative achieved refraction.
Topics: Monte Carlo Method; Humans; Refraction, Ocular; Lenses, Intraocular; Retrospective Studies; Optics and Photonics; Eyeglasses; Cross-Sectional Studies; Biometry; Uncertainty; Prosthesis Design; Lens Implantation, Intraocular; Visual Acuity; Male; Female
PubMed: 37495264
DOI: 10.1136/bjo-2023-323921 -
Molecular Therapy. Nucleic Acids Sep 2023Congenital aniridia is a rare, pan-ocular disease causing severe sight loss, with only symptomatic intervention offered to patients. Approximately 40% of aniridia...
Congenital aniridia is a rare, pan-ocular disease causing severe sight loss, with only symptomatic intervention offered to patients. Approximately 40% of aniridia patients present with heterozygous nonsense variants in , resulting in haploinsufficiency. Translational readthrough-inducing drugs (TRIDs) have the ability to weaken the recognition of in-frame premature termination codons (PTCs), permitting full-length protein to be translated. We established induced pluripotent stem cell (iPSC)-derived 3D optic cups and 2D limbal epithelial stem cell (LESC) models from two aniridia patients with prevalent nonsense mutations. Both models show reduced PAX6 protein levels, mimicking the disease. The repurposed TRIDs amlexanox and 2,6-diaminopurine (DAP) and the positive control compounds ataluren and G418 were tested for their efficiency. Amlexanox was identified as the most promising TRID, increasing full-length PAX6 levels in both models and rescuing the disease phenotype through normalization of VSX2 and cell proliferation in the optic cups and reduction of ABCG2 protein and expression in LESCs. This study highlights the significance of patient iPSC-derived cells as a new model system for aniridia and proposes amlexanox as a new putative treatment for nonsense-mediated aniridia.
PubMed: 37483273
DOI: 10.1016/j.omtn.2023.06.016 -
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 panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive... (Review)
Review
Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive loss of corneal transparency and thereby loss of vision. Currently, there is no approved therapy to delay or prevent its progression, and clinical management is challenging because of phenotypic variability and high risk of complications after interventions; however, new insights into the molecular pathogenesis of AAK may help improve its management. Here, we review the current understanding about the pathogenesis and management of AAK. We highlight the biological mechanisms involved in AAK development with the aim to develop future treatment options, including surgical, pharmacological, cell therapies, and gene therapies.
Topics: Humans; Corneal Diseases; Aniridia; Cornea; Vision Disorders; Forecasting
PubMed: 37146692
DOI: 10.1016/j.survophthal.2023.04.003 -
Ophthalmology and Therapy Aug 2023The aim of our review article was to summarize the current literature on Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN). SJS/TEN is... (Review)
Review
The aim of our review article was to summarize the current literature on Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN). SJS/TEN is a serious, rare multi-system, immune-mediated, mucocutaneous disease with a significant mortality rate that can lead to severe ocular surface sequelae and even to bilateral blindness. Restoration of the ocular surface in acute and chronic SJS/TEN is challenging. There are only limited local or systemic treatment options for SJS/TEN. Early diagnosis, timely amniotic membrane transplantation and aggressive topical management in acute SJS/TEN are necessary to prevent long-term, chronic ocular complications. Although the primary aim of acute care is to save the life of the patient, ophthalmologists should regularly examine patients already in the acute phase, which should also be followed by systematic ophthalmic examination in the chronic phase. Herein, we summarize actual knowledge on the epidemiology, aetiology, pathology, clinical appearance and treatment of SJS/TEN.
PubMed: 37140876
DOI: 10.1007/s40123-023-00725-w -
Gene Therapy Sep 2023Recently safety concerns have been raised in connection with high doses of recombinant adeno-associated viruses (rAAV). Therefore, we undertook a series of experiments...
Recently safety concerns have been raised in connection with high doses of recombinant adeno-associated viruses (rAAV). Therefore, we undertook a series of experiments to test viral capsid (rAAV9 and rAAV-PHP.B), dose, and route of administration (intrastromal, intravitreal, and intravenous) focused on aniridia, a congenital blindness that currently has no cure. The success of gene therapy for aniridia may depend on the presence of functional limbal stem cells (LSCs) in the damaged aniridic corneas and whether rAAV can transduce them. Both these concerns were unknown, and thus were also addressed by our studies. For the first time, we report ataxia and lethality after intravitreal or intrastromal rAAV-PHP.B virus injections. We demonstrated virus escape from the eye and transduction of non-ocular tissues by rAAV9 and rAAV-PHP.B capsids. We have also shown that intrastromal and intravitreal delivery of rAAV9 can transduce functional LSCs, as well as all four PAX6-expressing retinal cell types in aniridic eye, respectively. Overall, lack of adverse events and successful transduction of LSCs and retinal cells makes it clear that rAAV9 is the capsid of choice for future aniridia gene therapy. Our finding of rAAV lethality after intraocular injections will be impactful for other researchers developing rAAV-based gene therapies.
Topics: Mice; Animals; Herpesvirus 1, Cercopithecine; Limbal Stem Cells; Cornea; Aniridia; Genetic Therapy; Genetic Vectors; Dependovirus; Transduction, Genetic
PubMed: 37072572
DOI: 10.1038/s41434-023-00400-6