Nonviral base editing of KCNJ13 mutation preserves vision in a model of inherited retinal channelopathy.

Clinical genome editing is emerging for rare disease treatment, but one of the major limitations is the targeting of CRISPR editors' delivery. We delivered base editors to the retinal pigmented epithelium (RPE) in the mouse eye using silica nanocapsules (SNCs) as a treatment for retinal degeneration. Leber congenital amaurosis type 16 (LCA16) is a rare pediatric blindness caused by point mutations in the KCNJ13 gene, a loss of function inwardly rectifying potassium channel (Kir7.

Human iPSC Modeling Reveals Mutation-Specific Responses to Gene Therapy in a Genotypically Diverse Dominant Maculopathy.

Dominantly inherited disorders are not typically considered to be therapeutic candidates for gene augmentation. Here, we utilized induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) to test the potential of gene augmentation to treat Best disease, a dominant macular dystrophy caused by over 200 missense mutations in BEST1. Gene augmentation in iPSC-RPE fully restored BEST1 calcium-activated chloride channel activity and improved rhodopsin degradation in an iPSC-RPE model of recessive bestrophinopathy as well as in two models of dominant Best disease caused by different mutations in regions encoding ion-binding domains.

Investigating cone photoreceptor development using patient-derived NRL null retinal organoids.

Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa.

Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines.

Numerous protocols have been described for producing neural retina from human pluripotent stem cells (hPSCs), many of which are based on the culture of 3D organoids. Although nearly all such methods yield at least partial segments of retinal structure with a mature appearance, variabilities exist within and between organoids that can change over a protracted time course of differentiation. Adding to this complexity are potential differences in the composition and configuration of retinal organoids when viewed across multiple differentiations and hPSC lines.

Generation of a rod-specific NRL reporter line in human pluripotent stem cells.

Reporter lines generated in human pluripotent stem cells can be highly useful for the analysis of specific cell types and lineages in live cultures. We created the first human rod reporter line using CRISPR/Cas9 genome editing to replace one allele of the Neural Retina Leucine zipper (NRL) gene with an eGFP transgene in the WA09 human embryonic stem cell (hESC) line. After confirming successful targeting, three-dimensional optic vesicle structures were produced to examine reporter specificity and to track rod differentiation in culture.

The surgical management of metastatic spinal tumors based on an Epidural Spinal Cord Compression (ESCC) scale.

Background Context: There have been no previous studies looking at the outcome of surgical decompression (+/-stabilization) for various grades of epidural spinal cord compression (ESCC) due to spinal metastases.

Purpose: The aim of this study was to determine the outcome of surgical treatment in patients with ESCC using the Bilsky six-point scale.

Study Design/setting: This was a retrospective cohort review of prospectively collected data.

Fast food and obesity: a spatial analysis in a large United Kingdom population of children aged 13-15.

Background: The childhood obesity epidemic is a current public health priority in many countries, and the consumption of fast food has been associated with obesity.

Purpose: This study aims to assess the relationship between fast-food consumption and obesity as well as the relationship between fast-food outlet access and consumption in a cohort of United Kingdom teenagers.

Methods: A weighted accessibility score of the number of fast-food outlets within a 1-km network buffer of the participant's residence at age 13 years was calculated.

The geography of Fast Food outlets: a review.

The availability of food high in fat, salt and sugar through Fast Food (FF) or takeaway outlets, is implicated in the causal pathway for the obesity epidemic. This review aims to summarise this body of research and highlight areas for future work. Thirty three studies were found that had assessed the geography of these outlets.