: Corneal dystrophies represent a group of heterogeneous hereditary disorders causing progressive corneal opacification and blindness. Current corneal transplant management for corneal dystrophies faces the challenges of repeated treatments, complex surgical procedures, shortage of appropriate donor cornea, and, more importantly, graft rejection. Genetic medicine could be an alternative treatment regime to overcome such challenges. Cornea carries promising scope for a gene-based therapy involving gene supplementation, gene silencing, and gene editing in both ex vivo and in vivo platforms. In the cornea, ex vivo gene therapeutic strategies were attempted for corneal graft survival, and in vivo gene augmentation therapies aimed to prevent herpes stromal keratitis, neovascularization, corneal clouding, and wound healing. However, none of these studies followed a clinical trial–based successful outcome. CRISPR/Cas system offers a broad scope of gene editing and engineering to correct underlying genetic causes in corneal dystrophies. Corneal tissue--specific gene correction in vitro with minimal off-target effects and optimal gene correction efficiency followed by their successful surgical implantation, or in vivo CRISPR administration targeting pathogenic genes finds a way to explore therapeutic intervention for corneal dystrophies. However, there are many limitations associated with such CRISPR-based corneal treatment management. This review will look into the development of corneal gene therapy and CRISPR-based study in corneal dystrophies, associated challenges, potential approaches, and future directions.
Background Congenital hereditary endothelial dystrophy (CHED) is a rare form of corneal dystrophy caused by SLC4A11 gene variations. This study aims to find the genetic alterations in SLC4A11, in two Indian familial CHED cases with affected members n = 3 and n = 2 respectively and five sporadic CHED cases using direct sequencing, followed by in silico analysis and characterization of the identified variants. Results All three affected members of the first CHED family were identified with a novel homozygous c.1514C > G (p.Ser489Trp) variation while second family showed presence of a compound heterozygous variation c.529A > C (p.Arg161Arg) + c.2461insT (p.Val805fs). Among five sporadic cases, two showed novel changes, homozygous c.1487G > T (p.Ser480Ile) and c.620-2A > G, while the other one had previously reported homozygous c.2653C > T (p.Arg869Cys) variation. The remaining two cases did not reveal the presence of SLC4A11-related pathogenic variations. The identified variations were excluded from the Indian control (n = 80). In silico analysis using homology-based protein modeling and pathogenicity prediction tools, which revealed these alterations as pathogenic, changing their protein stability, local flexibility, residue contact clashes, and the hydrogen bond interactions. Conclusions This study contributed to the CHED mutational spectrum, adding four novel variations and confirming a previously reported one. It demonstrates different type of variations in CHED cases, including coding, non-coding, homozygous, synonymous, and compound heterozygous variations. The identified variations revealed different degrees of pathogenic effects in silico. Moreover, two sporadic cases could not be identified with pathogenic variation emphasizing the involvement of other genes or genetic mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02521-4.
Dry eye disease (DED) is an emerging global health concern with meibomian gland dysfunction (MGD) being the most common subtype of DED. Despite being quite prevalent, the pathophysiological mechanisms governing MGD are poorly understood. Animal models for MGD can be a valuable resource to advance our understanding of this entity and explore novel diagnostic and therapeutic modalities. Although a lot of literature on rodent MGD models exists, a comprehensive review on rabbit animal models is lacking. Rabbits offer a great advantage over other animals as models for studying both DED and MGD. Rabbits have a widely exposed ocular surface and meibomian gland anatomy comparable with humans, which makes performing dry eye diagnostic tests possible using clinically validated imaging platforms. The existing MGD models in rabbits can broadly be classified as pharmacologically induced and surgically induced models. Most models show keratinization of the meibomian gland orifice with plugging as the final common pathway for developing MGD. Thus, understanding the advantages and disadvantages of each rabbit MGD model can help researchers choose the appropriate experimental plan based on the objective of the study. In this review, we discuss the comparative anatomy of the meibomian glands in humans and rabbits, various rabbit models of MGD, translational applications, unmet needs, and future directions in developing MGD models in rabbits.
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