Pathophysiology of aniridia-associated keratopathy: Developmental aspects and unanswered questions.

Aniridia, a rare congenital disease, is often characterized by a progressive, pronounced limbal insufficiency and ocular surface pathology termed aniridia-associated keratopathy (AAK). Due to the characteristics of AAK and its bilateral nature, clinical management is challenging and complicated by the multiple coexisting ocular and systemic morbidities in aniridia. Although it is primarily assumed that AAK originates from a congenital limbal stem cell deficiency, in recent years AAK and its pathogenesis has been questioned in the light of new evidence and a refined understanding of ocular development and the biology of limbal stem cells (LSCs) and their niche. Here, by consolidating and comparing the latest clinical and preclinical evidence, we discuss key unanswered questions regarding ocular developmental aspects crucial to AAK. We also highlight hypotheses on the potential role of LSCs and the ocular surface microenvironment in AAK. The insights thus gained lead to a greater appreciation for the role of developmental and cellular processes in the emergence of AAK. They also highlight areas for future research to enable a deeper understanding of aniridia, and thereby the potential to develop new treatments for this rare but blinding ocular surface disease.

Abnormal neovascular and proliferative conjunctival phenotype in limbal stem cell deficiency is associated with altered microRNA and gene expression modulated by PAX6 mutational status in congenital aniridia.

PURPOSE: To evaluate conjunctival cell microRNA (miRNAs) and mRNA expression in relation to observed phenotype of progressive limbal stem cell deficiency in a cohort of subjects with congenital aniridia with known genetic status. METHODS: Using impression cytology, bulbar conjunctival cells were sampled from 20 subjects with congenital aniridia and 20 age and sex-matched healthy control subjects. RNA was extracted and miRNA and mRNA analyses were performed using microarrays. Results were related to severity of keratopathy and genetic cause of aniridia. RESULTS: Of 2549 miRNAs, 21 were differentially expressed in aniridia relative to controls (fold change ≤ -1.5 or ≥ +1.5). Among these miR-204-5p, an inhibitor of corneal neovascularization, was downregulated 26.8-fold in severely vascularized corneas. At the mRNA level, 539 transcripts were differentially expressed (fold change ≤ -2 or ≥ +2), among these FOSB and FOS were upregulated 17.5 and 9.7-fold respectively, and JUN by 2.9-fold, all being components of the AP-1 transcription factor complex. Pathway analysis revealed enrichment of PI3K-Akt, MAPK, and Ras signaling pathways in aniridia. For several miRNAs and transcripts regulating retinoic acid metabolism, expression levels correlated with keratopathy severity and genetic status. CONCLUSION: Strong dysregulation of key factors at the miRNA and mRNA level suggests that the conjunctiva in aniridia is abnormally maintained in a pro-angiogenic and proliferative state, and these changes are expressed in a PAX6 mutation-dependent manner. Additionally, retinoic acid metabolism is disrupted in severe, but not mild forms of the limbal stem cell deficiency in aniridia.

Association between HbA1c and peripheral neuropathy in a 10-year follow-up study of people with normal glucose tolerance, impaired glucose tolerance and Type 2 diabetes.

AIMS: To explore the association between HbA1c and sural nerve function in a group of people with normal glucose tolerance, impaired glucose tolerance or Type 2 diabetes. METHODS: We conducted a 10-year follow-up study in 87 out of an original 119 participants. At study commencement (2004), 64 men and 55 women (mean age 61.1 years) with normal glucose tolerance (n=39), impaired glucose tolerance (n=29), or Type 2 diabetes (n=51) were enrolled. At the 2014 follow-up (men, n=46, women, n=41; mean age 71.1 years), 36, nine and 42 participants in the normal glucose tolerance, impaired glucose tolerance and Type 2 diabetes categories, respectively, were re-tested. Biometric data and blood samples were collected, with an electrophysiological examination performed on both occasions. RESULTS: At follow-up, we measured the amplitude of the sural nerve in 74 of the 87 participants. The mean amplitude had decreased from 10.9 µV (2004) to 7.0 µV (2014; P<0.001). A 1% increase in HbA1c was associated with a ~1% average decrease in the amplitude of the sural nerve, irrespective of group classification. Crude and adjusted estimates ranged from -0.84 (95% CI -1.32, -0.37) to -1.25 (95% CI -2.31, -0.18). Although the mean conduction velocity of those measured at both occasions (n=73) decreased from 47.6 m/s to 45.8 m/s (P=0.009), any association with HbA1c level was weak. Results were robust with regard to potential confounders and missing data. CONCLUSIONS: Our data suggest an association between sural nerve amplitude and HbA1c  at all levels of HbA1c . Decreased amplitude was more pronounced than was diminished conduction velocity, supporting the notion that axonal degeneration is an earlier and more prominent effect of hyperglycaemia than demyelination.

Artificial corneas: a regenerative medicine approach.

Corneal substitutes are being developed to address the shortage of human donor tissues as well as the current disadvantages in some clinical indications, which include immune rejection. In the past few years, there have been significant developments in bioengineered corneas that are designed to replace part or the full thickness of damaged or diseased corneas that range from keratoprostheses that solely address the replacement of the cornea's function, through tissue-engineered hydrogels that permit regeneration of host tissues. We describe examples of corneal substitutes that encourage regeneration of the host tissue. We also contend that it is unlikely that there will be a single "one-size-fits-all" corneal substitute for all indications. Instead, there will most likely be a small range of corneal substitutes ranging from prostheses to tissue-engineered matrix substitutes that are tailored to different clusters of clinical indications. The tissue-engineered matrices can either be produced as sterile acellular matrices, or complete with functional cells, ready for implantation.