Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of fluid-filled cysts in the kidney and end stage renal disease by the fourth or fifth decade of life. Mutations in the PKD1 gene account for 85% of all cases of ADPKD. No curative therapy exists for patients affected by this disease and an underexplored avenue for the treatment of ADPKD is the targeting of epigenetic changes that occur during cystogenesis. Limited data exists on alterations in DNA methylation that are associated with ADPKD. Given the similarities between cyst growth and neoplasia, and the fact that 2 DNA methylation inhibitors are already Food and Drug Administration-approved for the treatment of myelodysplastic syndrome, we hypothesized that global DNA methylation patterns in ADPKD would parallel that observed in neoplasia, and which may provide an opportunity to treat ADPKD with epigenetic inhibitors. To address this hypothesis, we undertook a global DNA methylation analysis of human ADPKD kidney. Methods: We generated single nucleotide resolution methylomes of cortical kidney tissue from individuals with ADPKD, and from non-ADPKD kidney tissue, using reduced representation bisulfite sequencing. Using quantitative reverse transcription polymerase chain reaction, we investigated expression of the PKD1 gene in both ADPKD and non-ADPKD kidney. Results: We have shown that ADPKD-derived genomic DNA exhibits global hypomethylation when compared with non-ADPKD kidney, a pattern commonly observed in DNA methylation studies of tumor-derived tissue. We have also identified 13 discrete regions that are significantly differentially methylated in ADPKD compared to non-ADPKD, and 8 of these are gene specific. The PKD1 gene shows an increase in methylation at the 3′ end of the gene body, but in contrast to previously published data, this is not associated with a decrease in PKD1 mRNA expression. Conclusion: This genome-scale single nucleotide resolution analysis of DNA methylation in human polycystic kidneys suggests that DNA methylation differences at specific loci are associated with ADPKD. Further exploration into the significance of these preliminary results may shed light on the disease process, and potentially reveal new therapeutic possibilities.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a heritable renal disease that results in end-stage kidney disease, due to the uncontrolled bilateral growth of cysts throughout the kidneys. While it is known that a mutation within a PKD-causing gene is required for the development of ADPKD, the underlying mechanism(s) causing cystogenesis and progression of the disease are not well understood. Limited therapeutic options are currently available to slow the rate of cystic growth. Epigenetic modifications, including DNA methylation, are known to be altered in neoplasia, and several FDA-approved therapeutics target these disease-specific changes. As there are many similarities between ADPKD and neoplasia, we (and others) have postulated that ADPKD kidneys contain alterations to their epigenetic landscape that could be exploited for future therapeutic discovery. Here we summarise the current understanding of epigenetic changes that are associated with ADPKD, with a particular focus on the burgeoning field of ADPKD-specific alterations in DNA methylation.

Autosomal dominant polycystic kidney disease (ADPKD) is a heritable disease characterized by bilateral renal enlargement due to the growth of cysts throughout the kidneys. Inheritance of a disease-causing mutation is required to develop ADPKD, which results in end-stage kidney disease and is associated with a high morbidity. The pathology underlying cyst formation is not well understood. To address this, we have previously shown the global methylome is altered in ADPKD tissue, suggesting a role of DNA methylation in disease-state renal tissue. As cysts are believed to arise independently, we hypothesize that DNA methylation changes vary accordingly. Here we further investigate the role of DNA methylation within independent cysts to characterize key intra-individual changes. We demonstrate that fragments within CpG islands and gene bodies harbor the greatest amount of variation across the ADPKD kidney, while intergenic fragments are comparatively stable. A proportion of variably methylated genes were also differentially methylated in ADPKD tissue. Our data provide evidence that individual molecular mechanisms are operating in the development of each cyst.

Polycystic kidney disease (PKD) is a significant cause of end-stage kidney failure and there are few effective drugs for treating this inherited condition. Numerous aberrantly expressed non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), may contribute to PKD pathogenesis by participating in multiple intracellular and intercellular functions through post-transcriptional regulation of protein-encoding genes. Insights into the mechanisms of miRNAs and other ncRNAs in the development of PKD may provide novel therapeutic strategies. In this review, we discuss the current knowledge about the roles of dysregulated miRNAs and other ncRNAs in PKD. These roles involve multiple aspects of cellular function including mitochondrial metabolism, proliferation, cell death, fibrosis and cell-to-cell communication. We also summarize the potential application of miRNAs as biomarkers or therapeutic targets in PKD, and briefly describe strategies to overcome the challenges of delivering RNA to the kidney, providing a better understanding of the fundamental advances in utilizing miRNAs and other non-coding RNAs to treat PKD.

Current approaches to co‐design with Māori and Pacific communities have varying success, highlighting the need for a clear and transparent understanding about the different ways that researchers and communities conceptualise and implement co‐design. This study set out to identify key elements of co‐designed research and health services important to working with, and achieving equity of health outcomes for, Māori and Pacific communities living in Aotearoa New Zealand. A qualitative evaluation of five research projects, which used co‐design with partners from Māori and Pacific communities, involved interviews with researchers and community partners. A Kaupapa Māori framework developed to assess six principles important to Māori co‐design was used, and data were coded and thematically analysed. Four additional principles of good co‐design and nine lessons for improving the conduct of co‐design research were identified. A conceptual model was developed, the Co‐design Research Integrity Poutama, which defines increasing levels of co‐design exemplified by greater levels of transparency and power‐sharing. Authentic co‐design of research and health services has a greater likelihood of achieving equitable health outcomes in Māori (the Indigenous People of Aotearoa New Zealand) and in other ethnicities experiencing similar inequities, notably Pacific Peoples, and to those experiencing racial and ethnic inequities worldwide.