Renal ciliopathies represent a collection of genetic disorders characterized by deficiencies in the biogenesis, maintenance, or functioning of the ciliary complex. These disorders, which encompass autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and nephronophthisis (NPHP), typically result in cystic kidney disease, renal fibrosis, and a gradual deterioration of kidney function, culminating in kidney failure. Here we review the advances in basic science and clinical research into ciliopathies which have yielded promising small compounds and drug targets, within both preclinical studies and clinical trials. Tolvaptan is currently the sole approved treatment option available for ADPKD patients, while no approved treatment alternatives exist for ARPKD or NPHP patients. Clinical trials are presently underway to evaluate additional medications in ADPKD and ARPKD patients. Based on preclinical models, other potential therapeutic targets for ADPKD, ARPKD, and NPHP look promising. These include molecules targeting fluid transport, cellular metabolism, ciliary signaling and cell-cycle regulation. There is a real and urgent clinical need for translational research to bring novel treatments to clinical use for all forms of renal ciliopathies to reduce kidney disease progression and prevent kidney failure.

Hepatitis C virus (HCV) is a common cause of hepatocellular carcinoma (HCC). The activation and mutagenic consequences of L1 retrotransposons in virus-associated-HCC have been documented. However, the direct influence of HCV upon L1 elements is unclear, and is the focus of the present study. L1 transcript expression was evaluated in a publicly available liver tissue RNA-seq dataset from patients with chronic HCV hepatitis (CHC), as well as healthy controls. L1 transcript expression was significantly higher in CHC than in controls. L1orf1p (a L1 encoded protein) expression was observed in six out of 11 CHC livers by immunohistochemistry. To evaluate the influence of HCV on retrotransposition efficiency, in vitro engineered-L1 retrotransposition assays were employed in Huh7 cells in the presence and absence of an HCV replicon. An increased retrotransposition rate was observed in the presence of replicating HCV RNA, and persisted in cells after viral clearance due to sofosbuvir (PSI7977) treatment. Increased retrotransposition could be due to dysregulation of the DNA-damage repair response, including homologous recombination, due to HCV infection. Altogether these data suggest that L1 expression can be activated before oncogenic transformation in CHC patients, with HCV-upregulated retrotransposition potentially contributing to HCC genomic instability and a risk of transformation that persists post-viral clearance.

Biallelic loss‐of‐function variants in TXNDC15 are a known cause of the perinatally lethal ciliopathy Meckel syndrome (MKS). TXNDC15 encodes an endoplasmic reticulum (ER)‐resident thioredoxin‐domain protein required for ciliary transition zone integrity. Many ciliopathy genes show a spectrum of severity, producing a clinical continuum from lethal MKS to the less severe Joubert syndrome (JS). Using genome and exome sequencing analysis, we identified four unrelated children with JS who harbor rare biallelic variants in TXNDC15. In contrast to the biallelic truncating variants typical of MKS, all individuals with JS carried a missense variant in trans with a truncating variant. Three of four missense variants cluster within the functionally critical thioredoxin domain. In silico structural modeling using AlphaFold and variant effect prediction (AlphaMissense, DynaMut2) support a deleterious effect on protein stability and function for the majority of these missense variants. This work expands the phenotypic spectrum of TXNDC15 ‐related ciliopathies to include JS. All four individuals carried a missense allele in trans with a truncating allele. Our findings underscore the importance of including TXNDC15 in the genetic diagnosis of JS.

Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to glycosphingolipid accumulation and progressive organ damage. Renal involvement is a major complication, yet diagnosis often requires an invasive kidney biopsy, and follow-up relies on indirect biomarkers or imaging, which lack specificity. Here, we present human urine-derived renal epithelial cells (hURECs) as a minimally invasive alternative for phenotyping renal Fabry disease and monitoring treatment response. Using hURECs from a newly diagnosed male Fabry disease patient, transmission electron microscopy (TEM) revealed lysosomal inclusions consistent with native kidney biopsy findings. Bulk RNA sequencing (RNA-seq) identified a transcriptomic disease signature, including dysregulated pathways involved in lipid metabolism homeostasis, ion transport, endoplasmic reticulum stress response, and collagen processing. Following systemic treatment of the patient with chaperone therapy, partial amelioration of the hUREC transcriptomic signature was observed during the first few months. However, by nine months, the signature began reverting toward baseline, correlating with continued kidney function decline. This prompted a transition to enzyme replacement therapy, with early evaluations showing transcriptomic stabilization. Our findings demonstrate that hURECs replicate key structural and molecular markers of renal Fabry disease and offer a non-invasive platform for longitudinal assessment of treatment response. TEM of hURECs provides a diagnostic alternative to biopsy, while RNA-seq-based transcriptomic profiling offers a sensitive and dynamic view of molecular changes, including key dysregulated pathways. This dual utility positions hURECs as a novel tool for improving the diagnosis, monitoring, and personalized management of kidney involvement in Fabry disease.