Besse, Whitney

Autosomal dominant polycystic kidney disease is the most common inherited kidney disorder and a leading monogenic cause of kidney failure. Reduction or loss of polycystin-1 and polycystin-2 function disrupts ciliary calcium signaling, elevates cyclic AMP (cAMP), reprograms cellular metabolism, and activates proliferative cascades that drive cyst expansion. Tolvaptan, a vasopressin V2 receptor antagonist, established cAMP modulation as a disease-modifying strategy but is limited by aquaretic effects and hepatotoxicity risk. This review highlights emerging therapeutic strategies in clinical trial development that extend beyond vasopressin antagonism. Gene-directed therapies aim to restore polycystin dosage, including anti–miR-17 oligonucleotides ( e.g ., farabursen) and pharmacochaperones that rescue misfolded polycystin-1 and restore trafficking in select PKD1 missense variants ( e.g ., VX-407). Paracrine signaling can be modulated with anti–pregnancy-associated plasma protein A antibodies that reduce insulin-like growth factor-1 bioavailability in cystic microenvironments. Metabolic reprogramming is targeted by agents such as metformin, bempedoic acid, glucagon-like peptide-1 receptor agonists, and structured dietary interventions. Sodium-glucose cotransporter 2 inhibitors hold theoretical promise but await definitive results from ongoing trials. A novel cAMP-lowering strategy through phosphodiesterase-4 activation is advancing toward clinical testing. Looking ahead, gene therapy, and genome editing offer the potential to raise polycystin levels above the threshold for cystogenesis, although challenges in vector capacity, kidney-specific delivery, and durability remain. Artificial intelligence–guided discovery, coupled with human organoid platforms, is accelerating therapeutic repurposing and rational combination design. Collectively, these advances signal a transition toward a layered, mechanism-guided framework in which vasopressin blockade is integrated with metabolic, other signaling, and genotype-specific therapies. As biomarkers and risk stratification tools mature, autosomal dominant polycystic kidney disease management is poised to become increasingly precise, tolerable, and effective.

Significance Statement Dominantly inherited polycystic kidney and liver phenotypes occur when epithelial cells in these organs have reduction of polycystin-1 functional dosage. In a cohort of genetically unresolved polycystic liver and kidney disease, the authors identified heterozygous loss of function mutations in ALG9 . ALG9 encodes an endoplasmic reticulum enzyme that builds N -glycans, and the authors show that Alg9 inactivation results in impaired polycystin-1 maturation. Using a novel ‘genotype-first’ approach to ascertain individuals based strictly on their ALG9 genotype from a large cohort of exome-sequenced individuals, the authors find that 7/8 (88%) of ALG9 mutation carriers over age 50 have multiple kidney cysts. Together, these findings identify ALG9 as a novel human polycystic kidney and liver disease gene and support the utility of a genotype-driven approach to candidate disease gene validation and genotype-phenotype correlation. Background Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). Methods We used whole-exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9 , and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. Results Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9 , which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. Conclusions ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.