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New Insights into Polycystic Kidney Disease from Freedman’s Lab | ATLAS-D2K Center


New Insights into Polycystic Kidney Disease from Freedman's Lab

Apr 18, 2024

Congratulations on a new publication from Beno Freedman’s lab (Cell-specific Delivery of Novel Therapies to Enhance Glomerular Regeneration and Repair project in RBK):

Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease

Authors: Courtney E Vishy, Chardai Thomas, Thomas Vincent, Daniel K Crawford, Matthew M Goddeeris, Benjamin S Freedman

Journal: Cell Stem Cell



In polycystic kidney disease (PKD), microscopic tubules expand into macroscopic cysts. Among the world’s most common genetic disorders, PKD is inherited via heterozygous loss-of-function mutations but is theorized to require additional loss of function. To test this, we establish human pluripotent stem cells in allelic series representing four common nonsense mutations, using CRISPR base editing. When differentiated into kidney organoids, homozygous mutants spontaneously form cysts, whereas heterozygous mutants (original or base corrected) express no phenotype. Using these, we identify eukaryotic ribosomal selective glycosides (ERSGs) as PKD therapeutics enabling ribosomal readthrough of these same nonsense mutations. Two different ERSGs not only prevent cyst initiation but also limit growth of pre-formed cysts by partially restoring polycystin expression. Furthermore, glycosides accumulate in cyst epithelia in organoids and mice. Our findings define the human polycystin threshold as a surmountable drug target for pharmacological or gene therapy interventions, with relevance for understanding disease mechanisms and future clinical trials.

Browse through more RBK-related publications here.