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Abstract: TH-PO405

Delivering Nucleic Acids to ADPKD Cystic Cells via a Nucleic Acid Binding and Cell-Penetrating Antibody

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Onuchic, Laura, Yale School of Medicine, New Haven, Connecticut, United States
  • Quijano, Elias, Yale School of Medicine, New Haven, Connecticut, United States
  • Reyna-Neyra, Marcela Andrea, Yale School of Medicine, New Haven, Connecticut, United States
  • Rai, Victoria, Yale School of Medicine, New Haven, Connecticut, United States
  • Glazer, Peter M., Yale School of Medicine, New Haven, Connecticut, United States
  • Caplan, Michael J., Yale School of Medicine, New Haven, Connecticut, United States

Mutations in PKD1, which encodes polycystin-1 (PC1), cause ~78% of autosomal dominant polycystic kidney disease (ADPKD) cases. We have shown that transgenic expression of the 200-aa PC1 C-terminal tail (CTT) in the Pkd1fl/fl;Pax8rtTA;TetO-Cre (Pkd1-KO) mouse model of ADPKD suppresses cystic phenotype and preserves renal function. To overcome the challenge of delivering CTT-encoding cDNA or mRNA to cystic epithelia we used the lupus-derived antibody 3E10-D31N and its humanized version, V66. These cell-penetrating antibodies non-covalently bind and deliver nucleic acids to tumors by targeting the nucleoside transporter ENT2. Specific targeting of tumors occurs due to increased ENT2 expression in proliferative tissues.


Trial #1: one 200μg dose of 3E10-D31N labeled with fluorochrome IR700, administered to 11-week Pkd1-KO mice.
Trial #2: 3 doses of V66 (100μg/dose) combined with mRNA encoding GFP (20μg/dose), administered 24 hours apart to 13-week Pkd1-KO mice.
In vivo imaging system (IVIS) and immunofluorescence microscopy (IF) were used to assess treatment results.


IVIS imaging of Trial #1 kidneys revealed absence of fluorescently labeled 3E10-D31N in untreated controls, suggesting specificity of the total radiant efficiency (TRE) observed in treated WT and pre-cystic mice. Interestingly, treated pre-cystic mice showed an ~ 50% increase in TRE relative to treated WT, suggesting that this approach can successfully target highly proliferative ADPKD tissue.
IVIS imaging of kidneys from Trial #2 revealed GFP fluorescence only in cystic kidneys from mice that were treated with V66/GFP mRNA, and not in cystic tissue from mice that received GFP mRNA alone or untreated mice. Interestingly, a positive correlation was observed between kidney size and TRE levels. Finally, IF studies revealed GFP present in a punctate cytoplasmic pattern in cystic epithelial cells of animals that received V66/GFP mRNA and not in controls.


3E10-D31N/V66 targets cystic epithelia and delivers GFP mRNA that drives protein expression in vivo. We will next deliver CTT mRNA and assess protein expression and potential impacts of this intervention on the development of cystic phenotype. This strategy could support the delivery of other potentially therapeutic mRNAs or cDNAs in the context of other renal diseases.


  • NIDDK Support