# In vivo investigation of PKD1 upstream open reading frames as a therapeutic target in autosomal dominant polycystic kidney disease

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $423,535

## Abstract

Project Summary:
Autosomal dominant polycystic kidney disease (ADPKD) affects over 12 million people worldwide resulting in
fluid-filled cysts in the kidney and liver and 5-10% of all kidney failure. The one FDA-approved therapy provides
only a modest delay in ongoing growth of cysts in the kidney and liver that can progress to kidney failure and
devastating abdominal pain. Approximately one third of ADPKD patients have non-truncating mutations in the
primary disease gene PKD1/Polycystin-1(PC1), and a significant subset of these likely encode a version of
PC1 that is pathogenic because of a quantitative rather than qualitative deficit at its site of action on the cell
surface due to inefficient maturation of PC1. PC1 “dosage”—the functional amount of PC1 protein at its site of
action—correlates with disease severity. Our laboratory has contributed to the identification of additional
disease genes to explain cases of symptomatic polycystic liver disease (PLD) resulting from in inefficient
maturation of PC1 in the endoplasmic reticulum (ER). Proof of concept studies using genomic alterations in
mice suggest cysts could be avoided in these patients if more PC1 was expressed. Recent studies inhibiting
microRNA 17 from repressing Pkd1 mRNA have provided benefit to a Pkd1 missense mouse model. We
hypothesize that increasing PC1 protein expression in patients with mutations in these ER genes and
in a substantial subset of patients with PKD1 non-truncating mutations in ADPKD will dramatically
reduce cyst burden.
We have identified that the 5’ untranslated region (5’UTR) of human PKD1 contains alternative sites of translation
known as upstream open reading frames (uORFs) whose translation significantly blunts the translation of PC1
from PKD1 mRNA in vitro. Our in vitro data shows that interventions to block PKD1 uORF translation results in
3-4 times more PC1 protein, and that blocking uORF translation is achievable using antisense oligonucleotides
(ASO). ASOs are approved therapies for patients with other diseases.
For this proposal we will determine the role of PKD1 uORFs on cyst formation in vivo. We have made a
novel humanized PKD1 5’UTR mouse model with or without single nucleotide edits to remove uORF initiation
codons and we will use this to test effect of uORFs in two models of ADPKD (Dnajb11 model and a Pkd1
p.R2216W model) as well as quantify effect in primary cells in different biological contexts to consider a role for
in vivo regulation. Independently, we will test our hypothesis that ASOs targeting PKD1 uORFs are effective
treatment in mouse models of ADPKD and would be—due to ability to effect translation efficiency—a unique,
specific, and additive approach to any previously proposed therapies.

## Key facts

- **NIH application ID:** 10779312
- **Project number:** 1R01DK138015-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Whitney Elise Besse
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,535
- **Award type:** 1
- **Project period:** 2023-12-15 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10779312

## Citation

> US National Institutes of Health, RePORTER application 10779312, In vivo investigation of PKD1 upstream open reading frames as a therapeutic target in autosomal dominant polycystic kidney disease (1R01DK138015-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10779312. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*