# Therapeutic rescue of Polycystin-1 protein expression by targeting PKD1 upstream open reading frames

> **NIH NIH R03** · YALE UNIVERSITY · 2023 · $125,625

## Abstract

Project Summary/Abstract
Autosomal dominant polycystic kidney disease (ADPKD) affects over 12 million people worldwide. Available
therapies provide only a slight delay in ongoing growth of fluid-filled cysts in the kidney and liver that progress
to kidney failure and in some cases devastating pain and abdominal distension. Approximately one third of
ADPKD patients have non-truncating mutations in the primary disease gene PKD1/Polycystin-1(PC1). A
significant subset of these encode a version of PC1 that fails to mature to its site of action at the cell surface
yet may be an at least partially functional PC1 protein. PC1 “dosage”—the functional amount of PC1 protein at
its site of action—correlates with disease severity. Nonetheless, feasible approaches to increase PC1 dosage
had not previously been identified to evaluate therapeutically.
We have contributed to the identification and characterization of several disease genes that encode proteins in
the endoplasmic reticulum (ER) that are necessary for PC1 maturation. Patients with mutations in these genes
also get kidney and liver cyst due to insufficient PC1 dosage, and many are in desperate need of treatmentsIn
mouse models for these genes, increasing PC1 production by increasing a mouse’s genomic copy number of
Pkd1 provides a striking rescue of cyst formation. 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 will dramatically reduce cyst burden.
We have identified, with supportive preliminary data, that the 5’ untranslated region of human PKD1 contains
likely highly relevant upstream open reading frames (uORFs). uORF translation distracts ribosomes away from
translating the intended protein. Our data suggests that blocking PKD1 uORF translation would produce a many-
fold increase in translation of PC1. Blocking uORF translation is achievable as a clinical therapy using antisense
oligonucleotides (ASO). ASOs are approved therapies for other diseases. For this proposal we will test and
characterize the effect of abolishing human PKD1 uORF translation to increase PC1 expression and
generate in vivo models for preclinical evaluation of this treatment on cystic disease severity. For our
first aim we will evaluate two independent approaches in vitro: (1) edit uORF initiation codon sequence in the
human PKD1 5’UTR using CRISPR to test the effect of uORF translation on PC1 expression, and (2) test and
optimize ASOs to characterize the effect of steric inhibition of uORF translation and RNA secondary structure
on PC1 expression. For aim 2 we will use CRISPR to humanize the 5’UTR of our epitope-tagged Pkd1-V5 mouse
with or without uORF initiation codon edits. We will test the benefit of abolished uORFs to have a clinically
meaningful effect on cyst formation and severity in our PC1 dosage-dependent mouse models and optimize
models to evaluate for preclinical therapies.

## Key facts

- **NIH application ID:** 10575251
- **Project number:** 1R03DK134793-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Whitney Elise Besse
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $125,625
- **Award type:** 1
- **Project period:** 2023-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10575251

## Citation

> US National Institutes of Health, RePORTER application 10575251, Therapeutic rescue of Polycystin-1 protein expression by targeting PKD1 upstream open reading frames (1R03DK134793-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10575251. Licensed CC0.

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