# Development of siRNA conjugates for combination treatment of acute kidney injury

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $411,750

## Abstract

PROJECT SUMMARY
Acute kidney injury (AKI) is a major unmet medical need due to the lack of effective pharmacological treatment
options and significant healthcare burden of the disease. The fact that AKI mortality remains at 50-80% and has
not improved in decades underscores the critical need for better treatments. Ischemia-reperfusion injury (IRI)
and nephrotoxic agents (e.g., cisplatin) are critical causative factors in AKI pathophysiology. IRI is a major
challenge during organ transplantation and cardiothoracic, vascular and general surgery. A wide range of
pathological processes including oxidative stress, inflammation and activation of cell death programs, such as
apoptosis and necrosis contribute to tissue injury and renal dysfunction in AKI. We have selected p53 and
CXCR4 as potential targets for combination therapies that affect important metabolic and proinflammatory
pathways in AKI. This proposal addresses the urgent need for new renoprotective treatments by developing a
novel integrated siRNA delivery platform capable of selective combined inhibition of p53 and CXCR4 in AKI. The
objective is to develop innovative polymer-siRNA conjugates for efficient and safe delivery of CXCR4 antagonist
and anti-p53 siRNA (sip53) to proximal tubule cells of the injured kidneys. To achieve the objective, we will use
polymeric CXCR4 antagonist (PCX) as the sip53 carrier and test if delivery of PCX-sip53 conjugates to CXCR4
overexpressing proximal tubule reverses ATP depletion and ameliorates inflammation, renal injury and
dysfunction. We will accomplish the overall objective by pursuing the following specific aims. In aim 1, we will
synthesize covalent PCX-siRNA conjugates using different linker chemistries and different molecular weight and
chemical composition of PCX. We will establish the conjugate safety, CXCR4 antagonism, and the ability to
deliver siRNA to proximal tubule cells due to the beneficial effect of PCX on facilitating cytoplasmic delivery of
the siRNA. In aim 2, we will validate the proximal tubule-selective delivery of the conjugates by conducting
comprehensive pharmacokinetic and biodistribution study and evaluating therapeutic efficacy in IRI and cisplatin
models of AKI in mice. In aim 3, we will assess in detail the therapeutic efficacy of the best-performing PCX-
sip53 conjugate. Using a set of mechanistic studies in wild type mice and in mice with proximal tubule-selective
p53 knockout, we will illuminate how the combined inhibition of p53 and CXCR4 ameliorates the pathophysiology
of AKI. Overall, the innovative design of the PCX-siRNA conjugates will establish a widely applicable approach
for specific delivery of therapeutic siRNA to the injured kidney. The PCX-siRNA conjugate design will also have
broader impact and serve as a prelude to efficacious treatment approaches in various other ischemic diseases
including myocardial ischemia and stroke.

## Key facts

- **NIH application ID:** 10434824
- **Project number:** 5R01DK120533-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** David Oupicky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $411,750
- **Award type:** 5
- **Project period:** 2018-09-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434824

## Citation

> US National Institutes of Health, RePORTER application 10434824, Development of siRNA conjugates for combination treatment of acute kidney injury (5R01DK120533-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434824. Licensed CC0.

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