# Targeting PHLPP to treat interval disc degeneration using surgical and drug delivery methods

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $396,162

## Abstract

PROJECT SUMMARY
The rapid increase in painful intervertebral disc (IVD) degeneration (IDD) makes it an urgent need to develop
solutions for delaying IDD progression. IDD is associated with chronic inflammation, loss of IVD cellularity,
matrix degradation and apoptosis, which are accelerated by dephosphorylation of AKT, PKC, and MAPK
signaling pathways. We present preliminary evidence that the phosphatase Pleckstrin homology domain
leucine-rich repeat protein phosphatase 1 (PHLPP1) promotes IDD. Thus global deletion of PHLPP1
repressed IDD progression in old mice by preventing matrix degradation and reducing pro-inflammatory
cytokine expression. Our preliminary data on degenerated human NP cells suggested that pro-inflammatory
responses were decreased after treatment with a small molecule PHLPP inhibitor. We previously developed
injectable, nanoformulations that are capable of delivering small molecules at constant rates over an extended
period of time. Based on these findings, our preliminary proof of concept and feasibility as well as our recent
publication, we propose to test the novel hypothesis that NP compartment specific inhibition of PHLPP1 will
delay disease progression via suppressing inflammation and matrix degradation in age-induced spontaneous
IDD.
Aim 1 will identify the role of PHLPP1 on IDD in the NP compartment in vivo using a model of age-induced
spontaneous IDD in conditional Phlpp1 knockout mice. Phlpp1 will be depleted in NP (NPcKO) and the role
of Phlpp1 will be assessed with immunohistochemical, molecular, and biomechanical methods. In vitro studies
will evaluate the differentially regulated pathways by single cell RNA-sequencing and molecular-biological
analysis of mouse NPcKO as well as PHLPP1 knockdown in human NP cells. Aim 2 will test the efficacy of a
small molecule PHLPP inhibitor to decelerate IDD by developing an injectable nanoformulation for long-term
PHLPP inhibitor release and evaluate its efficacy in a mouse model of spontaneous IDD.
This project is highly significant because discogenic backpain is a major burden in the United States. New
insights in mechanisms and minimal invasive treatments of IDD will combine mechanistic and translational
studies. This study is innovative because the development of a small molecule PHLPP inhibitor has not been
previously described and the use of NIR labeled nanoformulations for controlled PHLPP inhibitor delivery to
treat IDD is a technical innovation. Successful completion of this study will provide new insights into NP
compartment specific progression of IDD and advance small molecule PHLPP inhibitor laden nanoformulation
injection as a potential disease-modifying treatment for IDD in humans.

## Key facts

- **NIH application ID:** 10620152
- **Project number:** 5R01AR078908-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Svenja Illien-Junger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $396,162
- **Award type:** 5
- **Project period:** 2022-05-10 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620152

## Citation

> US National Institutes of Health, RePORTER application 10620152, Targeting PHLPP to treat interval disc degeneration using surgical and drug delivery methods (5R01AR078908-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10620152. Licensed CC0.

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