# In situ Cell Engineering for On-demand TIMP Expression in Osteoarthritis

> **NIH NIH R21** · VANDERBILT UNIVERSITY · 2021 · $118,875

## Abstract

Osteoarthritis (OA) is a prevalent degenerative joint disorder and the leading cause of disability. Presently, there
are no disease-modifying osteoarthritis drugs (DMOADs). Diagnosis and pharmacological intervention occur
mostly at a late stage, and current treatments offer only temporary, palliative relief before disease progression
necessitates joint replacement. OA prevalence is high, at roughly 27% of those over 40 years old, and occurrence
of post-traumatic OA (PTOA) is even higher (over 50%) following injury of large joints such as the knee. Given
its high incidence and predictability, PTOA has potential to be treated prophylactically, a strategy that is both
conducive to achieving disease-modifying outcomes and commercially/clinically feasible, provided treatment
offers long-term protection. We aim to achieve persistent joint protection by permanently converting cells in situ
into “on-demand” TIMP-3 “factories”, harnessing TIMP-3 as a pan-MMP inhibitor that blocks multiple aspects of
OA pathology, including cartilage degradation, angiogenesis, and inflammation. “On-demand” expression of
TIMP-3 will be achieved via a targeted and permanent gene insertion that hijacks the Mmp13 promoter. This
approach is based on a nonviral CRISPR-based nanoparticle and activates TIMP-3 expression only when
pathological (OA) stimuli are present, minimizing potential side-effects. We propose to optimize a nanoparticle
formulation for non-viral gene knock-in and quantify the therapeutic efficacy of TIMP-3 knock-in in vitro and in
vivo. This therapy has potential to avoid significant loss in quality of life for patients who experience a large joint
injury and is uniquely enabled by our team with expertise in intracellular delivery (Duvall), polymer and
nanoparticle chemistry (D’Arcy), genome editing and synthetic biology (Brunger), and PTOA biology (Hasty).

## Key facts

- **NIH application ID:** 10236032
- **Project number:** 1R21AR079245-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Jonathan Matthew Brunger
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $118,875
- **Award type:** 1
- **Project period:** 2021-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236032

## Citation

> US National Institutes of Health, RePORTER application 10236032, In situ Cell Engineering for On-demand TIMP Expression in Osteoarthritis (1R21AR079245-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10236032. Licensed CC0.

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