# Targeted delivery of a proangiogenic and promyogenic protein for regeneration of diabetic ischemic limbs

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $568,987

## Abstract

Program Director/Principal Investigator (Last, First, Middle): GUAN, JIANJUN
 Project Summary
 Diabetic patients with critical limb ischemia (CLI) have significantly high rates of limb amputation and mortality.
CLI is featured by extremely low blood perfusion and degenerated skeletal muscle. Accordingly, regeneration of
vasculature and skeletal muscles will salvage the limbs. Yet the poor endothelial and skeletal muscle cell survival,
and inferior cell functions under the hyperglycemia and ischemic conditions of diabetic CLI impair the limb repair.
Currently, there is no effective treatment available although growth factor therapy represents a promising strategy.
However, growth factor therapy has relatively low therapeutic efficacy in regenerating both vasculature and skeletal
muscles, as multiple growth factors are simultaneously needed for vascularization and myogenesis, and these cannot
be readily delivered by current approaches.
 In this project, we propose to use a novel TRIM72 protein with both pro-angiogenic and pro-myogenic properties
to regenerate vasculature and skeletal muscles in diabetic CLI. The TRIM72 will be engineered to have longer
retention time (slower diffusion rate) in ischemic tissue, thus exhibiting longer therapeutic effect. To deliver the
engineered TRIM72 (ETRIM72), it will be encapsulated into ischemic limb-targeting nanoparticles, followed by
delivering via clinically attractive IV injection. The nanoparticles will then predominantly accumulate in the ischemic
limbs and gradually release ETRIM72. The released protein will promote vascularization and myogenesis by (1)
improving the survival of endothelial cell and skeletal muscle cell through cell membrane repair, and activation of cell
survival kinase; and (2) stimulating endothelial cell and skeletal muscle cell migration and morphogenesis under the
hyperglycemia and ischemic conditions of diabetic CLI.
 In our preliminary studies, we have developed ETRIM72 by genetically fusing TRIM72 with peptide CSTSMLKAC
that targets ischemic environment of ischemic limbs. This first version of ETRIM72 was able to retain in the ischemic
limbs significantly longer than TRIM72. After IV injection of ischemic limb-targeting, ETRIM72-releasing nanoparticles,
the released ETRIM72 significantly promoted regeneration of both vasculature and skeletal muscles in diabetic
ischemic limbs. The function of TRIM72 in promoting vascularization and myogenesis under hyperglycemia and
ischemic conditions has not been reported before.
 Based on our preliminary studies, we hypothesize that controlled release of ETRIM72 will simultaneously increase
endothelial and skeletal muscle cell survival, migration and morphogenesis under hyperglycemia and ischemic
conditions, leading to accelerated regeneration of both vasculature and skeletal muscles in diabetic ischemic limbs.
 Aim #1 will test the hypothesis that optimal ETRIM72 release profiles will significantly promote survival, migration
and morphogene...

## Key facts

- **NIH application ID:** 10834166
- **Project number:** 5R01HL164062-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jianjun Guan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $568,987
- **Award type:** 5
- **Project period:** 2022-05-02 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834166

## Citation

> US National Institutes of Health, RePORTER application 10834166, Targeted delivery of a proangiogenic and promyogenic protein for regeneration of diabetic ischemic limbs (5R01HL164062-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10834166. Licensed CC0.

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