# Developmental Programming of the Liver and Kidney in Fetal Growth with or without Gene Therapy

> **NIH NIH K99** · UNIVERSITY OF FLORIDA · 2023 · $89,894

## Abstract

PROJECT SUMMARY
Non-Communicable Diseases (NCDs), including cardiovascular disease, hypertension, central obesity, type 2
diabetes mellitus and respiratory disease, are responsible for 80% of adult deaths annually, and are
responsible for having the greatest impact on health adjusted life expectancy and quality of life. Fetal growth
restriction (FGR; estimated fetal weight <10th percentile), which occurs in up to 10% of pregnancies, is
associated with increased risk of developing NCDs later in life. This is potentially because FGR results in
developmental programming of fetal tissues and organs in order to adapt to the adverse conditions resulting in
FGR, which persist into adulthood but ultimately predispose physiological and metabolic dysfunction. We have
developed the use of a polymer-based, nanoparticle that facilitates non-viral gene delivery specifically to the
placenta. Our placenta-specific, nanoparticle gene therapy is capable of increasing expression of human
insulin-like growth factor 1 (hIGF1) in multiple animal and human placenta models. Importantly, our
nanoparticle gene therapy is proven to be safe to both mother and fetus. We have consistently
demonstrated that treatment increases placental glucose and amino acid transporter, and growth factor
expression in diverse models of FGR (surgically-induced, genomic manipulation, maternal nutrient restriction
(MNR)) because IGF1 is central to most mechanisms responsible for FGR associated with placental
dysfunction, and a major regulator of placental and fetal growth and development. This proposal aims to 1)
determine the impact of placental nanoparticle gene therapy treatment on developmental programming in fetal
liver and kidney in late pregnancy, in the proven guinea pig MNR model of FGR, 2) Identify the mechanisms by
which manipulating placenta signaling with nanoparticle gene therapy affect communication with fetal liver and
kidney cells in human cell culture models, and 3) investigate the long-term impact of placenta-specific
nanoparticle gene therapy on offspring liver and kidney physiology and metabolic health. Preliminary
investigations confirm that placenta-specific, nanoparticle gene therapy increased fetal weight in preexisting
FGR using the guinea pig MNR model. Furthermore, short-term placenta-specific nanoparticle gene therapy
normalizes changes associated with FGR in fetal liver gene expression and kidney collagen deposition, hereby
establishing a model in which further investigations into developmental programming of fetal organs can be
investigated. This proposal is innovative and significant as it utilizes a nanoparticle technology currently being
trialed in the treatment of cancer, but in the setting of reproductive medicine, thus generating knowledge that
will inform clinical innovation in order to set the foundation for a healthy pregnancy and lifelong wellness.

## Key facts

- **NIH application ID:** 10663585
- **Project number:** 1K99HD109458-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Rebecca L Wilson
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $89,894
- **Award type:** 1
- **Project period:** 2023-07-14 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10663585

## Citation

> US National Institutes of Health, RePORTER application 10663585, Developmental Programming of the Liver and Kidney in Fetal Growth with or without Gene Therapy (1K99HD109458-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10663585. Licensed CC0.

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