Nanoparticle-mediated delivery of placental gene therapy via uterine artery catheterization in a pregnant rhesus macaque

Jenna K Schmidt; Rebecca L Wilson; Baylea N Davenport; Timothy A Hacker; Casey Fitz; Heather A Simmons; Michele L Schotzko; Thaddeus G Golos; Helen N Jones

doi:10.1016/j.placenta.2024.09.013

Nanoparticle-mediated delivery of placental gene therapy via uterine artery catheterization in a pregnant rhesus macaque

Placenta. 2024 Sep 20:S0143-4004(24)00656-8. doi: 10.1016/j.placenta.2024.09.013. Online ahead of print.

Authors

Jenna K Schmidt¹, Rebecca L Wilson², Baylea N Davenport², Timothy A Hacker³, Casey Fitz¹, Heather A Simmons¹, Michele L Schotzko¹, Thaddeus G Golos⁴, Helen N Jones⁵

Affiliations

¹ Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA.
² Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Research in Perinatal Outcomes, College of Medicine, University of Florida, Gainesville, FL, USA.
³ Model Organisms Research Core, Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁴ Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA; Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA.
⁵ Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Research in Perinatal Outcomes, College of Medicine, University of Florida, Gainesville, FL, USA. Electronic address: jonesh@ufl.edu.

PMID: 39362807
DOI: 10.1016/j.placenta.2024.09.013

Abstract

Nanoparticles offer promise as a mechanism to non-invasively deliver targeted placental therapeutics. Our previous studies utilizing intraplacental administration demonstrate efficient nanoparticle uptake into placental trophoblast cells and overexpression of human IGF1 (hIGF1). Nanoparticle-mediated placental overexpression of hIGF1 in small animal models of placental insufficiency and fetal growth restriction improved nutrient transport and restored fetal growth. The objective of this pilot study was to extend these studies to the pregnant nonhuman primate and develop a method for local delivery of nanoparticles to the placenta via maternal blood flow from the uterine artery. Nanoparticles containing hIGF1 plasmid driven by the placenta-specific PLAC1 promoter were delivered to a mid-gestation pregnant rhesus macaque via a catheterization approach that is clinically used for uterine artery embolization. Maternal-fetal interface, fetal and maternal tissues were collected four days post-treatment to evaluate the efficacy of hIGF1 treatment in the placenta. The uterine artery catheterization procedure and nanoparticle treatment was well tolerated by the dam and fetus through the four-day study period following catheterization. Nanoparticles were taken up by the placenta from maternal blood as plasmid-specific hIGF1 expression was detected in multiple regions of the placenta via in situ hybridization and qPCR. The uterine artery catheterization approach enabled successful delivery of nanoparticles to maternal circulation in close proximity to the placenta with no concerns to maternal or fetal health in this short-term feasibility study. In the future, this delivery approach can be used for preclinical evaluation of the long-term safety and efficacy of nanoparticle-mediated placental therapies in a rhesus macaque model.

Keywords: Gene therapy; IGF1; Macaque; Nanoparticles; Placenta.

Grants and funding

R01 HD090657/HD/NICHD NIH HHS/United States