Targeted Nanoparticle Delivery of Placenta-specific Gene Therapy for In Utero Treatment of Fetal Growth Restriction

Date(s) - 08/29/2022
3:00 pm - 4:00 pm

Communicore, C1-009

Helen Jones, Ph.D., Associate Professor, Department of Physiology and Functional Genomics, University of Florida College of Medicine

Fetal growth restriction (FGR) occurs in 5-10% of all pregnancies in the developed world and has higher rates in the developing world. FGR contributes significantly to perinatal morbidity and mortality, primarily due to prematurity and hypoxia.  The problems of the small fetus continue well beyond the perinatal period.  Not only are these babies at increased risk of impaired cognitive development, but survivors of pregnancies complicated by fetal growth restriction are also at markedly increased risk of developing diabetes, obesity, hypertension and coronary artery disease later in life. At present, there are no treatments for FGR and the childhood and adulthood sequelae comprise a significant burden on healthcare costs worldwide. Placental insufficiency is believed to underlie the majority of idiopathic growth restriction cases and appropriate placental development, growth and function is vital for the growth and development of the fetus. Current interventions for fetal growth and the short- and long-term sequelae are extremely limited and commonly include iatrogenic preterm delivery and admittance to the NICU, a procedure that can exacerbate detrimental developmental outcomes. Therapeutic intervention during pregnancy enabling a fetus to remain in utero and on an upwards growth and developmental trajectory until term may have the potential to not only avoid a premature delivery and NICU stay but also remove predisposition to long-term sequelae in later life such as metabolic syndrome and cardiovascular disease. Water-soluble polymers have a distinguished record of clinical relevance. They have been used in the clinics and/or clinical trials for the modification of proteins, modification of liposomes, surface modification of biomaterials, and as carriers of drugs, genes, and oligonucleotides. We have demonstrate that HPMA, a water-soluble polymer is biocompatible and non-immunogenic and purified plasmid DNA containing an expression cassette for our transgene (reporter or functional) when complexed with poly[2-hydroxypropyl) methacrylamide-poly(2-(N,N-dimethylamino) ethyl methacrylate (HPMA-DMAEMA), a tertiary amine that acts as a weak base capable of being protonated at biological pH is capable of successful delivery and transgene expression in vitro and ex vivo in human trophoblast and placenta models. We have previously demonstrated that placental over-expression of IGF-1 following nanoparticle-mediated placental gene therapy in a surgically-induced mouse model of placental insufficiency can alter placental nutrient transport mechanisms and maintain appropriate fetal growth. In our current studies in the Guinea pig model of maternal nutrient restriction, we and others see robust fetal growth restriction by mid-gestation and demonstrate significant alterations to placenta, fetal development which are positively impacted by delivery of trophoblast-promoter driven IGF-1 in mid- and late gestation. Multiple treatments across latter pregnancy is able to restore normal birth weight and transcriptomic analysis of the treated placentas reveals signatures which reflect the normal placenta instead of one exposed to the maternal nutrient restriction. We have recently demonstrated robust transgene expression and downstream signaling in the nonhuman primate placenta with no evidence of immunogenic response. For targeted, venous delivery we have identified a cyclic peptide which leads to an increase in nanoparticle uptake in human placenta syncytium in vitro and shows preferential syncytial delivery in pregnant mice. While feasible to utilize this peptide in conjunction with our nanoparticle to test targeting in the nonhuman primate with delivery via the maternal circulation, the cost would be restrictive for future clinical use. Therefore, in conjunction with the in vivo studies in nonhuman primates we are utilizing recently developed AI platforms with our placental syncytium microvillous membrane proteomic data to perform in silico target identification. We have modeled the 3D structure of our cyclic peptide using Pepfold  and the structures of the 430 common proteins identified in our proteomic analysis of normal human MVM using Alphafold and are assessing the interactions between our peptide model and the proteins with a Convolutional Attention-based Neural Network for Multi-level Peptide-protein Interaction Prediction called CAMP, which includes binary peptide-protein interaction prediction and corresponding peptide binding residue identification.

Dr. Helen Jones completed her undergraduate degree in Biochemistry at the University of St. Andrews and went on to do her Ph.D. at the Rowett Research Institute and the University of Aberdeen studying regulation mechanisms of placental nutrient transfer, compensation, and stress responses. Helen then moved to the University of Cincinnati for her postdoc fellowship investigating the impact of maternal obesity on placental function. Upon completion of this she wanted to expand her research beyond just understanding the placenta in complicated pregnancies to develop in utero interventions specific to the placenta to improve its development and function. A short move (literally across the road) to the Center for Molecular Fetal Therapy at Cincinnati Children’s Hospital facilitated this in 2009, along with promotion to assistant professor and NIH funding from 2011, and in 2017 Helen became the scientific lead for the newly established Center for Fetal and Placental research.

In 2019, Helen was invited to join the Faculty at the University of Florida as an associate professor in the departments of Physiology & Ageing and Obstetrics & Gynecology and has been the Director of the Interface research program and Co-director of the Center for Research in Perinatal Outcomes since 2020.

Helen was awarded the Andree Gruslin Mid-career award by the International Federation of Placenta Associations in 2022 for her research and mentoring contributions to the field.