Rebecca L Wilson, Jenna Kropp Schmidt, Baylea N Davenport, Emily Ren, Logan T Keding, Sarah A Shaw, Michele L Schotzko, Kathleen M Antony, Heather A Simmons, Thaddeus G Golos, Helen N Jones
{"title":"非人灵长类动物母体、胎盘和胎儿对非病毒聚合纳米粒子基因疗法的反应。","authors":"Rebecca L Wilson, Jenna Kropp Schmidt, Baylea N Davenport, Emily Ren, Logan T Keding, Sarah A Shaw, Michele L Schotzko, Kathleen M Antony, Heather A Simmons, Thaddeus G Golos, Helen N Jones","doi":"10.1101/2023.06.16.545278","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Currently, there are no placenta-targeted treatments to alter the <i>in utero</i> environment. Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human <i>insulin-like 1 growth factor</i> ( <i>IGF1</i> ) transgene to correct placental insufficiency in small animal models of fetal growth restriction (FGR). Our goal was to extend these studies to the pregnant nonhuman primate (NHP) and assess maternal, placental and fetal responses to nanoparticle-mediated <i>IGF1</i> treatment.</p><p><strong>Methods: </strong>Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles ( <i>GFP-</i> or <i>IGF1-</i> expressing plasmid under the control of the trophoblast-specific <i>PLAC1</i> promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h ( <i>GFP</i> ; n =1), 48 h ( <i>IGF1</i> ; n = 3) or 10 days ( <i>IGF1</i> ; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues, and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4) and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using western blot and qPCR.</p><p><strong>Findings: </strong>Fluorescent microscopy and in situ hybridization confirmed placental uptake and transgene expression in villous syncytiotrophoblast. No off-target expression was observed in maternal and fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the <i>IGF1</i> nanoparticle treatment. In maternal blood, CBCs, P4 and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 d after <i>IGF1</i> nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent over activity in the normal pregnancy environment.</p><p><strong>Interpretation: </strong>Maternal toxicity profile analysis and lack of adverse reaction to nanoparticle-mediated <i>IGF1</i> treatment, combined with changes in placental signaling to maintain homeostasis indicates no deleterious impact of treatment.</p><p><strong>Funding: </strong>National Institutes of Health, and Wisconsin National Primate Research Center.</p>","PeriodicalId":47568,"journal":{"name":"Body & Society","volume":"14 1","pages":""},"PeriodicalIF":0.9000,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10760006/pdf/","citationCount":"0","resultStr":"{\"title\":\"Maternal, placental and fetal response to a non-viral, polymeric nanoparticle gene therapy in nonhuman primates.\",\"authors\":\"Rebecca L Wilson, Jenna Kropp Schmidt, Baylea N Davenport, Emily Ren, Logan T Keding, Sarah A Shaw, Michele L Schotzko, Kathleen M Antony, Heather A Simmons, Thaddeus G Golos, Helen N Jones\",\"doi\":\"10.1101/2023.06.16.545278\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Currently, there are no placenta-targeted treatments to alter the <i>in utero</i> environment. Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human <i>insulin-like 1 growth factor</i> ( <i>IGF1</i> ) transgene to correct placental insufficiency in small animal models of fetal growth restriction (FGR). Our goal was to extend these studies to the pregnant nonhuman primate (NHP) and assess maternal, placental and fetal responses to nanoparticle-mediated <i>IGF1</i> treatment.</p><p><strong>Methods: </strong>Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles ( <i>GFP-</i> or <i>IGF1-</i> expressing plasmid under the control of the trophoblast-specific <i>PLAC1</i> promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h ( <i>GFP</i> ; n =1), 48 h ( <i>IGF1</i> ; n = 3) or 10 days ( <i>IGF1</i> ; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues, and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4) and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using western blot and qPCR.</p><p><strong>Findings: </strong>Fluorescent microscopy and in situ hybridization confirmed placental uptake and transgene expression in villous syncytiotrophoblast. No off-target expression was observed in maternal and fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the <i>IGF1</i> nanoparticle treatment. In maternal blood, CBCs, P4 and E2 remained within the normal range for pregnant macaques across the treatment period. 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Maternal, placental and fetal response to a non-viral, polymeric nanoparticle gene therapy in nonhuman primates.
Background: Currently, there are no placenta-targeted treatments to alter the in utero environment. Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like 1 growth factor ( IGF1 ) transgene to correct placental insufficiency in small animal models of fetal growth restriction (FGR). Our goal was to extend these studies to the pregnant nonhuman primate (NHP) and assess maternal, placental and fetal responses to nanoparticle-mediated IGF1 treatment.
Methods: Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles ( GFP- or IGF1- expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h ( GFP ; n =1), 48 h ( IGF1 ; n = 3) or 10 days ( IGF1 ; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues, and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4) and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using western blot and qPCR.
Findings: Fluorescent microscopy and in situ hybridization confirmed placental uptake and transgene expression in villous syncytiotrophoblast. No off-target expression was observed in maternal and fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4 and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 d after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent over activity in the normal pregnancy environment.
Interpretation: Maternal toxicity profile analysis and lack of adverse reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis indicates no deleterious impact of treatment.
Funding: National Institutes of Health, and Wisconsin National Primate Research Center.
期刊介绍：
Body & Society has from its inception in March 1995 as a companion journal to Theory, Culture & Society, pioneered and shaped the field of body-studies. It has been committed to theoretical openness characterized by the publication of a wide range of critical approaches to the body, alongside the encouragement and development of innovative work that contains a trans-disciplinary focus. The disciplines reflected in the journal have included anthropology, art history, communications, cultural history, cultural studies, environmental studies, feminism, film studies, health studies, leisure studies, medical history, philosophy, psychology, religious studies, science studies, sociology and sport studies.
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