Placenta-directed gene therapy for fetal growth restriction

Krishnan, Tara; David, Anna L.

doi:10.1016/j.siny.2017.04.005

Cited by 18 publications

(12 citation statements)

References 62 publications

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“…Differential methylation of VEGFA CpG-1 is of importance with regard to emerging preclinical research in placenta-directed gene therapy for FGR [38]. If this gene therapy would reach the clinical stage, assessment of VEGFA methylation in fetal cells derived from the maternal blood might be used to identify fetuses that could potentially benefit from placenta-directed gene therapy such as adenovirus vectors containing VEGFA .…”

Section: Discussionmentioning

confidence: 99%

Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio

et al. 2019

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Background In Fetal Growth Restriction ‘fetal programming’ may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) <1. We aimed to determine whether brain-sparing is associated with altered DNA methylation of selected genes. Methods We compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO , HIF1A , VEGFA , LEP , PHLDA2 , and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing. Results Growth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG ( VEGFA -309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs ( LEP -123, p = .049; LEP -51, p = .020). No differences in methylation were observed for the other genes. Conclusions VEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA -309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP -51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life.

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Section: Discussionmentioning

confidence: 99%

Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio

et al. 2019

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“…Placenta-directed gene therapy induces the production of a therapeutic transgenic protein for a brief period, which might be effective in the treatment of fetal growth restriction (FGR). In preclinical FGR tests, adenoviral vascular endothelial growth factor gene therapy delivered to the placenta via maternal uterine arteries increased fetal growth velocity, and placental insulin-like growth factor gene therapy may enhance glucose and amino acid transport while also increasing fetal development [22]. Gene therapy for obstetric diseases is difficult to translate from the laboratory to the clinic and requires multidisciplinary skills.…”

Section: Fetal Growth Restrictionmentioning

confidence: 99%

“…Gene therapy for obstetric diseases is difficult to translate from the laboratory to the clinic and requires multidisciplinary skills. The risks to the mother and fetus, particularly the possibility of fetal gene transfer, will impact the ethical and societal acceptability of utilizing placenta-directed gene therapy [22].…”

Section: Fetal Growth Restrictionmentioning

confidence: 99%

Intrauterine Fetal Gene Therapy: Is That the Future and Is That Future Now?

Peddi¹,

Ramesh²,

Gude³

et al. 2022

Cureus

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Researchers are looking into techniques to intervene sooner and earlier in the disease process thanks to advances in disease genetics, etiologies, and prenatal diagnosis. We conducted a literature search in PubMed-indexed journals to provide an overview of the evolution of gene therapy, rationale for prenatal gene therapy, uses and risks of gene therapy, and ethical issues following the usage of gene therapy. Recent animal research has revealed that transmitting genetic material to a growing fetus through viral and nonviral vectors is conceivable besides proving how gene-editing technology is achieved by various mechanisms that utilize zinc finger nucleases, TAL effector nucleases, and clustered short palindromic repeats-Cas9 complex. This review offers an overview of the current knowledge in the field of prenatal gene therapy, as well as potential future research avenues. In addition, it weighs the risks of prenatal gene therapy, such as oncogenesis, genetic mutation transfer from mother to child, and fetal disruption, against the expected benefits, such as preventing the development of severe early-onset illness symptoms, targeting previously inaccessible organs, and establishing tolerance to the therapeutic transgenic protein, all of which lead to permanent somatic gene correction. This review discusses the scientific, ethical, legal, and sociological implications of these groundbreaking genetic disease prevention techniques, as well as the parameters that must be satisfied for a future clinical application to be considered.

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“…However, mechanistic understanding of the causes of FGR could lead to the development of novel therapeutic approaches, such as repurposing of existing drugs 95 and gene therapy. 96 -…”

Section: Expert Reviewsmentioning

confidence: 99%

Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers

Gaccioli

Aye

Sovio

et al. 2018

American Journal of Obstetrics and Gynecology

126

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Fetal growth restriction is a major determinant of perinatal morbidity and mortality. Screening for fetal growth restriction is a key element of prenatal care but it is recognized to be problematic. Screening using clinical risk assessment and targeting ultrasound to high-risk women is the standard of care in the United States and United Kingdom, but the approach is known to have low sensitivity. Systematic reviews of randomized controlled trials do not demonstrate any benefit from universal ultrasound screening for fetal growth restriction in the third trimester, but the evidence base is not strong. Implementation of universal ultrasound screening in low-risk women in France failed to reduce the risk of complications among small-for-gestational-age infants but did appear to cause iatrogenic harm to false positives. One strategy to making progress is to improve screening by developing more sensitive and specific tests with the key goal of differentiating between healthy small fetuses and those that are small through fetal growth restriction. As abnormal placentation is thought to be the major cause of fetal growth restriction, one approach is to combine fetal biometry with an indicator of placental dysfunction. In the past, these indicators were generally ultrasonic measurements, such as Doppler flow velocimetry of the uteroplacental circulation. However, another promising approach is to combine ultrasonic suspicion of small-for-gestational-age infant with a blood test indicating placental dysfunction. Thus far, much of the research on maternal serum biomarkers for fetal growth restriction has involved the secondary analysis of tests performed for other indications, such as fetal aneuploidies. An exemplar of this is pregnancy-associated plasma protein A. This blood test is performed primarily to assess the risk of Down syndrome, but women with low first-trimester levels are now serially scanned in later pregnancy due to associations with placental causes of stillbirth, including fetal growth restriction. The development of "omic" technologies presents a huge opportunity to identify novel biomarkers for fetal growth restriction. The hope is that when such markers are measured alongside ultrasonic fetal biometry, the combination would have strong predictive power for fetal growth restriction and its related complications. However, a series of important methodological considerations in assessing the diagnostic effectiveness of new tests will have to be addressed. The challenge thereafter will be to identify novel disease-modifying interventions, which are the essential partner to an effective screening test to achieve clinically effective population-based screening.

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Placenta-directed gene therapy for fetal growth restriction

Cited by 18 publications

References 62 publications

Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio

Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio

Intrauterine Fetal Gene Therapy: Is That the Future and Is That Future Now?

Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers

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