Regulatory and Ethical Issues for Phase I<i>In Utero</i>Gene Transfer Studies

Strong, Carson

doi:10.1089/hum.2011.062

Cited by 4 publications

(7 citation statements)

References 34 publications

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“…It will be necessary to design trials to make fair and appropriate use of these subject populations (Dresser, 2004; Chervenak and McCullough, 2007; Strong, 2011; Coutelle and Ashcroft, 2012). …”

Section: Moving To Humans: Questions To Considermentioning

confidence: 99%

“…However, IVF and PGD are costly, burdensome, and thus unavailable for many couples, and abortion is morally unacceptable to many and increasingly difficult to obtain for many others. Thus, these alternatives by no means eliminate the need for or the value of in utero interventions, and cannot justify failure to support in utero research (Strong, 2011 ).…”

Section: Reasons For Reluctancementioning

confidence: 99%

“…In addition, in some disorders, earlier interventions may be more effective. Characteristics of the immune system in fetuses, their size, and the opportunity to intervene at an earlier stage of illness all may help increase the effects of cell- and gene-based interventions, though much remains unknown (Niyibizi and Li, 2009 ; Strong, 2011 ).…”

Section: Reasons To Proceed (With Caution)mentioning

confidence: 99%

“…First, couples who have undertaken IVF and PGD may be willing to donate affected embryos for research rather than discarding them (Lyerly and Faden, 2007 ), and couples who have learned that their fetus is affected may be willing to participate in research prior to obtaining an abortion. It will be necessary to design trials to make fair and appropriate use of these subject populations (Dresser, 2004 ; Chervenak and McCullough, 2007 ; Strong, 2011 ; Coutelle and Ashcroft, 2012 ).…”

Section: Moving To Humans: Questions To Considermentioning

confidence: 99%

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Cell-based interventions in utero: time to reconsider

King

Iltis

2014

Front. Pharmacol.

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Section: Moving To Humans: Questions To Considermentioning

confidence: 99%

Section: Reasons For Reluctancementioning

confidence: 99%

Section: Reasons To Proceed (With Caution)mentioning

confidence: 99%

Section: Moving To Humans: Questions To Considermentioning

confidence: 99%

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Cell-based interventions in utero: time to reconsider

King

Iltis

2014

Front. Pharmacol.

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“…The two issues identified in scientific advice were firstly whether the Ad vector would damage the structure and function of the human placenta, and secondly how much, if any, of the Ad vector would cross the placental barrier between the mother and the fetus. Direct delivery of gene therapy to the fetus is currently deemed unacceptable because of concerns 24,37 . For severe early onset FGR, the proposal is to deliver gene therapy to the maternal circulation, and not to directly target the fetus.…”

mentioning

confidence: 99%

In VitroHuman Placental Studies to Support Adenovirus-MediatedVEGF-D^ΔNΔCMaternal Gene Therapy for the Treatment of Severe Early-Onset Fetal Growth Restriction

Desforges

Rogue

Pearson

et al. 2018

Human Gene Therapy Clinical Development

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Severe fetal growth restriction (FGR) affects 1 in 500 pregnancies, is untreatable, and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) is one cause. Transduction of uterine arteries in normal and FGR animal models using an adenovirus (Ad) encoding VEGF isoforms increases UBF and improves fetal growth in utero. Understanding potential adverse consequences of this therapy before first-in-woman clinical application is essential. The aims of this study were to determine whether Ad.VEGF-D (1) transfers across the human placental barrier and (2) affects human placental morphology, permeability and primary indicators of placental function, and trophoblast integrity. Villous explants from normal term human placentas were treated with Ad.VEGF-D (5 × 10 virus particles [vp]/mL), or virus formulation buffer (FB). Villous structural integrity (hematoxylin and eosin staining) and tissue accessibility (LacZ immunostaining) were determined. Markers of endocrine function (human chorionic gonadotropin [hCG] secretion) and cell death (lactate dehydrogenase [LDH] release) were assayed. Lobules from normal and FGR pregnancies underwent ex vivo dual perfusion with exposure to 5 × 10 vp/mL Ad.VEGF-D or FB. Perfusion resistance, para-cellular permeability, hCG, alkaline phosphatase, and LDH release were measured. Ad.VEGF-D transfer across the placental barrier was assessed by quantitative polymerase chain reaction in DNA extracted from fetal-side venous perfusate, and by immunohistochemistry in fixed tissue. Villous explant structural integrity and hCG secretion was maintained at all Ad.VEGF-D doses. Ad.VEGF-D perfusion revealed no effect on placental permeability, fetoplacental vascular resistance, hCG secretion, or alkaline phosphatase release, but there was a minor elevation in maternal-side LDH release. Viral vector tissue access in both explant and perfused models was minimal, and the vector was rarely detected in the fetal venous perfusate and at low titer. Ad.VEGF-D did not markedly affect human placental integrity and function in vitro. There was limited tissue access and transfer of vector across the placental barrier. Except for a minor elevation in LDH release, these test data did not reveal any toxic effects of Ad.VEGF-D on the human placenta.

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Fetal gene therapy

Waddington

Peranteau

Rahim

et al. 2023

J of Inher Metab Disea

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Fetal gene therapy was first proposed toward the end of the 1990s when the field of gene therapy was, to quote the Gartner hype cycle, at its “peak of inflated expectations.” Gene therapy was still an immature field but over the ensuing decade, it matured and is now a clinical and market reality. The trajectory of treatment for several genetic diseases is toward earlier intervention. The ability, capacity, and the will to diagnose genetic disease early—in utero—improves day by day. A confluence of clinical trials now signposts a trajectory toward fetal gene therapy. In this review, we recount the history of fetal gene therapy in the context of the broader field, discuss advances in fetal surgery and diagnosis, and explore the full ambit of preclinical gene therapy for inherited metabolic disease.

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Regulatory and Ethical Issues for Phase IIn UteroGene Transfer Studies

Cited by 4 publications

References 34 publications

Cell-based interventions in utero: time to reconsider

Cell-based interventions in utero: time to reconsider

In VitroHuman Placental Studies to Support Adenovirus-MediatedVEGF-D^ΔNΔCMaternal Gene Therapy for the Treatment of Severe Early-Onset Fetal Growth Restriction

Fetal gene therapy

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Regulatory and Ethical Issues for Phase IIn UteroGene Transfer Studies

Cited by 4 publications

References 34 publications

Cell-based interventions in utero: time to reconsider

Cell-based interventions in utero: time to reconsider

In VitroHuman Placental Studies to Support Adenovirus-MediatedVEGF-DΔNΔCMaternal Gene Therapy for the Treatment of Severe Early-Onset Fetal Growth Restriction

Fetal gene therapy

Contact Info

Product

Resources

About

In VitroHuman Placental Studies to Support Adenovirus-MediatedVEGF-D^ΔNΔCMaternal Gene Therapy for the Treatment of Severe Early-Onset Fetal Growth Restriction