Organ targeted prenatal gene therapy—how far are we?

Abstract

Prenatal gene therapy aims to deliver genes to cells and tissues early in prenatal life, allowing correction of a genetic defect, before long-term tissue damage has occurred. In contrast to postnatal gene therapy, prenatal application can target genes to a large population of dividing stem cells, and the smaller fetal size allows a higher vector-to-target cell ratio to be achieved. Early-gestation delivery may allow the development of immune tolerance to the transgenic protein which would facilitate postnatal repeat vector administration if needed. Targeting particular organs will depend on manipulating the vector to achieve selective tropism and on choosing the most appropriate gestational age and injection method for fetal delivery. Intra-amniotic injection reaches the skin, and other organs that are bathed in the fluid however since gene transfer to the lung and gut is usually poor more direct injection methods will be needed. Delivery to the liver and blood can be achieved by systemic delivery via the umbilical vein or peritoneal cavity. Gene transfer to the central nervous system in the fetus is difficult but newer vectors are available that transduce neuronal tissue even after systemic delivery.

Placenta-directed gene therapy for fetal growth restriction

“…Pre-clinical studies show that adeno-associated viral vector gene therapy to the fetus can cure single-gene disorders such as haemophilia. Concerns about germline gene transfer and off-target effects in the fetus however, are holding back translation into the clinic of fetal-directed gene therapy (3). Serious maternal obstetric diseases such as pre-eclampsia and fetal growth restriction (FGR) also affect the fetus, and neonate long term.…”

In Utero Stem Cell and Gene Therapy: Current Status and Future Perspectives

“…[48][49][50] Adeno-associated virus vectors (AAV) are single-stranded DNA viruses that are gaining in application because of their safety and low immunogenicity. 4,51 Tissue specificity can be influenced by the AAV serotype, but peak expression might take a few weeks (due to low integration frequency and slow expression profile). AAV vectors can be used to achieve adequate (but not permanent) transgene expression in tissues with low cell turnover including muscle, hepatocytes and neurons.…”

“…Stem cell and gene therapies have shown the greatest potential for clinical use in this setting, but postnatal applications have been limited by poor efficacy and significant toxicity. 3,4 A prenatal approach might alleviate such limitations by exploiting normal fetal development (immune or otherwise) to enhance therapeutic benefits and minimize the risk of harm. 5 If the latter is true, in utero therapy may become the preferred treatment modality for any congenital disease that can be prenatally diagnosed and cured by stem cell transplantation and/or gene transfer.…”

Noninvasive prenatal testing: the paradigm is shifting rapidly

“…Fetal treatment options remain very limited. However, advances in gene therapy make in utero treatment increasingly possible, and early diagnosis based on the analysis of cffDNA will enable optimal timing for any such treatment. This may not solely be limited to monogenic disorders, as expounded by Guedj and Bianchi, who review the information on fetal brain pathology in Down syndrome and argue that there is a theoretical opportunity to improve neurogenesis and brain morphogenesis by in utero treatment …”