Gene modification therapies for hereditary diseases in the fetus

Abstract

Proof-of-principle disease models have demonstrated the feasibility of an intrauterine gene modification therapy (in utero gene therapy (IUGT)) approach to hereditary diseases as diverse as coagulation disorders, haemoglobinopathies, neurogenetic disorders, congenital metabolic, and pulmonary diseases. Gene addition, which requires the delivery of an integrating or episomal transgene to the target cell nucleus to be transcribed, and gene editing, where the mutation is corrected within the gene of origin, have both been used successfully to increase normal protein production in a bid to reverse or arrest pathology in utero. While most experimental models have employed lentiviral, adenoviral, and adenoassociated viral vectors engineered to efficiently enter target cells, newer models have also demonstrated the applicability of non-viral lipid nanoparticles. Amelioration of pathology is dependent primarily on achieving sustained therapeutic transgene expression, silencing of transgene expression, production of neutralising antibodies, the dilutional effect of the recipient's growth on the mass of transduced cells, and the degree of pre-existing cellular damage. Safety assessment of any IUGT strategy will require long-term postnatal surveillance of both the fetal recipient and the maternal bystander for cell and genome toxicity, oncogenic potential, immuneresponsiveness, and germline mutation. In this review, we discuss advances in the field and the push toward clinical translation of IUGT. Key pointsWhat's already known about this topic? � Transgenic rodent models of monogenic diseases have demonstrated the feasibility and efficacy of intrauterine gene addition therapy.� Diseases most successfully treated in utero in disease models include haemophilia B, neuronopathic Gaucher disease (nGD), surfactant deficiency syndrome, and certain metabolic diseases.� Non-human primate models of haemophilia B have demonstrated long-term safety and sustained transgene expression.

The research progress of correcting pathogenic mutations by base editing

“…Germline editing is currently only permitted for basic research purposes, and it remains forbidden in clinical settings. In utero gene therapy (IUGT) has gained attention, and many researches have been conducted on animals [86]. There are several advantages for IUGT, such as small fetal size, tolerogenic immune system, and prevalent progenitor cells [87].…”

Embryo and fetal gene editing: Technical challenges and progress toward clinical applications

“…Putative benefits of this approach over postnatal therapy are numerous and have been demonstrated in proof-of-principle animal models. 18 These include arrest of cellular pathology, prevention of irreversible organ damage, avoidance of neutralizing antibodies or cytokine-mediated cell death as the fetal immune system is not fully alloresponsive, the highest concentration of stem cells available for correction, immature blood-brain barrier allowing access to the central nervous system (CNS), and the highest therapeutic efficiency due to the small mass of the fetus. Multiple invasive diagnostic and therapeutic procedures can be performed during pregnancy ( Figure 1 ) with excellent tolerance and low fetal loss rates, 19 while multiple organ systems can be specifically targeted under ultrasound guidance, permitting directed delivery to the brain, lungs, retina, liver, and skeletomuscular and hematopoietic systems.…”

“…Gene addition and replacement therapy has proved successful in small and large intrauterine animal models of hereditary conditions, ranging from the hemophilias and hemoglobinopathies, to mucopolysaccharidoses and glycogen storage disease. 18 , 21 Delivery of transgenes has been accomplished using adenoviruses (AdVs), adeno-associated viral (AAV), gammaretroviral (γRV), and lentiviral vectors (LV), and more recently non-viral lipid nanoparticles (LNPs). 22 Longevity of transgene expression depends on certain critical factors, including vector tropism and biodistribution for cell types, cell entry (transduction efficiency), integration versus episomal localization of the transgene, transgene dilutional loss or silencing, and lineage restriction of the transgene expression by cell-specific promoters.…”

“…Additionally, effects on the mother related to invasive procedures, transplacental passage of delivery vectors, and remote indels and mutations in maternal tissues must be considered. 18 , 88 Researchers have taken advantage of various routes of administration to increase correct organ targeting in the fetus, a feat achievable because of the confined intrauterine space with the aid of amniotic fluid. 20 Thus, intra-amniotic injection after the onset of fetal respiratory function can aid in the delivery of vectors to the lung parenchyma and to the intestinal tract, allowing direct targeting of respiratory and intestinal epithelia, a task made harder postnatally by the blood-organ barriers and inflammatory secretions in conditions such as cystic fibrosis.…”