In utero stem cell transplantation and gene therapy: rationale, history, and recent advances toward clinical application

Abstract

Recent advances in high-throughput molecular testing have made it possible to diagnose most genetic disorders relatively early in gestation with minimal risk to the fetus. These advances should soon allow widespread prenatal screening for the majority of human genetic diseases, opening the door to the possibility of treatment/correction prior to birth. In addition to the obvious psychological and financial benefits of curing a disease in utero, and thereby enabling the birth of a healthy infant, there are multiple biological advantages unique to fetal development, which provide compelling rationale for performing potentially curative treatments, such as stem cell transplantation or gene therapy, prior to birth. Herein, we briefly review the fields of in utero transplantation (IUTx) and in utero gene therapy and discuss the biological hurdles that have thus far restricted success of IUTx to patients with immunodeficiencies. We then highlight several recent experimental breakthroughs in immunology, hematopoietic/marrow ontogeny, and in utero cell delivery, which have collectively provided means of overcoming these barriers, thus setting the stage for clinical application of these highly promising therapies in the near future.

In Utero Gene Therapy Consensus Statement from the IFeTIS

“…The authors engineered human CD4 + and CD8 + T cell-targeted LVs capable of selective gene delivery into human CD4 + or CD8 + T cells, respectively. 4,5 The targeting of LVs is based on the principle that fusion-activation of a chimeric envelope should be triggered by the interaction of the ligand displayed on the vector surface with its specific receptor on the target cell. Buchholz and co-workers 3 designed a novel strategy based on the fact that paramyxoviruses separated the two functions, cell binding and virus-cell fusion, into separate glycoproteins.…”

“…3 Further attesting to this leap in technological progress is the recent joint statement from the NIH and US Food & Drug Administration (FDA), which reports more than 700 active investigational new drug (IND) applications for gene therapy. 4 IUGT has also evolved at a rapid pace and, for the last 20 years, studies using mouse, sheep, and non-human primate models have demonstrated the safety and efficacy of IUGT (reviewed in Almeida-Porada et al 5 and Wit et al 6 ). For example, a recent study 7 demonstrated the first successful application of prenatal gene therapy in a mouse model of acute neuronopathic Gaucher disease (nGD).…”

“…With respect to safety, the panel members acknowledged that, as with any fetal intervention, maternal safety is a critical consideration for IUGT and noted that infection, preterm labor, and fetal loss are all theoretically possible. They felt it important to make the public aware, however, that a considerable amount of clinical data exist that provide unassailable proof that the human fetus can be accessed multiple times with an extremely low procedure-related risk, assuming that a minimally invasive, ultrasound-guided approach is employed, 5 and they stressed that the technical aspects of injections using fetal umbilical vein access or intraperitoneal injection are safe and straightforward mainstream procedures.…”

What is the Future of Intrauterine Surgery?

“…By patching the defect earlier the severity of side effects may be reduced. 15 A significant number of congenital diseases can benefit from fetal surgery. As early as the 4th century, Hippocrates stated: "What medicines do not heal, the lance will….".…”

Gene Therapy: A Paradigm Shift in Dentistry

“…Currently, gene therapy has emerged as a major medical breakthrough and a number of researchers have focused on using modern advancements in genetic therapy to treat life-threatening and refractory diseases such as prevention of HIV [9], management of hematological disorders [10], metabolic disorders [11,12], cancer treatment [13,14,15] and stem cell approaches [16]. Since the introduction of gene therapy for dental applications in the 1990s [4], progressive clinical trials are being carried out in humans and on animal models for various applications with promising outcomes.…”