Concepts in Fetal Gene Therapy

Abstract

Many congenital anomalies have a genetic basis. With the evolution of fetal therapy over the past half‐century since the first intrauterine transfusion was performed, novel treatments including genetic correction of such diseases may be possible. Using a variety of therapeutic vector constructs, proof of concept for fetal gene therapy (FGT) has been achieved in several single‐gene disorders including thalassaemia and haemophilia B. The current challenge is to determine the long‐term safety and efficacy of FGT, as well as important maternal bystander effects, in clinically relevant large‐animal models, and to individualise FGT strategies according to the disease of interest, with respect to target organ and vector construct.

Key Concepts:

  • Fetal gene therapy research has been directed towards monogenic diseases, but there is scope for this target to be expanded to include chromosomal and structural anomalies in the near future.

  • The fetus, weighing several log‐fold less than an infant or child, allows gene therapy to be economised, facilitating a widespread effect with a smaller amount of vector, and an easier task in adjusting vector dose to achieve the desired outcome.

  • The goal of fetal gene therapy is to achieve phenotypic rescue of a lethal or severely morbid monogenic disease. If cure is not achievable, correction of the disorder to the point of downgrading its severity is the other worthy goal.

  • In addition to genetic correction, treatment initiated in early gestation may encourage tolerance to the gene therapy vector and transgenic protein, events critical to facilitating sustained transgene expression.

  • Gene therapy may be achieved in vivo, through the direct introduction of the transgene enveloped in a vector, or ex vivo with the use of genetically manipulated stem cells to achieve the desired effect.

  • Proof of this concept has been demonstrated using viral vectors in small genetic knockout models of diseases, including haemophilia B and inborn errors of metabolism disease.

  • Evidence of safety and efficacy has been demonstrated in sheep and nonhuman primates which, being physiologically more representative of human pregnancies, are considered robust preclinical models.

  • The success of this intervention depends on the efficacy of cellular transduction, accessibility of the target organ, the type of vector used, immune maturity and route of vector administration.

  • Fetal gene therapy must be optimised to each condition of interest, in terms of appropriate gestation at intervention, efficacy of vector and principal objectives of therapy (gestation at which peak transgene expression is desired, importance of immune maturity and desired duration of transgene expression).

  • Several ethical issues raised by fetal gene therapy have to be considered in anticipation of eventual clinical translation. These include reliance on data from preclinical large animal models that are not genetic knockouts, the consequences of partial correction, the possibility of germ‐line transmission and the long‐term risk of oncogenesis.

Keywords: gene therapy; vector; transgene; fetus; animal models

Figure 1.

The roles of various animal models in demonstrating proof of concept for the advancement of FGT.

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Roybal JL, Endo M, Buckley SM et al. (2012) Animal models for prenatal gene therapy: rodent models for prenatal gene therapy. Methods in Molecular Biology 891: 201–218.

Waddington SN, Kramer MG, Hernandez‐Alcoceba R et al. (2005) In utero gene therapy: current challenges and perspectives. Molecular Therapy 11(5): 661–676.

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Mattar, Citra N, Biswas, Arijit, Choolani, Mahesh, and Chan, Jerry KY(Sep 2013) Concepts in Fetal Gene Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024978]