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Chapter 21 - Gene therapy

physiological principles and clinical potential

from Section 2 - Fetal disease

Published online by Cambridge University Press:  05 February 2013

By
Vedanta Mehta  and
Anna L. David
Edited by
Mark D. Kilby ,
Anthony Johnson  and
Dick Oepkes
Mark D. Kilby
Affiliation:
Department of Fetal Medicine, University of Birmingham
Anthony Johnson
Affiliation:
Baylor College of Medicine, Texas
Dick Oepkes
Affiliation:
Department of Obstetrics, Leiden University Medical Center
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Summary

Introduction

Gene therapy uses a vector to deliver a gene to its required site where expression of the protein can produce a therapeutic effect. It may be administered either prenatally or postnatally, though an advantage of the prenatal approach is the ability to deliver a therapeutic gene to an individual before the onset of organ damage, an important issue for metabolic diseases, such as some types of mucopolysaccharidoses for example, where irreversible brain damage can occur before birth. Prenatal application targets a rapidly dividing population of stem cells, providing a large population of transduced cells to produce a better therapeutic effect. The fetus also presents a size advantage, allowing a higher vector-to-target cell ratio. Organs which are difficult to target after birth may be more easily accessible during fetal life because of their developmental stages, or relative immaturity. The fetal epidermis, for example, undergoes remodeling by programmed cell death to be replaced by mature keratinocytes which form a thick barrier to gene transfer postnatally [1]. The fetal airways may also be more amenable to gene transfer since they are fluid filled in fetal life, whereas after birth there is an air–fluid interface that is difficult to penetrate particularly in diseased lungs such as exists with cystic fibrosis.

A major obstacle to postnatal gene therapy has been the development of an immune response against the transgenic (therapeutic) protein or the vector itself. Some individuals may have pre-existing antibodies to the viral vector that will prevent long-term expression of the transgenic protein, limiting therapeutic efficacy and thwarting repeated vector administration. Delivering foreign protein to the fetus can take advantage of immune tolerance which is induced during fetal life, a concept that was first proposed nearly 60 years ago [2, 3]. Induction of tolerance depends first on the foreign protein being expressed sufficiently early in gestation before the immune system is fully developed and second, the protein being maintained at a sufficient level within the fetus. Proof-of-principle prenatal gene therapy studies have shown long-term expression of proteins at therapeutic levels and induction of immune tolerance [4] in both small [5] and large animals [6] and cured congenital disease in some animal models.

Keywords

retrovirus vectorslentivirusprenatal gene therapygene therapygenodermatosesadenoviruscandidate diseases
Type
Chapter
Information
Fetal Therapy
Scientific Basis and Critical Appraisal of Clinical Benefits
 , pp. 417 - 432
Publisher: Cambridge University Press
Print publication year: 2012

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