GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 181Gene Ther Mol Biol Vol 7, 181-209, 2003The current status and future direction of fetal genetherapyReview ArticleAnna L David 1 , Michael Themis 2 , Simon N Waddington 2 , Lisa Gregory 2 , SuzanneMK Buckley 2 , Megha Nivsarkar 2 , Terry Cook 3 , Donald Peebles 1 , Charles HRodeck 1 , Charles Coutelle 21 Department of Obstetrics and Gynaecology, Royal Free and University College London Medical School, London WC1E6HX2 Gene Therapy Research Group, Section of Cell and Molecular Biology, Division of Biomedical Sciences, ImperialCollege School of Medicine, London SW7 2AZ3 Department of Histopathology, Imperial College School of Medicine, London W12 0HS__________________________________________________________________________________*Correspondence: Dr A.L. David, Room 212, 2 nd floor, Department of Obstetrics and Gynaecology, Royal Free and University CollegeMedical School, 86-96 Chenies Mews, London, WC1E 6HX, UK. Telephone: +44-20-7679-6059; Fax: +44-20-7383-7429; e-mail:a.david@ucl.ac.ukKey words: fetal gene therapy; adenovirus; retrovirus; lentivirus; adeno-associated virus; Sendai virus; liposomeAbbreviations: Cystic fibrosis (CF), Cystic Fibrosis Transmembrane Regulator (CFTR), and ornithine transcarbamylase (OTC),lysosomal storage disorders (LSDs), cerebrospinal fluid (CSF), Duchenne muscular dystrophy (DMD), Spinal muscular atrophy (SMA),survival motor neuron gene 1 (SMN 1), adeno-associated viral (AAV), severe combined immunodeficiency disorders (SCID), recessiveadenosine deaminase deficiency (ADA), bone marrow transplantation (BMT), dystrophic form of epidermolysis bullosa (DEB),congenital diaphragmatic hernia (CDH), Intrauterine growth restriction (IUGR)Received: 18 September 2003; Accepted: 29 October 2003; electronically published: November 2003SummaryApplication of gene therapy in utero has been considered as a strategy for treatment or even prevention of earlyonset genetic disorders such as cystic fibrosis and Duchenne muscular dystrophy. Prenatal gene transfer may targetrapidly expanding stem cell populations that are inaccessible after birth, permit induction of immune toleranceagainst vector and transgene and allow permanent gene transfer by use of integrating vector systems. Application ofthis therapy in the fetus must be safe, reliable and cost-effective. Recent developments in the understanding ofgenetic disease, vector design, and minimally invasive delivery techniques have brought fetal gene therapy closer toclinical practice. Prenatal studies in animal models are being pursued in parallel with adult studies of gene therapy,but they remain presently at the experimental stage.I. IntroductionGene therapy uses the intracellular delivery ofgenetic material for the treatment of disease. A wide rangeof diseases including cancer, vascular andneurodegenerative disorders and inherited genetic diseasesare being considered as targets for this therapy in adults.Application of gene therapy in utero has been consideredas a strategy for treatment or even prevention of earlyonset genetic disorders such as cystic fibrosis andDuchenne muscular dystrophy (Coutelle et al, 1995). Genetransfer to the developing fetus may target rapidlyexpanding stem cell populations that are inaccessible afterbirth and may allow permanent gene transfer by use ofintegrating vector systems. The functionally immaturefetal immune system may permit induction of immunetolerance against vector and transgene, and therebyfacilitate repeated treatment after birth. Finally, and mostimportantly for clinicians, fetal gene therapy would give athird choice to parents following prenatal diagnosis ofinherited disease, where currently termination ofpregnancy or acceptance of an affected child have been theonly options. Application of this therapy in the fetus mustbe safe, reliable and cost-effective. Recent developmentsin the understanding of genetic disease, vector design, andminimally invasive delivery techniques have brought fetalgene therapy closer to clinical practice. Prenatal studies inanimal models are being pursued in parallel with adultstudies of gene therapy, but they remain presently at theexperimental stage. This review explores the latestdevelopments in the field of in utero gene therapy andtheir implications for its future clinical application.181