UCL Institute for Women's Health (IfWH)

Prenatal Cell and Gene Therapy Group

Lead: Dr Anna David, Senior Lecturer

Research Overview

Dr Anna David leads a team aiming to develop prenatal treatment of severe  early onset and life-threatening disorders using gene and cellular therapy, and to investigate the efficacy, safety and ethical issues of such treatment.

Background

Research into fetal gene therapy began under a 5 year MRC Programme grant (Professor Charles Rodeck) in collaboration with the Gene Therapy Research Group (Professor Charles Coutelle) at Imperial College, London in 2000. Dr David obtained a PhD on clinically applicable methods of delivering fetal gene therapy in 2005 at UCL and the group was established in 2007.

Key staff

• Dr Anna David, Senior Lecturer in Obstetrics and Maternal/Fetal Medicine funded by an NIHR Senior Lectureship
• Professor Donald Peebles, Lead Maternal/Fetal Medicine
• Mr Vedanta Mehta, PhD student (Dorothy Hodgkin Postgraduate Award)
• Dr David Carr, Research Associate and PhD student (Wellcome Trust and Wellbeing of Women charitable funding).
• Dr Steven Shaw, PhD student (UCL Overseas Research Scholarship, National Science Council of Taiwan funding)
• Dr Panicos Shangaris, PhD student (UCL/UCLH Comprehensive Biomedical Research Centre Entry Level Fellowship)

The group has been funded over £1.25 million since 2007. Our work has been featured in The Times, New Scientist  and on YouTube.

Prenatal gene therapy for treatment of obstetric disorders

Fetal growth restriction and pre-eclampsia are major obstetric problems that cause substantial maternal and fetal morbidity and mortality; there is no current treatment. The underlying cause of these conditions is reduced blood flow to the placenta via the uterine artery. In 2006 we set up a collaboration with Professors John Martin and Ian Zachary, UCL Centre for Cardiovascular Medicine and Biology  and with Ark Therapeutics Group Plc , to develop a novel gene therapy treatment. We have shown that adenovirus mediated over-expression of Vascular Endothelial Growth Factor (VEGF) increases blood flow in the uterine arteries, and reduces constriction of these blood vessels both short and long term. In a project funded by the Wellcome Trust, we have now demonstrated that this gene therapy approach improves fetal growth in sheep pregnancies affected by fetal growth restriction, without harmful effects to the mother or fetus. Research funded by Action Medical Research  and Rosetrees Trust  is also ongoing in another growth restricted animal model to explore these results further.

Toxicology studies funded by our industrial collaborator are now underway to evaluate adenovirus gene transfer across the human placenta, in collaboration with the Maternal and Fetal Health Research Centre  (Professor Colin Sibley and Dr Paul Brownbill, University of Manchester), in preparation for clinical translation. If successful, this may provide the first therapy for severe fetal growth restriction.

Prenatal gene therapy for genetic disorders

We are working to develop prenatal therapies that can be delivered to the fetus while in the womb and cure genetic disease before birth. Recent encouraging results came from a collaboration with Dr Amit Nathwani , Reader in Haematology, UCL Cancer Institute and Dr Simon Waddington , UCL Institute for Women’s Health using an adeno-associated virus (AAV) vector.  We showed for the first time in a large animal, that long term expression of the human coagulation factor IX could be achieved in the blood of neonates born after gene therapy in fetal life using a clinically applicable ultrasound guided delivery method. At the same time our collaborators Dr Jerry Chan , and Dr Citra Mattar, Experimental Fetal Medicine Group, National University of Singapore achieved similar results using the same AAV vector in an NHP model after fetal delivery. These results support that concept that prenatal gene therapy will be a therapeutic approach in some severe early-onset genetic disorders.

Fetal stem cell gene therapy

We are exploring whether fetal stem cells such as those found in the amniotic fluid or placenta, may be used to deliver gene therapy to the fetus in the womb. This work results from our collaboration with Mr Paolo De Coppi , Senior Lecturer in Paediatric Surgery, UCL Institute of Child Health, who was the first to demonstrate cells with potential for cell therapy in the amniotic fluid. We also work closely with Dr Simon Waddington’s group  at Institute for Women’s Health.

With funding from Newlife Foundation  and the National Science Council of Taiwan we have performed autologous (self) stem cell transplantation in the womb. Taking cells collected from the amniotic fluid of sheep that were gene marked using viral vectors, we returned them to each donor fetal sheep using clinically applicable ultrasound guided delivery. These cells stably engrafted in the fetus long term. We are now embarking on studies using this therapeutic approach to treat haematological genetic disease in the fetus, such as thalassaemia. This work is in collaboration with Professor Adrian Thrasher , Professor Bobby Gaspar , Dr Waseem Qasim at UCL Institute of Child Health, and Dr Michael Antoniou , Kings College.

Ethics of prenatal gene and cellular therapy

Working with Richard Ashcroft , Professor of Biomedical Ethics at Queen Mary, University of London we have considered ethical issues in relation to prenatal gene and cell therapy for genetic and obstetric conditions.

Key Publications

1. V Mehta, KN Abi-Nader, DM Peebles, E Benjamin, V Wigley, B Torondel, E Filippi, SWS Shaw, M Boyd, I Zachary, J Martin, AL David. Local over-expression of human VEGF-A165 in the mid-gestation pregnant sheep uterine artery leads to a sustained increase in uterine artery blood flow and altered vascular reactivity. Gene Therapy 2011 in press doi:10.1038/gt.2011.158
2. DJ Carr, RP Aitken, JS Milne, AL David, JM Wallace. Ultrasonographic assessment of growth and estimation of birthweight in late gestation fetal sheep. Ultrasound in Medicine and Biology 2011;37(10):1588-95.
3. CNZ Mattar, AC Nathwani, SN Waddington, N Dighe, J Mcintosh, NB Johana, B Ogden, NM Fisk, AM Davidoff, AL David, DM Peebles, C Kappel, A Nowrouzi, M Schmidt, A Biswas, M Choolani, JKY Chan. Stable human FIX expression after 0.9G Intrauterine Gene Transfer of Self-complementary Adeno-Associated Viral Vector 5 and 8 in Macaques. Molecular Therapy 2011 May 31. Epub ahead of print
4. KN Abi-Nader, V Mehta, SWS Shaw, T Bellamy, N Smith, L Millross, B Laverick, E Filippi, M Boyd, DM Peebles, AL David. Telemetric monitoring of fetal blood pressure and heart rate in the freely moving pregnant sheep: A feasibility study.  Laboratory Animals 2011:45:50-4.
5. AL David, J McIntosh, DM Peebles, T Cook, S Waddington, B Weisz, V Wigley, K Abi-Nader, M Boyd, AM Davidoff, AC Nathwani. rAAV mediated in utero gene transfer gives therapeutic transgene expression in the sheep. Human Gene Therapy 2011;22:419-426.
6. SWS Shaw, S Bollini, KA Abi-Nader, A Gastadello, V Mehta, E Filippi, M Cananzi, HB Gaspar, W Qasim, P De Coppi, AL David. Autologous transplantation of amniotic fluid derived mesenchymal stem cells into sheep fetuses. Cell Transplantation 2010 Nov19. epub.
7. AL David, KN Abi-Nader, B Weisz, SWS Shaw, M Themis, T Cook, C Coutelle, CH Rodeck, DM Peebles.  Ultrasonographic development of the fetal sheep stomach and evaluation of early gestation ultrasound-guided in utero intragastric injection. Taiwan J Obstet Gynecol 2010;49:23-9.
8. K Abi Nader, V Mehta, V Wigley, E Filippi, B Tezcan, M Boyd, DM Peebles, AL David.  Doppler ultrasonography for the non-invasive measurement of uterine artery volume blood flow through gestation in the pregnant sheep. Reproductive Sciences 2010;17:13-19
9. AL David, B Torondel, I Zachary, V Wigley, K Abi Nader, V Mehta, SMK Buckley, T Cook, M Boyd, CH Rodeck, J Martin, DM Peebles. Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep. Gene Therapy 2008;15:1344-50.
10. David AL, Peebles DM, Gregory L, Waddington SN, Themis M, Weisz B, Ruthe A, Lawrence L, Cook T, Rodeck CH, Coutelle CH. Clinically applicable procedure for gene delivery to fetal gut by ultrasound-guided gastric Injection: Toward prenatal prevention of early-onset intestinal diseases. Human Gene Therapy 2006;17:767-9
11. David AL, Weisz B, Gregory L, Themis M, Cook T, Roubliova X, Deprest J, Coutelle C, Rodeck CH, Peebles DM. Ultrasound-guided injection and occlusion of the trachea in fetal sheep. Ultrasound in Obstetrics & Gynaecology 2006;28:82-8
12. Weisz B, David AL, Gregory LG, Perocheau D, Ruthe A, Waddington SN, Themis M, Cook T, Coutelle C, Rodeck CH, Peebles DM. Targeting the respiratory muscles of fetal sheep for prenatal gene therapy for Duchenne muscular dystrophy. American Journal of Obstetrics & Gynecology 2005;193:1105-9
13. Peebles D, Gregory LG, David A, Themis M, Waddington SN, Knapton HJ, Miah M, Cook T, Lawrence L, Nivsarkar M, Rodeck C, Coutelle C. Widespread and efficient marker gene expression in the airway epithelia of fetal sheep after minimally invasive tracheal application of recombinant adenovirus in utero. Gene Therapy 2004;11:70-8.
14. David AL, Peebles DM, Gregory L, Themis M, Cook T, Coutelle C, Rodeck CH. Percutaneous ultrasound-guided injection of the trachea in fetal sheep: a novel technique to target the fetal airways. Fetal Diagnosis and Therapy 2003;18:385-390
15. David A, Cook T, Waddington S, Peebles D, Nivsarkar M, Knapton H, Miah M, Dahse T, Noakes D, Schneider H, Rodeck C, Coutelle C, Themis M. Ultrasound guided percutaneous delivery of adenoviral vectors encoding the beta-galactosidase and human factor IX genes to early gestation fetal sheep in utero. Human Gene Therapy 2003;14:353-364

Review articles

1. Mehta V, Abi Nader K, Waddington S, David AL. Organ targeted prenatal gene therapy – how far are we? Prenatal Diagnosis 2011;31(7):720-34
2. Buckley SMK, Rahim AA, Chan JKY, David AL, Peebles DM, Coutelle C, Waddington SN. Recent advances in fetal gene therapy. Therapeutic Delivery 2011;2:461-469.
3. Shaw SWS, David AL, De Coppi P. Clinical applications of pre- and postnatal therapy using stem cells retrieved from amniotic fluid. Current Opinion in Obstetrics & Gynecology 2011;23:109-16.
4. Abi-Nader KN, David AL. Fetal muscle gene therapy/gene delivery in large animals. Methods Mol Biol 2011;709:239-56
5. Rahim AA, Wong AM, Buckley SM, Chan JK, David AL, Cooper JD, Coutelle C, Peebles DM, Waddington SN. In utero gene transfer to the mouse nervous system. Biochem Soc Trans 2010;38:1489-93
6. David AL, Ashcroft R. Placental gene therapy. Obstetrics, Gynaecology & Reproductive Medicine 2009;19:296-298
7. Abi-Nader K, Rodeck CH, David AL. Prenatal gene therapy for early treatment of genetic disorders. Expert Review of Obstetrics & Gynecology 2009;4:25-44.
8. David AL, Peebles DM.  Gene therapy for the fetus: is there a future? Best Pract Res Clin Obstet Gynaecol. 2008:22:203-218
9. Waddington SN, Buckley SMK, David AL, Peebles DM, Rodeck CH, Coutelle C. Fetal gene transfer. Current Opinion in Molecular Therapeutics 2007;9:432-8
10. Coutelle C, Themis M, Waddington SN, Buckley SM, Gregory LG, Nivsarkar MS, David AL, Peebles D, Weisz B, Rodeck C. Gene Therapy Progress and Prospects: Fetal gene therapy - first proofs of concept - some adverse effects. Gene Therapy 2005;12:1601-7
11. Coutelle C, Themis M, Waddington S, Gregory L, Nivsarkar M, Buckley S, Cook T, Rodeck C, Peebles D, David A.  The hopes and fears of in utero gene therapy for genetic disease – a review. Placenta 2003;24:S114-S121

Book chapters

We contributed four chapters to a book on Prenatal Gene Therapy edited by Professor Charles Coutelle and Dr Simon Waddington to be published in 2012.

1. Abi-Nader K, David AL. Prenatal gene therapy in “Reproductive Genetics” published following RCOG 57th Study Group February 2009. RCOG Press.
2. David AL, Rodeck CH. Prenatal diagnosis in “Preimplantation Genetic Diagnosis and Screening” edited by J Harper 2008. Cambridge University Press
3. David AL, Rodeck CH.  Fetal gene therapy in “Fetal Medicine” edited by CH Rodeck and M J Whittle 2008. Elsevier Ltd.
4. David AL, Rodeck CH. The place of fetal therapy in preventive genetics. In “Preventive Genetics” edited by S Gogate published by Jaypee Brothers Medical Publishers, New Delhi, 2006.
5. David AL, Rodeck CH. Gene therapy. In “Prenatal Medicine” edited by JMG van Vugt and LP Shulman, published by Taylor & Francis New York, 2006.
6. David AL, Themis, Rodeck C. Fetal gene therapy: the present and the prospects. Yearbook of Obstetrics and Gynaecology 2004 published by RCOG Press, London.