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Prenatal Cell and Gene Therapy

Prenatal Cell and Gene Therapy

Professor Anna David leads a team developing 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 she established the group in 2007.

Current research projects

Maternal gene therapy

Preclinical

Overview: Fetal growth restriction (FGR) is a pregnancy complication in which the baby in the womb (fetus) does not grow as well as it should. In some pregnancies the fetus stops growing very early in pregnancy. FGR is associated with stillbirth and neonatal death, and survivors have a high risk of cardiovascular disease and diabetes. There is no treatment that can improve fetal growth. The underlying problem is poor blood flow in the mother's uterine arteries. We have developed a novel therapy for FGR. This delivers a short term gene therapy (adenovirus vector, Ad) containing the Vascular Endothelial Growth Factor (VEGF) gene to the maternal uterine arteries. We have shown that this maternal VEGF growth factor gene therapy improves uterine artery blood flow, and improves fetal growth.

Design: Preclinical studies are being done in growth restricted guinea pigs that have been born after our treatment. We are studying their blood pressure, sugar control and their development. 

GPs and experimental timeline

Experimental timeline for follow-up study on Guinea Pig pups

Clinical 

EVERREST Clinical Trial: The EVERREST Project aims to carry out a phase I/IIa trial of maternal VEGF growth factor gene therapy for severe early onset fetal growth restriction (FGR). Reproductive toxicology work will complete in August 2016. We will apply for ethical and regulatory approval at the end of 2016, aiming to start the trial in 2017. This is potentially the first trial of gene therapy in pregnancy.  An important part of the project conducted with Queen Mary University of London considered the ethical implications of the proposed intervention.

EVERREST Prospective Study: Along with our clinical partners in Germany, Spain, and Sweden we are studying in detail pregnancies affected by severe early onset FGR. We are collecting clinical data, including serial ultrasound scans and neuro-developmental follow-up for surviving babies, along with a bio-bank of samples taken at enrolment and delivery. The findings of this study will help to interpret the safety data from the EVERREST Clinical Trial. We are also investigating ultrasound and biochemical predictors of outcome for affected pregnancies. We are working with our partners Magnus Growth, FinVector, University of Eastern Finland and Euram to translate the therapy into the clinic.

EVERREST timeline with logo

Participant timeline in the EVERREST Prospective Study

Team (Preclinical): Dr Carlo Rossi, Dr Owen Vaughan

Team (Clinical): Dr Rebecca Spencer, Susan Tebbs, Jade Dyer, Alison Evans

Funding: Action Medical ResearchEVERREST FP7, Magnus Life Science

Magnus Growth Logo
Fetal gene therapy

In utero Gene Therapy (IUGT) for Congenital Blood Disorders

Beta thalassaemia is a genetic blood disease that causes life-threatening anemia. Hematopoietic stem cell (HSC) transplantation successfully cures the disease but in only 30% of patients.

In humans, successes with in utero transplantation using allogeneic haematopoietic stem cells, has been limited to fetuses with severe immunologic defects where there is an effective lack of immune response to allogeneic cells.

We hypothesized that IUGT to the fetal HSC compartment (Liver) using a vector carrying the corrected beta globin gene (GLOBE, Dr Mike Antoniou Kings College London) might cure the disease before birth.

Ideally, having a diagnosis using Non Invasive Prenatal Diagnosis (NIPD) at 10 weeks of gestation will give enough time to administer IUGT and correct the disease before birth. 

Fetale gene therapy

Team: Panicos Shangaris, Stavros P Loukogeorgakis, Sindhu Subramaniam, Christina Flouri, Simon Waddington

Funding: Wellcome TrustSparksUCLH CharitiesUKTS

Fetal stem cell gene therapy

Overview: Inherited genetic disorders are important causes of morbidity and mortality. Prenatal diagnosis is now possible early in pregnancy using the maternal blood. Postnatal stem cell transplantation is limited by the immune response to the cells. Stem cells in the amniotic fluid (AF) cells may be a good cell source for prenatal therapy. Some of these AF stem cells have hematopoietic activity meaning they may be used to treat inherited blood disorders such as thalassaemia or sickle cell anaemia. We are studying how to use AF stem cells to correct inherited anaemias before birth.

Design:

Fetal stem cell therapy


Team: Durrgah L RamachandraStavros P Loukogeorgakis, Dr Panicos ShangarisEleni Antoniadou, Sindhu Subramaniam.

Funding: Wellcome Trust, Sparks, Rosetrees Trust

Links: Wellcome Trust, Sparks, Rosetrees Trust, UK Thalassaemia Society

In utero stem cell transplantation

Overview: Osteogenesis imperfecta (OI) is an inherited genetic disease characterised by brittle bones. When severe, babies present in the womb with fractures that can be seen on ultrasound scan. Patients with severe OI have repeated, multiple fractures through life, pain and handicap. There is no cure and current treatment is palliative. Fetal therapy using stem cells presents an opportunity. Transplantation before birth at the onset of disease may give better engraftment with less rejection than transplantation after birth. Mesenchymal stem cells (MSC) are promising candidates with minimal cancer risk.

Our aim is to develop prenatal and postnatal transplantation of MSC as a therapy for severe types of OI.

Design: We are conducting a multicentre case control study of MSC transplantation in severe types of OI (types II/III, severe type IV). We will compare prenatal (in utero) and postnatal transplantation and evaluate safety and efficacy outcomes (fracture frequency and growth). The multicentre study is lead by Sweden, with three other clinical centres at UCL, Koln in Germany, and Leiden in The Netherlands. We are also working with Great Ormond Street Hospital to develop non-invasive prenatal testing for OI.

Osteogenesis Imperfecta

Team: Dr Anna David, Dr Pascale Guillot, Professor Mark Lowdell (UCL Royal Free Biobank), Professor Lyn Chitty (Institute of Child Health), Dr Catherine De Vile (Great Ormond Street Hospital).

Funding: “Stem cell therapy to treat severe osteogenesis imperfecta”. Swedish Krona 16,500,000 (£1,357,887) over 3 years. Funded by a “Framework grant in clinical therapy research” from Swedish Research Council. Collaboration with Dr Cecilia Götherström and Professor Magnus Westgren.

Links: BOOSTB4

Healing the amniotic membrane

Overview: Pre-term prelabour rupture of the fetal membrane (PPROM) is a major cause of preterm birth. It accounts for 40 % of early infant death and costs the NHS £3 billion annually.  Infection, blood and uterine stretch weaken the membrane. Little is known about the factors which initiate the damaging process. PPROM occurs commonly after prenatal fetoscopic and open fetal surgery for identical twin problems and fetal abnormalities. Spontaneous wound healing of the amniotic membrane (AM) does not occur after invasive fetal therapy. A visible membrane defect is seen in the majority of cases. Attempts to seal the defect with glues or decellularised collagen plugs are not clinically effective. Fetal therapy is therefore limited by the complications of prematurity.

Design: We are examining the role of the stretch-sensitive protein connexin-43 (Cx43) in fetal membrane healing and tissue strength. We are also studying the effect of cyclic tensile strain on Cx43 expression and production of inflammatory mediators. With the help of material scientists our aim is to develop a novel bioactive sealing method to heal fetal membrane defects after fetal surgery. 

David Barrett UCL Webpages

(A-C) Microstructure analysis for the human amniotic membrane following fetoscopy surgery the defect and fibrous architecture of the exposed fetal membrane. (D) Development of novel sealing strategy based on self-assembling membranes at the amniotic fluid interface.

Team: David Barrett (PhD student), Dr Anna David, Dr Chris Thrasivoulou (UCL), Professor David Becker (UCL), Dr. Tina Chowdhury and Dr. Alvaro Mata (Queen Mary University of London), Prof. Jan Deprest and Dr. Alexander Engels (University of Leuven, Belgium), Prof. Che Connon (University of Newcastle).

Funding: Rosetrees Trust, Queen Mary University of London, Prenatal Therapy Charity

Biobanking fetal stem cells for therapy

Overview: Human amniotic fluid stem cells (hAFSC) rapidly expand and differentiate into many types of cell. They have a low risk for causing tumours.  They can easily be collected at prenatal diagnosis or at birth. We are establishing an experimental pathway for biobanking human AFSCs for clinical use under GMP conditions. In the future, we hope to test their therapeutic efficacy for intestinal diseases such as Necrotizing Enterocolitis (NEC) a common serious disease of preterm born neonates.

Design: We are processing and charactering stem cells in the human amniotic fluid for growth yield, population purity, cellular potency, and viability, using standard culture conditions and xeno-free (animal-cell free) culture conditions.

Biobanking design

The roadmap from AFSC biobanking to NEC treatment.

Team: Eleni Antoniadou, Durrgah Ramachandra, Sindhu Subramaniam

PI: Dr Anna David, Professor Paolo De Coppi, Professor Mark Lowdell

Funding: Rosetrees Trust, Stoneygate Trust, NIHR Great Ormond Street Hospital UCL Institute of Child Health Biomedical Research Centre

Imaging for fetal therapy

Overview: 1% of babies are born with severe defects. These are collectively responsible for over 1/3 of all paediatric hospital admissions. Early intervention, when the baby is still in the womb, in some cases improves outcome in terms of morbidity and mortality. Guided Instrument for Fetal Therapy and Surgery is a seven-year project in collaboration with KU Leuven, Great Ormond Street Hospital and University College Hospital. We aim to develop low-risk techniques for the diagnosis, treatment and therapy of a range of debilitating abnormalities of the baby during pregnancy. 

Fetal MRI

Team: Dr Rosalind Pratt, Efthymios Maneas

Funding: Guided Instrument for Fetal Therapy and Surgery is a seven-year project funded by the Wellcome Trust and Engineering and Physical Sciences Research Council.

Links: GIFT Surg, The Guardian

Developing obstetric therapies

The development of new drugs for use in obstetrics is long overdue. Maternal and perinatal disease counts for approximately 7% of global disease, yet fewer than 5% of the number of drugs being developed to combat cardiovascular disease are designed to help new mothers and pregnant women.

Our research is developing new obstetric therapies. We have also worked with the Royal College of Obstetricians and Gynaecologists (RCOG) to suggest ways that barriers to finding new treatments could be overcome.

https://www.rcog.org.uk/globalassets/documents/news/sip-50-obstetric-drug-development-key-messages.pdf

See the paper here https://www.rcog.org.uk/globalassets/documents/guidelines/scientific-impact-papers/sip-50.pdf

Developing Maternal and Fetal Adverse Event severity grading criteria

To assess the safety of a potential new therapy, researchers record any Adverse Events (AEs) which occur during clinical trials. To get the most detailed safety data these AEs are usually graded from 1 to 5. Standard criteria exist for grading hundreds of AEs, but these are inadequate and inconsistent for trials of maternal and fetal therapies.

The EVERREST International Adverse Event Consensus Group met for the first time in May 2015 to begin the process of developing standard maternal and fetal AE severity grading criteria. This group includes fetal therapy, obstetric, neonatal, and pharmaceutical industry experts from Europe and the United States. A draft set of criteria are currently undergoing external review ahead of future publication.

AE meeting
Ethics of prenatal therapies

Ethics of prenatal therapies

Overview: Ethical considerations are an important part of developing prenatal therapies and are embedded in all our research. We have investigated ethical issues in relation to prenatal gene and cell therapy for genetic and obstetric conditions with stakeholders and potential patients.

Maternal gene therapy:

We considered the ethics of placental gene therapy here.

A recent review suggests that there is no objection of ethical, legal or regulatory principles to the maternal gene therapy intervention under development in the EVERREST programme.

Fetal surgery:

We are reviewing the ethical, legal and regulatory principles relating to novel fetal surgery.

Collaborations: Professor Richard Ashcroft (Queen Mary University of London); Professor Jan Deprest (UCL); Dr Kevin Cao, Alice Booth

Funding: European Commission, Wellcome Trust, EPSRC

Public engagement

Public engagement

Engaging with Patients

Overview: Involving patients in designing research pathways helps to achieve successful outcomes and is an important aspect of our research. The group engages with the public and patients in the following ways:

  • Identifying patient priorities for research
  • Discussing ethical issues relating to developing prenatal therapy
  • Understanding issues of informed consent relating to trials of prenatal therapy
  • Collaborating with patients to develop new ways to image and treat the fetus in the womb

Team: Preterm Birth

Anna David and Catherine James are members of the steering group for the Preterm Birth Priority Setting Partnership, James Lind Alliance. In conjunction with families with experience of preterm birth and organisations representing them we identified and prioritised the top 15 research questions of which the top is “Which interventions are most effective to predict or prevent preterm birth?”

Team: Prenatal Imaging and Surgery

The Patient Public Advisory Group for GIFT-Surg was set up as part of a 7 year programme grant funded by a Wellcome Trust and EPSRC Innovative Engineering for Health Award.  The group has parents and representatives from a number of UK charities (SHINE; CDH-UK; BLISS; TAMBA; ARC) who are providing continuous input to the project during the development of innovations.

Team: Maternal Gene Therapy for Fetal Growth Restriction

As part of the 6 year EVERREST programme, we consulted with patients who had experienced a pregnancy with severe early onset fetal growth restriction to understand their views about developing a treatment. The overall conclusion drawn from these interviews was that they had a generally favourable view of the ethical and social acceptability of a maternal gene therapy to treat this condition

Team: Prenatal Treatment of Congenital Disease

We are working with groups such as the UK Thalassaemia Society and The Sickle Cell Society to develop new treatments for these common blood disorders and to inform them of our work.

Links:

GIFT-Surg project: www.gift-surg.ac.uk

ARC – Antenatal Results and Choices: www.arc-uk.org

Bliss – for babies born to too soon, too small, too sick: www.bliss.org.uk

CDH UK – the Congenital Diaphragmatic Hernia Support Charity: www.cdhuk.org.uk

Shine – Spina bifida and Hydrocephalus information, networking and equality: www.shinecharity.org.uk

TAMBA – Twin and multiple birth association: www.tamba.org.uk

UK Thalassaemia Society: www.ukts.org

Sickle Cell Society: www.sicklecellsociety.org

Prenatal therapy charity

Prenatal therapy charity

The Prenatal Therapy Fund was set up in December 2013 to support research in the group. 

Prenatal birth clinic photo

To date the funds have supported:

  • A collaborative lab visit to Belgium to develop new techniques to plug the amniotic membrane after fetoscopic surgery.
  • Microscopic analysis of amniotic membrane after fetal therapy. 
  • Analysis of haemoglobin levels after fetal gene therapy for thalassaemia. 
  • A microscope to study bacteria in the urine of women at high risk of spontaneous preterm birth.

The fund has a webpage on Just Giving. We are also supported by “Little heartbeats raises for UCLH heal membranes project”.

All funds raised go directly to support research into developing prenatal therapies.

Cheque charity

You can donate online at:

www.justgiving.com/UCLH-Prenatal-Therapy-Fund

Or donate by text. Send the amount you would like to donate, with the code UCLH63, to 70070 (e.g. UCLH63 £10).

You can donate £1, £10 or more.

News

News

Our work has been featured in The Times, New Scientist , BBC Future Health and on YouTube.

Featured news:

  • UCL/ParisDescartes University Collaborative

    The objective of the project is to initiate a UCL – Paris Descartes Collaborative program in Women’s Health. The UCL- Paris Descartes Collaborative will be launched in May 2017 with a symposium involving the two university departments and their affiliated hospital systems. This faculty-led initiative originating in women’s health medicine could expand to other biomedical fields and disciplines in due course. UCL and Paris Descartes present both a great environment for care, research and teaching, with many similarities but also many differences. Students, carers and scientists could all highly benefit from this collaboration. The objective of the Collaborative is therefore to create deep interactions and broader relationship between the two institutions and also to take better advantage of complementary resources. This will be built on seminars, workshops, visits for lectures, joint projects and on exchanges of medical students. Professorships positions could also be created. This project is also supported by the French Embassy in London.

Read the report 

Twitter

@PrenatalTherapy: Obstetrician and specialist in maternal fetal medicine, with an interest in developing prenatal therapies for pregnancy complications and congenital disease

@FP7EVERREST: Does vascular endothelial growth factor gene therapy safely improve outcome in severe early-onset fetal growth restriction?

Further information