Fetal gene therapy for neurodegenerative disease of infants

For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood-brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains

Gene therapy for obstetric conditions

The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy

Perinatal Gene Transfer to the Liver

The liver acts as a host to many functions hence raising the possibility that any one may be compromised by a single gene defect. Inherited or de novo mutations in these genes may result in relatively mild diseases or be so devastating that death within the first weeks or months of life is inevitable. Some diseases can be managed using conventional medicines whereas others are, as yet, untreatable. In this review we consider the application of early intervention gene therapy in neonatal and fetal preclinical studies. We appraise the tools of this technology, including lentivirus, adenovirus and adeno-associated virus (AAV)-based vectors. We highlight the application of these for a range of diseases including hemophilia, urea cycle disorders such as ornithine transcarbamylase deficiency, organic acidemias, lysosomal storage diseases including mucopolysaccharidoses, glycogen storage diseases and bile metabolism. We conclude by assessing the advantages and disadvantages associated with fetal and neonatal liver gene transfer

Fetal gene therapy: Balancing ethical theory, scientific progress and the rights of others

This thesis examines the relationship between rights and duties in the field of fetal gene therapy and assesses if the current regulatory position within England and Wales is compatible with the intergenerational aspects of scientific progress within fetal gene therapy (FGT). Within the field of genomics, the fetal junction has become a site where gene therapists are developing a range of medical techniques, such as fetal gene therapy and in utero stem cell therapy. Utilising such techniques raises questions about the intergenerational aspects of scientific progress and how intergenerational rights can reshape regulation. The thesis focuses upon these key questions: Are the intergenerational issues of FGT taken into account by both direct and indirect stakeholders? Can intergenerational issues override the reproductive rights of the mother? Have intergenerational issues impacted upon the clinical applications implicit and manifest in this work? Addressing such questions is important because the conflict between the rights of the mother, fetus, clinical researchers and society have the potential to delay progress in FGT. In addressing these questions the thesis utilised thematic analysis of relevant regulatory institutional documents, from international declarations to regulatory guidelines; and semi structured interviews of identified FGT practitioners to identify areas of potential conflict. Following the data collection and analysis, the field data identified five key areas of potential conflict, which were then assessed using the Principle of Generic Consistency (PGC) as proposed by Alan Gewirth (1978) and later altered by Beyleveld and Brownsword (2001). The thesis will argue that the field data shows that established regulatory principles such as human dignity are of limited value in relation to FGT. In other areas such as informed choice, autonomy and intergenerational equity the PGC is applied to define and partially resolve the outstanding areas necessary for consistent ethical and regulatory guidance in FG

Principles of Fetal Surgery

Fetal therapy (in utero therapy) is a type of special therapy which aims to prevent or correct congenital anomalies in fetus, and prevents their severe consequences on later fetal development. It includes the use of in utero human fetal stem cell transplantation, fetal gene therapy and gene-editing technology as a new treatment for fetal genetic disorders. It started with open fetal surgery and then significantly advancing with innovations, toward minimally invasive fetal procedures, which are undoubtedly the future of fetal surgery, with the goal of providing the best possible fetal outcome, while minimizing the morbidity and mortality to the mother. The goal of fetal treatments is to decrease both fetal and maternal risks and prevent premature rupture of membranes. Fetal ultrasound and MRI are crucial for successful fetal interventions. Moreover, multidisciplinary fetal teams, including fetal surgeon, ultrasonographer, perinatologist, and anesthesiologist, are essential for optimum care to both mother and fetus. Finally, any new modality of fetal therapy must be thoroughly evaluated in animal models before clinical practice. In this chapter, we discuss the basic principles of fetal surgery, milestones of fetal surgery, specific fetal anomalies that are amenable for fetal surgery, successful fetal surgery criteria and future of fetal surgery