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Families with monogenic disease

30 November 2009

By Rosie Beauchamp

Appeared in BioNews 536
On Wednesday 18th November 2009 a Progress Educational Trust (PET) conference - 'Does Genetics Matter? Help Hype and the New Horizon of Epigenetics' - was held at Clifford Chance in Canary Wharf. The initial session of the day was called 'Families with Monogenetic Disease' and was chaired by Dr Christine Patch, Chair of the British Society for Human Genetics and Consultant Genetic Counsellor and Manager at Guy's Hospital.

The panel for this session comprised of Dian Donnai, Professor of Medical Genetics at the University of Manchester, Adrian Thrasher, Professor of Paediatric Immunology and Director of the Centre for Immunodeficiency at the Institute of Child Health and Irwin McLean, Professor of Human Genetics and Head of Molecular Medicine at the University of Dundee.

The first speaker was Professor Donnai, who opened the session with a talk entitled 'The importance of information'. Her key theme was the continued importance of research and increased knowledge in the area monogenetic diseases and the value of this information for affected families, clinical care, the public, and as an infrastructure for research. She stressed the therapeutic value that information and increased knowledge can bring to those who live with the uncertainty of unidentified conditions, either in relation to themselves or to an affected member of the family.

Professor Donnai presented a case study concerning a family in which a number of related members had suddenly and inexplicably dropped dead, a condition referred to clinically as 'sudden death syndrome'. The diagnosis can encompass a range of conditions, but often a heart problem is determined as the cause of death and in some cases there is a genetic origin. Through pinpointing the specific genetic mutation responsible for the disease, it was possible to identify members of the family who were at risk from the condition and offer them genetic counselling to help them understand the implications of this information. Those found to carry the gene mutation could be offered preventative treatment in the form of a defibrillator, an electronic device which delivers a therapeutic dose of electrical energy to the heart to normalise the heartbeat, while those who were found not to carry the gene mutation benefited from the relief of knowing that they were not at risk. Furthermore, this information made it possible for affected members of the family to screen pregnancies to provide them with information about whether or not the developing fetus would be at risk from the condition. By diagnosing this condition, and finding the relevant gene mutation, the family were effectively freed from the burden of uncertainty surrounding the risk to themselves and their future children of inheriting the condition.

In another example, she recalled a family who had a son diagnosed with Duchenne Muscular Dystrophy (DMD), a devastating childhood muscle wasting condition. Before the identification of the genetic mutation, the family's only option to reduce their risk of future children having the condition was to have prenatal diagnosis and terminate all male pregnancies. But after the genetic mutation specific to the family had been identified it was possible to offer the couple preimplantation genetic diagnosis to ensure that only embryos without the mutation were implanted back into the woman's womb to continue developing. The couple went on to have a healthy son, as did their daughter, who was also a carrier of the condition. Furthermore, there were a thousand other women at Professor Donnai's clinic who were in exactly the same situation as the couple, and genetic testing was able to show that only 300 of them carried the DMD gene mutation, meaning that 600 people were freed from the terrible burden of not knowing whether they were at risk from having a child with the condition.

Professor Donnai emphasised the commonality of monogenetic diseases, citing that at least a third of deaths in childhood in the UK, 50 per cent of hospitalisations and 50 per cent of cases of blindness or deafness in children, are linked in some way to a monogenic disorder.

In her closing remarks Professor Donnai reinforced the crucial place of information in informing and educating families, publics and clinical care about monogenetic disorders. She urged government and funding bodies to recognise the value of this information and to respond by providing further funding and resources to support research into these conditions.

Second to speak was Professor Thrasher who spoke on 'Progress in Gene Therapy' and began by addressing the expectations surrounding gene therapy and the general feeling that it has yet to deliver on the promise of providing a potential treatment for a wide range of monogenic conditions. In response to this concern, Professor Thrasher highlighted that advances were occurring in this field, however incrementally, and predicted that they would continue to develop over the coming years and decades.

Professor Thrasher used the example of gene therapy for treating immunodeficiency in children. Originally developed as a treatment for so-called 'bubble' children, Professor Thrasher described the success that his team at the Institute for Child Health had had in using gene therapy to treat severe combined immunodeficiency (SCID). Children affected by SCID have a faulty gene that means their immune systems do not work properly, so their bodies cannot fight infections effectively. In the absence of any effective treatment or cure, they must be kept in a completely sterile environment, hence the name 'bubble' children. A bone marrow transplant from a tissue matched donor can cure the condition, but the procedure carries significant risks and in some cases a suitable donor can't be found. In cases where only a partially matched donor can be found, the risk of tissue rejection is high, with only 1 in 2 children surviving the procedure.

Professor Thrasher described how he and his team lead a pioneering trial of gene therapy for 20 children with X-linked SCID carried out earlier this decade. The London team extracted bone marrow from the children and, using a retrovirus which had been engineered to make it harmless, inserted a working copy of the gene into some of the bone marrow stem cells, before transfusing the bone marrow back into the children. After several months, eighteen of the children started to develop normal immune system cells. Although five of the eighteen children later developed leukaemia as a direct result of their treatment, given the prognosis of the condition without treatment, many experts still hail the trial as a huge success.

Professor Thrasher provided another example of successful gene therapy in relation to an inherited form of blindness called Leber Congenital Syndrome (LCS), which causes progressive deterioration in vision and can lead to blindness in teenagers. Each participant underwent a complex operation, during which a harmless virus, injected into the retina at the back of the eye, delivered working copies of the defective gene into the cells.

Professor Thrasher demonstrated the success of the trial by showing the audience a video of a man with LCS attempting to manoeuvre through a darkened maze. Before his treatment the journey took him seventy seven seconds and he made several collisions with the partitions. Six months after having the treatment, the participant travelled through the maze in just fourteen seconds.

Professor Thrasher drew attention to the ongoing need to improve and refine gene therapy technologies in order to increase their efficacy and make them safer for patients. He pointed to the recent reports of gene therapy being successfully used to treat two young boys with a devastating and fatal brain disease called adrenoleukodystrophy (ALD) and also to new trials for a broad range of conditions, including cystic fibrosis and Duchenne muscular dystrophy, as evidence for the burgeoning field of gene therapy and its huge potential for providing cures for a broad range of monogenic disorders.

The final speaker on the topic of monogenetic disease was Professor Irwin McLean who presented on the topic: 'A winning candidate gene for eczema and allergic asthma'. Professor McLean began by introducing a gene called Filaggrin. The filaggrin gene produces a protein in the outer layers of the skin that helps it produce a protective barrier. This barrier stops allergens entering the body and causing eczema and asthma, as well as hay fever and other allergies, and also prevents water loss to keep the skin hydrated. A mutation in the filaggrin gene affects the integrity of the barrier, thereby making the skin more permeable to allergens and causing allergic reactions. It has also been discovered that Filaggrin is a risk factor for some types of asthma, creating a genetic link between eczema and asthma sufferers.

Previous work has suggested that about half of severe cases of eczema in children were caused by defects in the filaggrin gene. The gene defect is carried by 10 per cent of the population. Mice with the gene defect have been shown to have an allergic inflammation comparable to eczema in humans. Professor Irwin McLean said that the filaggrin-deficient mice could help with the identification of key substances in the environment responsible for the huge increase in allergic disease. These mice may also provide the key to unlocking new and improved therapies for eczema, asthma and allergies by targeting or supplementing the defective filaggrin gene.
The discovery of the filaggrin gene has helped scientists to better understand what goes wrong in the skin of patients with eczema, paving the way for the development of new treatments, Professor McLean said. This case provides just one example of how research into a monogenic disorder has lead to better understanding and improved treatment of a widespread and common condition.

Following the talks questions were taken from the floor. The first question posed to Professor Donnai, asked why she had not mentioned the government in her presentation. Professor Donnai's reply focused on what she perceived to be the recent neglect of monogenic disorders in the literature and the tendency of health policy to focus on more complex genetics. Professor McLean supported this opinion, pointing out that we largely owe our current understanding of genetics to the research on monogenic, not polygenic, disorders.

The next question was directed at Professor Thrasher, asking him to elaborate on the disadvantages of gene therapy. Professor Thrasher admitted that gene therapy had been linked to leukemia, but pointed out that, unlike SCID, these cases were treatable and that more work has since been done to refine vectors and reduce the likelihood of this side effect.

Finally, Marcus Pembrey, Chair of PET, asked Professor McLean how, from an evolutionary perspective, ten per cent of the white British population now carry a defective filaggrin gene? McLean said that one theory was that people with less filaggrin protein had more porous skin, which meant they were expose to more allergens and therefore developed a heightened immunity to diseases. He noted that eczema is in fact modern problem, perhaps caused by overzealous washing and cleanliness during childhood, but that further research was needed to prove this theory.

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