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30 March 2004The Department of Health has awarded a total of £3 million in funding for trials of gene therapy for three single gene disorders, Duchenne muscular dystrophy (DMD), haemophilia and childhood blindness. An additional £1 million has been allocated to fund research into the long-term safety of gene therapy techniques. This funding is part of the £50 million set aside by the government in the 2003 Genetics White Paper “Our inheritance, our future - realising the potential of genetics in the NHS” to incorporate new genetic technologies into the NHS. Gene therapy refers to the deliberate replacement, removal or introduction of genes (or other genetic material) into the somatic cells of an individual to prevent or treat disease. Announcing the allocation of funding, Health Secretary John Reid commented: “Investment saves lives - that is why it is vital that we fund research into the latest cutting edge treatments such as gene therapy so that Britain remains at the forefront of medical research” (see press release).
The Muscular Dystrophy Campaign will receive £1.6 million for research at Imperial College London aimed at developing a ‘molecular patch’ (comprising anti-sense oligonucleotides) to replace part of the defective dystrophin gene, with the aim of restoring partial dystrophin production to affected children. It is hoped this would significantly moderate the severity of DMD in treated individuals; there is currently no treatment for DMD, and affected individuals usually suffer progressive disability followed by death in their early twenties. £500,000 will go to Oxford BioMedica, a spin-out company from the University of Oxford, for a trial of their treatment for Haemophilia A (an inherited blood-clotting disorder caused by a mutation in the gene for blood-clotting Factor VIII), and the remaining £900,000 will fund a trial of therapies for inherited childhood blindness led by Dr Robin Ali of the Institute of Ophthalmology and Institute of Child Health, University College London. These gene therapy trials will all be the first of their kind in the UK. The £1 million for research into safety issues has been allocated to four groups at the University of Glasgow, the Royal Free and University College London Medical School, Kings College London and University College London for research in areas including the safety of retroviral and adenovirus-associated vectors and hydrodynamic gene delivery.
11 March 2004An Australian woman is pregnant with the country’s first ‘designer baby’ and due to deliver in August. The parents, from Tasmania, have travelled to Sydney in New South Wales, a state where pre-implantation genetic diagnosis (PGD) is legal, to have the procedure to create a sibling who would be an exact tissue match for their four-year-old son, BJ. BJ has Hyper IgM Syndrome and is one of only 30 children in the Australia to suffer from the rare and incurable genetic disease. The disorder leaves BJ prone to infections; he currently undergoes blood transfusions to boost his immunity. BJ needs a blood marrow transplant from someone with his exact tissue type to cure the disease so his parents decided to undergo PGD. During IVF treatment, the embryos produced are screened to choose those that are disease-free. The healthy embryos are then tissue-typed to determine those that will match the tissue-type of the child to be treated. An embryo with the matching tissue-type is then implanted in the woman’s womb. PGD was successfully used in the United States, where Adam Nash was born to provide umbilical cord blood to cure his sister Molly.
There are ethical concerns about the use of PGD. The president of the Australian Medical Association, Bill Glasson, noted the fine line between the acceptability and unacceptability of the procedure. “If the intent is to create another child that is disease free and can help the sibling then it could be argued that it is ethically correct” he stated. “But if the intent is to create an embryo that is compatible with the sick child and in doing so discards a series of other embryos, then the process has to be questioned.” The Human Fertilisation and Embryology Authority (HFEA) has drawn the line slightly differently. It approved an application for PGD from the Hashmi family because there would be no guarantee that another child conceived naturally would not suffer from the same disease that afflicted Zain. However, the Whittaker family had to travel to the United States for PGD when their application was denied by the HFEA because the disease suffered by their child was not genetic. The HFEA’s argument was that PGD had to be used only when the embryo was at risk of inheriting the disease that affected the existing child.
BJ’s family is not concerned about the ethics of their decision to pursue PGD. They are happy that a new child is on the way, as they had planned to have more children, and pleased that their new child can help BJ. It is unclear whether BJ’s brother will indeed ‘save’ his brother’s life as BJ is currently responding well to the conventional treatment for Hyper IgM syndrome. If by the time of the baby’s birth BJ is still doing well, the baby’s umbilical cord blood will be stored.
9 March 2004President Bush has fired three members of his Council of Bioethics, including one member who has criticised his position on stem cell research. Elizabeth Blackburn has in the past publicly disagreed with the Bush administration’s position on human embryonic stem cell research, research that she supports but which is currently severely limited in the US. She has also in the past criticised the information in Council reports as misrepresenting the science. She believes that these disagreements are behind the reason she was replaced; she will publish her views on her dismissal in the online journal PLOS. As two of the new members are known for their conservative views on cloning, critics have raced to accuse Bush of filling the Council with only those with conservative views in line with his. White House officials deny this claim, stating that they had simply wanted to appoint new people with different expertise. Others see danger in this move, concerned that the current membership of the Council, with its conservative leanings, does not represent a wide range of views and will not be able to give well-balanced, neutral advice on the issues. As the president of the US Federation of American Societies for Experimental Biology, Robert Wells, stated in a letter to President Bush, “This decision undercuts the panel’s capacity to make recommendations based on the highest quality of information and a broad spectrum of viewpoints” [Check E (2004) Nature 428, 4].
This controversy follows concerns raised last month that Bush administration officials were distorting scientific advice to bring it in line with their conservative ideological stance. Scientists accused Bush of “…stacking scientific committees, censoring results and dissolving advisory panels” [Brumfiel G (2004) Nature 427, 663]. With this history of ill will, it is unclear how much support the future work of the Council will receive from the scientific community.
11 March 2004A new National Screening Committee (NSC) report (available from the National electronic Library for Screening) has recently been released following an NSC project to review ethnic issues in screening, with reference to the Race Relations (Amendment) Act 2000, which underlined the commitment of healthcare providers to provide equality of access to high quality health care, and to promote good race relations. Ethnic minorities comprise 9% of the total population of England and Wales; the most common ethnic groups are Chinese, Afro-Caribbean and Asian from India, Pakistan and Bangladesh. The NSC Ethnic Issues Review set out to investigate potential barriers and solutions to the provision of equitable access to screening programmes, including the legal obligations of the NSC and guidance available from the Department of Health and elsewhere. This was achieved by literature searching and review, and by consultation with key individuals.
One key observation from the interviews conducted was that race and health are frequently perceived as being separate issues, except in those areas with large ethnic minority populations. Problems relating to recruitment into screening programmes and obtaining informed consent due to language barriers and lack of cultural sensitivity were underlined, as were misconceptions among healthcare staff about certain ethnic communities; an example cited was that Muslim women were frequently not given the opportunity to discuss family planning although many would be happy to do so. Literature searches revealed a significant body of work on ethnic minority access to cancer screening programmes, but little had been done to meet the needs of ethnic minorities with respect to other programmes. In particular, there was relatively little research from the UK as opposed to countries such as the US and Australia. Barriers to the uptake of screening were found to include linguistic and cultural difficulties (such as embarrassment about personal issues) as well as a lack of knowledge and understanding about the conditions being screened for. Effective interventions to improve uptake by minority groups included various means to improve understanding by providing multilingual and culturally sensitive information, particularly aimed at local communities.
Key points from the Race Relations Act proposed in the report to be relevant to screening include the need to monitor the effects of policies and to assess the likely impact of proposed policy changes on the promotion of race equality. The report concludes that there is a legal and professional requirement for the health service to ensure equitable access to services for ethnic minorities, and proposes that individual screening programmes should eventually develop their own Race Equality Scheme. No specific recommendations are made for these schemes, but hope is expressed that the evidence available on effective interventions to improve uptake will be of use in developing solutions. A draft pilot Race Equality Scheme (for the national Down Syndrome Screening Programme) is provided as part of the report, in which five key areas are identified: production and delivery, accessibility and monitoring of information, along with staff training and research.
Comment: This report poses a significant challenge to UK screening programmes in terms of developing equitable access for ethnic minorities, particularly since there are often greater differences between different ethnic groups than between minority ethnic population as a whole and the general population. Moreover, the uneven distribution of ethnic minorities across the UK (concentrated primarily in urban centres, with almost half of the total ethnic minority population living in London) means that national screening initiatives will have to consider specialised regional approaches to adequately address this brief. However, as the ethnic minority population continues to rise, the importance of ethnic issues in healthcare is likely to become increasingly prominent.
18 March 2004The Chancellor’s 2004 Budget speech includes positive gains for the medical research community. Brown has promised that the Government will spend more money in the areas of science and engineering, while also protecting the increases announced in the 2004 Spending Review. Under his plans, spending will increase by £100m by 2008. In order to determine how this investment will be handled, there are plans to develop a ten-year strategy framework, the UK Clinical Research Collaboration (UKCRC), bringing together government, business, research foundations and the investment community. The Government has stated in their press release that it aims, as a result of this targeted investment, for Britain to be “…one of the most competitive locations for science, research and development and for innovation.”
In addition to increased spending and as part of the 10-year plan, the Government is also planning to create new specialist research institutes, modelled on the National Cancer Research Institute (NCRI). The NCRI was set up in 2001 to take a strategic view of cancer research activities, identify gaps and coordinate efforts. This same format could work for other research efforts on specific diseases.
The overall purpose of the UKCRC “…will be to achieve effective and efficient translation of scientific advances into patient care, thereby improving national health and contributing to national wealth.” This continues the theme made clear recently in such reports as the Biosciences Innovation and Growth Team report, Bioscience 2015, and the Academy of Medical Sciences report, Strengthening Clinical Research. If this trend continues, it can be expected that more collaborations will be created between the major stakeholders to encourage investment aimed at supporting and strengthening basic science and translating it into patient care.
29 March 2004The Wellcome Trust, an independent UK research-funding charity, has called for a new public health strategy, “…to foster and enhance research into major public health problems which threaten the UK population…” according to a press release today. This is based on the recommendations of a report, commissioned by the Wellcome Trust, prepared by an independent working party of experts in public health medicine, the Public Health Sciences Working Group. Their report, Public Health Sciences: Challenges and Opportunities,” focusses on an issue raised in the 2002 Wanless Report, Securing Our Future Health: Taking a Long-Term View. In that report, Deryck Wanless recommended that more effort needed to be put into health improvement and disease prevention in order to reduce future NHS expenditures.
The Working Group was asked, “…to consider the current state of the public health sciences in the UK and make recommendations on measures that will enhance their impact upon the public health.” They concluded, like Wanless, that more attention needs to given to preventive measures and promoting healthy behaviour. In this way, the emphasis can shift the NHS’ focus, eventually, from treating ill health to disease prevention. This change in focus could save the NHS millions of pounds in the future. However, there is a lack of evidence upon which to judge the cost-effectiveness of public health measures.
The Working Group acknowledged the history successful public health measures and, in order to increase support for this work, has recommended that more investment be made in the area of public health sciences. Several actions were recommended: a strategic planning group should be created to develop future policy, regulatory barriers to effective public health work need to be identified, more investment needs to be put into academic training for future public health professionals, Public Health Centres should be created to bring together experts in different fields to address public health issues, more effort should be put into bettering public understanding of public health risks, and evidence-based policy should be developed.
The government will most likely take this report ‘on board’ as it is preparing a new initiative in the area of public health. Deryck Wanless was asked last year to update his 2002 report; his 2004 report, Securing Good Health for the Whole Population, published in February, reconfirmed his belief for the need to move towards “…the maintenance of good health.” In addition, the government has stated it plans to publish a White Paper on Public Health this summer
30 March 2004The Department of Health has awarded a total of £3 million in funding for trials of gene therapy for three single gene disorders, Duchenne muscular dystrophy (DMD), haemophilia and childhood blindness. An additional £1 million has been allocated to fund research into the long-term safety of gene therapy techniques. This funding is part of the £50 million set aside by the government in the 2003 Genetics White Paper “Our inheritance, our future - realising the potential of genetics in the NHS” to incorporate new genetic technologies into the NHS. Gene therapy refers to the deliberate replacement, removal or introduction of genes (or other genetic material) into the somatic cells of an individual to prevent or treat disease. Announcing the allocation of funding, Health Secretary John Reid commented: “Investment saves lives - that is why it is vital that we fund research into the latest cutting edge treatments such as gene therapy so that Britain remains at the forefront of medical research” (see press release).
The Muscular Dystrophy Campaign will receive £1.6 million for research at Imperial College London aimed at developing a ‘molecular patch’ (comprising anti-sense oligonucleotides) to replace part of the defective dystrophin gene, with the aim of restoring partial dystrophin production to affected children. It is hoped this would significantly moderate the severity of DMD in treated individuals; there is currently no treatment for DMD, and affected individuals usually suffer progressive disability followed by death in their early twenties. £500,000 will go to Oxford BioMedica, a spin-out company from the University of Oxford, for a trial of their treatment for Haemophilia A (an inherited blood-clotting disorder caused by a mutation in the gene for blood-clotting Factor VIII), and the remaining £900,000 will fund a trial of therapies for inherited childhood blindness led by Dr Robin Ali of the Institute of Ophthalmology and Institute of Child Health, University College London. These gene therapy trials will all be the first of their kind in the UK. The £1 million for research into safety issues has been allocated to four groups at the University of Glasgow, the Royal Free and University College London Medical School, Kings College London and University College London for research in areas including the safety of retroviral and adenovirus-associated vectors and hydrodynamic gene delivery.
15 March 2004An increasing number of epidemiological studies are utilising genetic technology to provide a more detailed insight into the underlying causes of complex diseases. Recently, two such studies have identified a number of single nucleotide polymorphisms (SNPs) that may predict susceptibility to type II, or non-insulin dependant, diabetes (NIDDM). These findings have been the subject of several press releases (The Washington Times, Reuters, and NHGRI). The two studies, conducted on Finnish (Silander, K., et al. Genetic variation near the hepatocyte nuclear factor-4a gene predicts susceptibility to type 2 diabetes. Diabetes 53:1141-1149) and Ashkenazi Jewish (Love-Gregory, L.D., et al. A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4a gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an Ashkenazi Jewish population. Diabetes:53;1134-1140) populations identified four SNPs located in the P2 regulatory region of the hepatocyte nuclear factor 4 alpha (HNF4A) gene which may be associated with an increased risk of developing NIDDM. HNF4A is a member of the transcription factor family of genes and acts as a switch to regulate the expression of many other genes. For example, HNF4A regulates the expression of genes involved in glucose metabolism and insulin secretion and directly activates insulin gene expression. The Finland-United States Investigation of NIDDM Genetics (FUSION) study applied a DNA pool-based, case-control design and identified ten SNPs to be associated with disease status in a Finnish population, with the strongest association suggesting that one particular SNP (rs2144908) may increase the risk of NIDDM by around 30%. Genotyping of additional SNPs, identified in the Ashkenazi Jewish population by Love-Gregory and colleagues, showed evidence for an association between four HNF4A SNPs and NIDDM in both Finnish and Ashkenazi Jewish populations. When taken together these results provide some initial evidence for a variant(s) near to the P2 promoter of HNF4A that may increase the susceptibility to NIDDM, however, they require verification in larger studies conducted in different populations.
Comment: These two studies, conducted in genetically distinct populations, provide initial evidence for a variant(s) located near or within HNF4A that may increase susceptibility to NIDDM. Among its many functions, HNF4A performs a regulatory role for a number of beta cell and liver cell genes and plays a role in regulating the secretion of insulin. Given the complex nature of diseases such as NIDDM, determining the precise association between gene variants and disease is problematic. It is to the author’s credit, therefore, that they sound a note of caution when attempting to draw firm conclusions on the basis of these results, including the caveat; “Additional variant identification and genotyping, study of other populations, and, finally, functional studies will be needed to identify the true type 2 diabetes susceptibility variant(s) at 20q13”.
26 March 2004Inborn errors of metabolism are a group of rare genetic disorders that, if untreated, can cause severely adverse clinical outcomes including irreversible mental retardation, physical disability and even death in affected babies. It is therefore extremely important to detect and accurately diagnose these disorders as soon as possible after birth. One of the best known examples of these diseases is phenylketonuria (PKU), an autosomal recessive disorder caused by mutation of the gene for a key enzyme involved in phenylalanine metabolism. In children with PKU, the levels of phenylalanine in the body build up to toxic levels, causing mental retardation and organ damage. However, early diagnosis and exclusion of phenylalanine from the diet allows affected babies to grow into normal, healthy adults.
A recent Health Technology Assessment report [Pandor A et al. (2004) Health Technol Assess. 8, 1-121] reviews the clinical efficacy and cost-effectiveness of neonatal screening for these inherited metabolic disorders using tandem mass spectrometry. Screening for inborn errors of metabolism involves measurement of the levels of specific metabolites present in the dried blood-spot specimens routinely collected from newborn babies. The presence of abnormal levels of certain metabolites (eg. amino acids and acylcarnitines) suggests the presence of particular metabolic disorders. Tandem MS (also called MS/MS) is a technique that has been shown to be suitable for the reliable detection of inborn errors of metabolism including PKU; it is highly accurate and able to measure multiple compounds simultaneously.
The review updated earlier HTA reports by means of a systematic review of research on tandem MS for newborn screening published since 1995, supplemented by a review of literature and a modelling exercise on the economics of tandem MS for neonatal screening in the UK. Evidence was mostly derived from studies of neonatal screening programmes using tandem MS in Australia, Germany and the USA, showing the technique to be rapid, highly sensitive (90–100%) and highly specific (99–100%), although direct comparison between studies was hampered by the lack of data on the false-positive and false-negative rates for individual disorders and different diagnostic criteria. Most of these programmes collected blood for screening within 72 hours of birth, in contrast to the UK where current practice is to take blood samples at 6-14 days; the report notes that “slightly earlier” collection in the UK might facilitate prompt detection of disease, but could also influence test performance.
The reviewers found the UK screening programme for PKU to be well established and that tandem MS is suitable for the reliable detection of PKU and of MCAD deficiency, a disorder of fatty acid metabolism that is also treated by dietary management. There was a lack of reliable evidence for the efficacy of the technique in the detection of other inborn errors of metabolism. Cost-effectiveness analysis using economic modelling is reported to indicate that replacing current techniques with tandem MS for screening of PKU alone could not be justified, but that the addition of screening for MCAD deficiency as part of a neonatal screening programme for PKU using tandem MS would be cost-effective. The review therefore concludes that current evidence supports the introduction of tandem MS into a UK combined neonatal screening programme for PKU and MCAD deficiency. Although the technique has the potential to simultaneously screen for multiple diseases, the lack of evidence precluded a decision with respect to other metabolic disorders. The authors therefore call for further research into the UK incidence of these genetic disorders, the effect of early detection on outcomes and the likely economic impact of screening.
5 March 2004Non-invasive prenatal tests such as serum screening and ultrasound are useful in the identification of potential foetal abnormalities, but do not permit definitive diagnoses to be made. Reliable diagnostic tests currently require the use of invasive techniques such as amniocentesis and chorionic villus sampling, procedures that carry an associated risk of miscarriage. For some years now there has been interest in sampling foetal DNA from maternal blood samples as a safe alternative to these invasive procedures; this approach has already been successfully used to determine the gender of male foetuses, by identification of sequences from the foetal Y chromosome in the maternal circulation. However, previous attempts to develop methods for screening foetal DNA from maternal blood for genetic abnormalities have been limited by the very low levels of foetal DNA that can typically be recovered.
Research published this month in the Journal of the American Medical Association (JAMA) by scientists from the US company Ravgen Inc. presents a method to increase the percentage of free foetal DNA that can be obtained from maternal blood samples [Dhallan R et al. (2004) JAMA 291, 1114-1119]. The key to their technique was limiting the degree of lysis (bursting) of maternal cells in the blood samples, since this releases free maternal DNA into the sample and effectively decreases the proportion of foetal DNA. This was achieved by careful processing of blood samples, and by the addition of formaldehyde (a chemical that stabilises cells and reduces levels of lysis) to the blood samples. The authors suggest that formaldehyde may also stabilise DNA and inhibit its breakdown by enzymes, increasing the total levels of free foetal DNA that can be recovered.
In the study, blood was collected and analysed from a total of 79 pregnant women, 75 of whom were carrying a male foetus. Two tubes of blood were collected from each woman: formaldehyde was added to one whilst the other was left untreated. The percentage of foetal DNA present in each sample was determined using PCR amplification of a Y-chromosome specific sequence (representative of foetal DNA), and a second sequence present in both the foetal and maternal DNA; the relative quantities of the foetal-specific and general sequence markers allowed the proportion of foetal DNA to be calculated.
In the first phase of the study, samples from ten women were analysed; the mean proportion of foetal DNA detected in the treated samples was 20.2%, whereas that in the untreated samples was only 7.7%. Because this difference was statistically significant, the study was then extended to a further 69 pregnant women, this time to determine the percentage of free foetal DNA in formaldehyde treated blood samples from a larger population; the mean figure was found to be 25%. However, a considerable degree of variability was observed between individual samples. The authors note that a larger study is desirable to investigate this phenomenon, whilst proposing several potential explanations, but conclude that their methods effectively increase the percentage of foetal DNA present in the maternal blood samples, making its detection and analysis for genetic abnormalities much more feasible.
Comment: The authors’ claim that their work provides a “solid foundation for the development of a non-invasive prenatal diagnostic test” may be somewhat premature; routine screening of foetal DNA from maternal blood would require a reliable minimum recovery of foetal DNA, which has not yet been shown to be practical. The difficulty of distinguishing the DNA of female foetuses from maternal DNA has not been addressed by this study. However, the significant increases in recovery of foetal DNA produced by a relatively simple technique is nevertheless promising, and could potentially bring maternal blood sampling as a safe and easy method for screening foetal DNA screening much closer to realisation.