Research News

Welcome to the National Information and Advice Centre for Metabolic Diseases Research News Sheet - Vol 1 No 2

The contents of this news sheet has been gathered from around the globe during our research to update our information on metabolic diseases. The contents are general and not specific to our cause.

The Human Fertilisation and Embryology Authority has granted a licence to the Roslin Institute, which shot to fame with the cloning of Dolly the Sheep, enabling it to clone human embryos for use in medical research.

Specifically, the licence will enable the Roslin Institute to create stem cells from embryos produced by cell nuclear replacement, a technique also known as therapeutic cloning. The Institute’s researchers will also be able to study motor neuron disease, particularly in patients whose condition cannot be linked to genes already identified as causing the disease. Using these embryonic stem cells made with genetic material from patients with the illness, researchers can study the disease’s development in those who do not have the genes that are currently known to cause the disease. Whilst these embryonic stem cells would not be used to correct the disease, the study of these cells could help develop future treatments.

Single Gene Defects can Manifest Themselves as Distinct and Different Syndromes and Diseases in Humans

As a result of several research presentations given at the Lowe Syndrome Trust UK Symposium at the Royal Society, Carlton House Terrace, London SW1 on Thursday 2nd December, 2004, it has now become apparent that several clinical syndromes and diseases that have been reported as distinct and separate clinical manifestations in the medical literature can now, interestingly, be accounted for by mutations in one gene. Presentations from Professor Robert Nussbaum (National Human Genome Research Institute, NIH) and other researchers working on the molecular mechanisms leading to Lowe Syndrome have shown that a mutation in the OCRL-1 gene is the common cause of Lowe Syndrome that affects only young male children and presents as a wide range of clinical manifestations which clearly define the Lowe Syndrome. However, in another presentation from Professor Steve Scheiman from Upstate Medical University, New York, USA, there was data presented showing that a proportion of his patients that had been diagnosed with the phenotype of Dent’s Disease did not present with the expected gene defect in the renal chloride ion transporter (i.e. the CLCN5 gene) but rather were genetically mapped as to having mutations in the OCRL-1 gene, which is purported to be the cause of Lowe Syndrome.

These studies indicate that the clinical, physiological manifestations of an OCRL-1 mutation do not singularly account for just the clinical manifestations used to describe Lowe Syndrome; rather they can be presented as another phenotype describing a different disease (Dent’s Disease) which has similar renal problems but very distinct clinical characteristics. Thus, the previously held assumption that different syndromes and diseases could be tracked through different gene mutations is now put into question, and indicates that the medical descriptions for syndromes of diseases still stand as a clinical diagnosis but they are not simply explained by a genetic mutation.

London, United Kingdom, 19 January 2004 -- The International Alliance of Patients' Organizations (IAPO) today announced a historic partnership with the global organizations representing nurses, pharmacists and physicians. The International Council of Nurses (ICN), the International Pharmaceutical Federation (FIP) and the World Medical Association (WMA) have granted official partnership status to IAPO – the global group representing patients of all nationalities across all disease areas. These partnerships provide an important mechanism for health professionals and patients to work together towards quality patient-centred healthcare around the world.

Albert van der Zeijden, Chair of IAPO, welcomed the partnerships commenting, “We know that we cannot achieve patient-centred healthcare working on our own – we welcome this opportunity to work within supportive and understanding partnerships with health professional associations.” Judith Oulton, ICN’s Chief Executive Officer said, “As health professionals, this partnership reflects our commitment to understanding the needs and perspectives of patients, the focus of our work”.

Commenting on the resource implications, Dr Otmar Kloiber, WMA Secretary General, said “Exchange of knowledge and skills and the pooling of expertise and networks will be beneficial to our interactions with our member associations and with the World Health Organization (WHO).” On behalf of FIP, General Secretary, Ton Hoek, added, “We are very pleased with this partnership and would also encourage our member associations to seek useful collaborations with patients’ organizations to improve the delivery of healthcare worldwide”.

The IAPO has also released exciting plans to forward relationships between health professionals and patients at IAPO’s first Global Patients Congress in February 2005 in London. Patients’ organizations from around the world will work together with the leaders of ICN, FIP and WMA to find and implement ways to develop relationships between health professionals and patients on national, regional and international levels. Virginia Ladd, Board Member of IAPO and a patient with a long term chronic illness, welcomed the focus of the Congress commenting, “Good relationships between patients and the health professionals that serve them are based on mutual respect, trust and effective communication and will encourage advantageous outcomes for both patients and health professionals including increased adherence to therapies and satisfaction with care.”

Research has demonstrated that adolescents with ADHD are 2 to 4 times more likely to experience motor vehicle accidents, and over three times more likely than other teenagers to incur associated injuries.

Trials have shown that medication can improve the driving performance of those affected. In the study, the performance of the males was significantly worse than matched controls when they had been given immediate release methylphenidate before the test. However, 1 to 1.5 hours after taking medication, their driving performance improved greatly. Although this result demonstrates that medication treatment can improve driving, short acting medications must generally be administered 3 times per day to cover the whole day and blood level concentrations can also wax and wane during the day, which may be associated with fluctuating levels of symptom managements. When the final daily dose of medication is wearing off, there may be a "rebound" of symptoms that could make driving at this time more difficult.

Recently, an important advance in ADHD has been the introduction of longer acting preparations (e.g., Concerta). These medications often provide full day symptom management with a single dose, and because there is also less fluctuation in blood level concentrations, may reduce the ebb and flow of symptoms associated with short acting meds. This suggests that such medications may be even more effective in promoting safer driving among adolescents with ADHD.

Results from a recent study involving six adolescent males with ADHD clearly indicated that when they were treated with Concerta, they demonstrated less variability and performed significantly better throughout the day on objective measures of driving performance than when they were treated with the short acting medication. Although driving performance was comparable during afternoon and late afternoon assessments, in the evening, when parents are often most concerned about their teens' driving, the improvement in driving safety was substantial.

There are limitations to this study that are important to be aware of, firstly, adolescent females were not included, and the extent to which similar results would be found with girls is unknown. Second, only six adolescent males were tested, which is why the authors describe their results as preliminary. However, it was also the case that every participant drove substantially better during the evening assessments while receiving Concerta, so it is likely that the findings are robust. It cannot be concluded that Concerta is superior to other long acting ADHD medications, e.g., Adderall XR, Ritalin LA, Strattera, as these were not tested. Results from this study should also not be used to suggest that all adolescent males with ADHD should receive medication treatment. The impact of treatment on adolescents' driving is only one of several considerations when deciding on the most appropriate treatment for an individual person, and not everyone will have a positive response to medication.

Dr. James Garbern of Wayne State University School of Medicine confirmed that Pelizaeus Merzbacher Disease (PMD) is triggered by a defect in the Plp1 gene that codes for proteolipid protein (PLP). A total absence of PLP results in a milder form of PMD than that observed in children who overproduce it. Therefore, gene-silencing techniques aimed at stopping PLP production could be a potential treatment strategy for children who overproduce the protein.

Dr. Garbern mentioned that researchers at Sanofi-Aventis had developed an experimental drug, HP184, which increases nerve conduction velocity in the Long Evans shaker rat, which has a mutation in the myelin basic protein gene. Because there are similarities between these and mouse leukodystrophy models (e.g., the shiverer mouse), there is reason to believe this drug could be effective also in Pelizaeus Merzbacher and other myelin diseases.

Dr. Franca Cambi of the University of Kentucky talked about studies directed at explaining PLP splicing, a process by which the RNA (one of a group of molecules similar in structure to a single strand of DNA.) non-coding segments, i.e., the introns**, are separated from exons* that carry the genetic code. Mutations that interfere with the splicing process are believed to be responsible for the underproduction of PLP in some patients with Pelizaeus Merzbacher. She said that identifying the affected gene sequences and regulating their function in splicing can, in principle, result in the normal production of PLP and might hold the key to future therapies. She is in the process of identifying those sequences and suggested cell-specific regulation strategies.

In collaboration with Dr. Odile Boespflug-Tanguy of INSERM, France, Dr. Cambi is also working with RNA interference (RNAi) as a technique that inhibits overproduction of PLP. RNAi is a double-stranded RNA that is a potent inhibitor of its corresponding DNA. Two types of synthetic RNAi have been developed and proven successful in cell studies, and the technique is expected to eventually be helpful in those children affected by Pelizaeus Merzbacher who overproduce PLP. Both researchers are now working towards fine-tuning the procedure so that only the defective gene is targeted. An efficient system to deliver these “drugs” will then be developed and tested.

The Cystinosis Research Network is looking to enrol six patients over the age of 12 with cystinosis to take part in a Cysteamine Absorption study.

The purpose of the study is to obtain data that will ultimately help to create a more effective way (controlled-release) of delivering cysteamine to the body. This in turn may allow cysteamine to be given less than 4 times a day without diminishing its effect and can hopefully be taken without the unwanted gastrointestinal side effects.

A specially designed soft tube will be inserted into the nose and slowly passed into the stomach and intestine. Blood samples will be measured to determine the absorption and effect of cysteamine when it is administered into different sites of the intestine. We will also measure blood gastrin levels, the hormone that is normally responsible for producing stomach acid and causing gastrointestinal symptoms, following a dose of cysteamine.

For more information regarding the Cysteamine Absorption Study, please
contact: Meredith Fidler, PhD, study coordinator, email mfidler@ucsd.edu, Tel. (619) 543 2049.

The Identification of Biomarkers in Mucopolysaccharidosis (MPS) Disorders at the Institute of Child Health, London – Report by Dr Clare Beesley

Lysosomal storage diseases (LSDs) result from a fault in a gene that normally produces a functional protein/enzyme in the lysosomal system. This leads to the accumulation of specific molecules within the lysosomes of affected cells. The mucopolysaccharidoses (MPS) are a group of LSDs in which the primary enzyme deficiency leads to the accumulation of partially degraded glycosaminoglycans (GAGs) inside the lysosomes of the cells of patients. The accumulation of storage products is progressive and therefore clinical symptoms deteriorate with age. Very little is known about the ‘knock-on’ effect of this accumulation on other components of the cell. It is envisaged that the increased storage of GAGs inside cells will result in the appearance of storage products and other components of cells in bodily fluids, such as blood, at much higher concentrations than seen in normal unaffected individuals. The disease may also cause a decrease in the amount of some proteins that are normally found in unaffected people. Measurement of these proteins (termed biomarkers), which are either increased or decreased in patients, may provide biomarkers for a specific MPS disease or it may be found that some are common to all MPS diseases. Identification of these biomarkers will enable us to understand more about what effect the storage is having inside the cells and how this is leading to the disease symptoms. For example, are the cells dying prematurely, a process known as apoptosis, or are the cells becoming infiltrated with molecules involved in inflammation? The rate of appearance of these biomarkers in an individual will depend upon the underlying mutation in the gene and other genetic and environmental factors but they should provide a good indicator of the course of the disease. As the novel forms of treatment being developed may reduce the storage in the lysosomes, the biomarkers could be used to monitor the effectiveness of the treatment and the improvement in disease symptoms.

In the Biochemistry, Endocrinology & Metabolism Unit at the Institute of Child Health, our aim is to identify biomarkers in MPS disorders and to investigate the ‘knock-on’ effect of GAG storage inside cells by analysing differences in protein and gene expression between normal and diseased cells. The project is for two years and is supported by The Society for Mucopolysaccharide Diseases with funding from Jeans For Genes. The work that has been carried out so far has focused on the identification of biomarkers in MPS I, IIIA and IIIB patient samples.

Our department at the Institute of Child Health recently purchased a machine from Ciphergen called a surface enhanced laser desorption/ionisation machine (SELDI) which helps identify putative biomarkers in patient samples. The technology involves the binding of proteins to the chemical surfaces of ‘ProteinChips’. Proteins exist in the human body as globular molecules, which carry charges that are dependent on their structure and environment. There are also proteins which are hydrophobic (avoid water) and some which will bind to metal ions. There are several types of chips that have different chemical surfaces and therefore bind different sub-groups of proteins. Some chips bind positively charged proteins, some negatively charged proteins, others bind either hydrophobic or metal binding proteins. After a sample has been applied to a specific chip, only proteins that interact with that chip surface will be retained whilst unbound proteins are washed off with a buffer. The SELDI machine then analyses the proteins bound to the chip and generates a fingerprint of the proteins that is based on their size, and which is representative of those proteins contained in the sample that have bound to that chip. Analysing the same sample on a different chip will generate a different protein fingerprint because it will bind different types of proteins e.g. hydrophobic proteins. The software on the machine then allows you to compare a protein fingerprint from a MPS patient with that from a normal individual and any differences are highlighted. The machine only gives you an indication of the size of the protein, its charge, solubility or metal binding properties. Unfortunately it does not identify it for you!

During the first year, blood samples from 4 normal individuals, 4 MPS I (Hurler), 4 MPS IIIA and 4 MPS IIIB patients were analysed, in duplicate, on the SELDI machine using 4 different chip surfaces. Potential biomarkers were identified in all 3 MPS groups but since only a small number of patient samples were screened, more samples need to be analysed in order to validate these findings. Analysis of additional patient samples is currently underway and early indications suggest that not all patients have elevated levels of one particular biomarker but, in fact, there are several elevated biomarkers characteristic of MPS and patients appear to show different patterns. Some patients only have one or two of the biomarkers whereas others have five or six of them. However, a significant amount of analysis is still required before any concrete conclusions can be drawn. Once biomarkers or patterns of biomarkers have been identified in the Hurler subtype of MPS I, it will be interesting to see if they are present in the less severely affected Hurler/Scheie and Scheie patients. Also, with the availability of enzyme replacement therapy for MPS I, it will be interesting to see if the levels of potential biomarkers approach normal values during treatment. Once confirmed and validated, the next stage of the project will be to identify these potential biomarkers and understand more about the disease process.

Scientists and physicians at the University of Rochester Medical Centre have established a Batten Disease Diagnostic and Clinical Research Centre, a one-stop medical resource for children and families affected by the disease. The centre's resources include genetic testing for the disease; visits with doctors; information on what families can expect as the disease progresses; and development of research tools to help scientists seek better treatments or a cure. More details are available on the Web at http://dbb.urmc.rochester.edu/labs/pearce/bddcrc/index.htm.

David Pearce, Ph.D., a biochemist and Batten disease researcher who pulled together the team that founded the centre is the scientific adviser for the Batten Disease Support and Research Association (BDSRA), which is funding the centre.

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