Metabolism, Endocrinology & Bone - Recent Highlights

Lysosomal storage disorders

The Cox group have extended preclinical studies of rAAV-mediated gene transfer to the brain in an inducible model of Sandhoff disease to both refine understanding of disease pathogenesis (Cox & Cachón-González, J Pathol 2012) and identify effective therapeutic stratagems.

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The Cox group have extended preclinical studies of rAAV-mediated gene transfer to the brain in an inducible model of Sandhoff disease to both refine understanding of disease pathogenesis (Cox & Cachón-González, J Pathol 2012) and identify effective therapeutic stratagems. Long-term expression of β-hexosaminidase in this model brings about sustained correction of the disease (Cachón-González et al., Mol Therapy, 2012). Collaborative studies to confirm these effects in a larger, naturally occurring model of GM2 gangliosidosis are underway (Bradbury et al., Mol Therapy, 2013) as a requirement for the planned clinical programme. Myeloma and B cell lymphoma are important causes of death in patients with non-neuronpathic Gaucher disease treated with enzyme replacement therapy. Cox and colleagues have established a model of Gaucher disease with these tumours, and identified predictive biomarkers for tumour development (Pavlova et al., J Path. 2013). This raises the possibility of developing a therapy to prevent tumour development and, in partnership with the NIHR, an application for a patent of use is under consideration.

Future plans for use of BRC resources: the MRC, under the DFPS-DCS scheme, approved funding to establish a UK-European trial of gene therapy for patients with Tay-Sachs and Sandhoff disease in May 2013. An application for designation of the therapeutic vectors as Advanced Therapies that are registered Orphan Medicinal Products is also planned. BRC support is crucial to sustain the impetus of the intensive developmental work for this translational phase, and to extend the studies to develop clinical therapies for a related disorder, Krabbe disease. Cox also leads a programme on ‘Predictive measures to stratify clinical outcomes in children and adults with Gaucher disease and responses to specific therapies’ as part of the MRC Stratified Medicine Programme. BRC support is crucial to understanding the causation and prevention of malignant sequelae in this disease in order to develop a therapy for patients at risk.

March 2014 


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Bone research

Having identified focal osteoporosis in living patients as a cause of femoral neck fracture using the Cortical Bone Mapping technique (co-invented with BRC support alongside Cambridge engineers), Poole and colleagues identified the anti-fracture effects of treatment with denosumab, an anti-RANK...

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Having identified focal osteoporosis in living patients as a cause of femoral neck fracture using the Cortical Bone Mapping technique (co-invented with BRC support alongside Cambridge engineers), Poole and colleagues identified the anti-fracture effects of treatment with denosumab, an anti-RANK ligand (manuscript under review), which adds mineral and thickens bone in areas of the hip at risk of fracture. Studies showed that a fracture-critical area of the elderly hip lost three times as much bone over 5 years as similar areas nearby (Johannesdottir et al., JBMR, 2013). Investigations into genetic determinants of bone stiffness identified 10 SNPs, including TMEM135 a gene recently linked to osteoblastogenesis and longevity (Moayyeri et al., Human Molecular Genetics, 2014). COBRA (Cambridge Outpatients Bone Registry) uses the JCIS platform (developed during BRC 2007-12) and now includes >650 patients with rare bone diseases. Collaborations have been established with Oxfords’ NIHR Rare Diseases Translational Research Collaboration for Osteogenesis imperfecta phenotyping, and with Cox (Lysosomal storage disorders) to characterise bony complications and treatment responses in patients with Gaucher disease.

McCaskie, recently appointed as Professor of Orthopaedics, is establishing a translational research program in regenerative surgery for bone, cartilage and other musculoskeletal tissues, adopting an inter-disciplinary approach that will utilise the BRC cell phenotyping hub and the GMP stem cell laboratory. Poole’s CT imaging findings have led to further clinical studies/industry grants and several innovation awards. BRC support is central to a recent NHS Innovation award applying hip CT imaging in clinical diagnosis. The technique is showing promise in diagnosing clinically relevant hip osteoarthritis. Studies are underway to show how targeted exercise affects bone and effects of anti-sclerostin antibodies on the spine.

March 2014


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Type 1 Diabetes

Dunger completed screening for the AdDIT study, a multi-national controlled trial of statins/ACE inhibitors in 3,500 young people with type 1 diabetes.

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Dunger completed screening for the AdDIT study, a multi-national controlled trial of statins/ACE inhibitors in 3,500 young people with type 1 diabetes.  Baseline data confirm that variation of albumin excretion within the normal range is associated with cardiovascular disease and risk for diabetic nephropathy (Marcovecchio et al., Diabetes Care, 2013). In the first closed loop insulin study in children with T1D at home, 16 adolescents used the artificial pancreas during night for 3 weeks (Hovorka et al., Diabetes Care, 2014) documenting improved glucose control and reduced number of nights with hypoglycaemia. Feasibility studies of first closed loop system in critically ill patients ( Leelarathna et al., Critical Care, 2013) and in type 2 diabetes ( Kumareswaran et al., Diabetes Care, 2013) have prepared the way for larger studies.

Future plans for use of BRC resources: home studies to evaluate use of the artificial pancreas in adults, children and adolescents, and pregnant women for up to three months are underway, with plans for a large, multicentre, multinational study in collaboration with an industrial partner. The artificial pancreas will be evaluated in non-critically ill inpatients with type 2 diabetes to address suboptimal glucose control on general wards.


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Thyroid disorders

We have found that defects in IGSF1, a membrane protein, cause X-linked, congenital, central, hypothyroidism and testicular enlargement (Sun et al., Nat Gen, 2012).

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We have found that defects in IGSF1, a membrane protein, cause X-linked, congenital, central, hypothyroidism and testicular enlargement (Sun et al., Nat Gen, 2012). We have identified the first adult female with defective thyroid receptor alpha, with tissue-selective hypothyroidism but normal thyroid function tests (Moran et al., JCEM, 2013). We have identified a novel albumin gene defect in familial dysalbuminaemic hyperthyroxinaemia. Dr Nadia Schoenmakers, previously a BRC-funded clinical research fellow, is now an independent investigator, studying the genetic basis of congenital hypothyroidism, supported by a Wellcome Trust Intermediate Fellowship. NIHR BRC funding has enabled a laboratory clinical scientist to develop tandem mass spectrometric assays for thyroid hormones & metabolites. Pituitary/Neuroendocrinology: Acromegaly: in collaboration with Quotient Bioresearch (Fordham, UK) we have developed a method to quantify IGF-1 in plasma/serum; in a parallel clinical trial (ACROPAT) we performed the most comprehensive phenotyping to date of patients with newly-diagnosed acromegaly pre- and post-primary medical therapy. Neuroendocrinology: in a cross-disciplinary (endocrinology, psychiatry, Judge Business School) study, we have shown that existing influential models in neurobiology, economics and finance, which assume stable risk preferences over time, are fundamentally flawed, and that physiology-induced shifts in risk preferences may be an important cause of financial market instability (Kandasamy et al., PNAS, 2014).

Dr Schoenmakers is developing a clinical genetic diagnostic platform for Congenital Hypothyroidism using multiplex gene amplification and sequencing. BRC support will also initiate consultant-led service with clinical, biochemical and genetic diagnostic management of Rare & Unusual Thyroid Disorders, with the expectation that National Specialist Commissioning will support this in the future.

March 2014


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Insulin resistance

Members of the MEB theme recently identified two novel monogenic causes of severe insulin resistance (IR) and contributed to the discovery of a third novel disorder (Weedon et al., Nat Gen, 2013).

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Members of the MEB theme recently identified two novel monogenic causes of severe insulin resistance (IR) and contributed to the discovery of a third novel disorder (Weedon et al., Nat Gen, 2013). Biallelic mutations in NSMCE2 were shown to cause a novel syndrome characterised by dwarfism, gonadal failure and extreme IR, and biallelic mutations in PCYT1A were shown to be associated with a novel lipodystrophic syndrome (under review). Following work outlined in the previous report, we established a study focusing on segmental overgrowth due to mosaic genetic activation of phosphatidylinositol-3-kinase. This has been adopted as part of the NIHR UK Rare Genetic Diseases Consortium, enabling nationwide recruitment.  BRC funding was crucial in the translational development of the original findings, and has recently been boosted by £200K from the NIHR Rare Disease Translational Research Collaboration for in-depth phenotyping of affected patients, with a view to designing clinical trials in collaboration with pharma and colleagues in France and at NIH. Our recently established National NHS Service for Patients with Severe Insulin Resistance continues to flourish and has led to significant clinical improvements for patients attending the clinic. We have also established clinically accredited genetic testing for a large majority of the prevalent causes of severe monogenic IR.

 We plan to continue to use BRC support strategically to bridge the gap between research and fully fledged clinical translation, as evidenced already by development of a National Severe Insulin Resistance Service, and current efforts to develop clinical trials in and multidisciplinary treatment of segmental overgrowth. Specifically, continuing BRC support will enable expansion of our cohorts of patients with severe IR and overgrowth disorders, and will support our efforts to make recombinant metreleptin available to patients. This is by far the most effective therapy for the metabolic disease associated with generalised lipodystrophy. It is currently under the auspices of a ‘compassionate use’ programme, which we hope will bolster efforts to ultimately licence this agent.

March 2014


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Obesity research

Major scientific discoveries include the first description of highly penetrant genetic obesity syndromes involving the disruption of SH2B1 (Doche et al, JCI, 2012), SIM1 (Ramachandrappa et al., JCI, 2013), MRAP2 (Asai et al., Science, 2013) and the cellular scaffolding protein, KSR2 (Pearce et al...

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Major scientific discoveries include the first description of highly penetrant genetic obesity syndromes involving the disruption of SH2B1 (Doche et al, JCI, 2012), SIM1 (Ramachandrappa et al., JCI, 2013), MRAP2 (Asai et al., Science, 2013) and the cellular scaffolding protein, KSR2 (Pearce et al., Cell, 2013). Characterising patients with loss-of-function mutations in KSR2 provided the first evidence that genes can affect metabolic rate and fuel utilisation. In addition, novel common variants associated with severe childhood obesity were discovered as part of a genome-wide-association study (Wheeler et al., Nat Genet, 2013). With the support of BRC-funded co-ordinators and nurses, we re-consented over 1000 patients in the Genetics of Obesity Study for whole exome sequencing as part of the Wellcome Trust UK10K Initiative. This project has identified multiple new genes associated with severe human obesity.

Future plans for use of BRC resources: BRC support in obesity will greatly aid the re-consenting of patients for whole genome sequencing as part of the Genome England Initiative in Rare Diseases. Identification of new genes will inform the development of a diagnostic test for the genetic obesity syndromes funded by the cross-cutting Genomics theme of the BRC. This will be available within the NHS, with the support of the East Anglia Regional Genetics Service. Our large cohort of patients, established and maintained with BRC support, forms the basis of several collaborations with Industrial partners (Pfizer, AstraZeneca, Eli Lilly, Takeda) to identify and validate obesity targets. With Rhythm Pharmaceuticals, we will lead the first Phase II clinical trial of a melanocortin receptor agonist in obese patients with MC4R deficiency in 2014.

March 2014


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Gene identified that could provide clues to brain pathways that regulate weight

Researchers from the University of Cambridge and Boston Children’s Hospital have discovered a genetic cause of severe obesity which, although rare, raises new questions about weight gain and energy use

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In order to explore the role of the signaling protein Mrap2, Dr Joseph Majzoub, Chief of Endocrinology at Boston Children’s Hospital and lead investigator on the study, developed a mouse model in which the Mrap2 gene was missing. The research found that the mice lacking this protein gained a significant amount of weight even when they didn’t eat more food, suggesting that the affected gene appears to be involved in regulating metabolism. The research is published in the 19 July 2013 edition of the journal Science.

“Mice with the mutation gain more weight and are somehow more efficient with the food they eat,” says Majzoub. “They’re not burning it; they’re somehow holding on to it.”

To investigate the gene in humans, Majzoub collaborated with Professor Sadaf Farooqi from the University of Cambridge to examine groups of severely obese patients from around the world. The team found four rare mutations in the MRAP2 gene among the 500 people they screened; each of the four affected patients had only one copy of the mutation. While the finding suggests that these MRAP2 mutations may contribute to obesity in less than 1 percent of the obese population, the finding of a new gene could provide clues into the brain pathways that regulate weight, which could ultimately be useful for developing new treatments.

Professor Farooqi said: “The discovery that the disruption of MRAP2 causes obesity adds to a growing body of work that illustrates how certain genes work in the brain to regulate weight. Our aim is to find the genetic determinants of body weight and by doing so, to find better ways to prevent and treat obesity and associated health problems such as diabetes.”

The Mrap2 gene appears to work by fine-tuning signals through a receptor in the brain called the Melanocortin 4 receptor (Mc4r). MC4R is one of the critical control points in the brain for the regulation of appetite and energy expenditure (how we burn calories). Prof Farooqi and colleagues in Cambridge have previously shown that genetic changes that disrupt the MC4R gene can cause obesity in people, which often begins in childhood. This new discovery adds a further piece to the puzzle, by suggesting that defects in a different gene can indirectly impact on MC4R and thus contribute to obesity.

While changes in diet and levels of physical activity underlie the recent increase in obesity in the UK and worldwide, there is a lot of variation in how much weight people gain. This variation between people is largely influenced by genetic factors. The discovery of a new obesity gene, MRAP2, shows that the body’s mechanisms for regulating weight are likely to be complex. The Cambridge team is continuing to work to find other new genes for obesity, findings which they hope to translate into beneficial therapies in the future.

Professor Farooqi’s research was funded by the Wellcome Trust.

- See more at: http://www.cam.ac.uk/news/genetic-mutation-causes-obesity#sthash.oKb5yhE...


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New cause of thyroid hormone deficiency discovered

An international collaboration involving Dr Nadia Schoenmakers and Krishna Chatterjee at the University of Cambridge Metabolic Research Laboratories, and scientists from McGill University and researchers in The Netherlands, Italy and Australia have discovered that mutations in a gene called...

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The disorder is X-linked, but many affected individuals remain undiagnosed; accordingly, genetic testing and ascertainment of cases is likely to be of clinical benefit.  The disorder is also associated with testicular enlargement and the mechanism for this remains to be elucidated.

The full article published in Nature is available to read here.

Loss-of-function mutations in IGSF1 cause a novel X-linked syndrome of central hypothyroidism and testicular enlargement.

 


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