Cambridge has been leading research into monoclonal antibodies to identify effective treatments for multiple sclerosis
What can be done when the body launches an immune attack against its own tissue? The autoimmune disease multiple sclerosis is the most common disabling neurological condition to affect young adults, with over 85,000 people affected in the UK, over 250,000 in the USA, and about 2.5 million people worldwide. Multiple sclerosis occurs when the protective sheath around nerve fibres in the central nervous system, called myelin, is damaged. Depending on the part affected, this leads to disturbances of vision, movement, sensation and basic bodily functions such as bladder control.
Researchers at Cambridge have pioneered the use of monoclonal antibodies to identify an effective treatment for multiple sclerosis. Antibodies provide a natural defence mechanism against invading foreign substances. In the 1980s, Nobel Prizewinning research at the Laboratory of Molecular Biology in Cambridge showed that monoclonal antibodies, designed to target specific antigens, could be produced in almost unlimited quantities. Researchers from the Department of Pathology seized on this discovery and went a step further to create ‘humanised’ monoclonal antibodies for use as medicines. The first, Campath-1H, went on to be developed as a treatment for chronic lymphatic leukaemia.
Scientists at the Cambridge Centre for Brain Repair and the Department of Clinical Neurosciences have recently begun a Medical Research Council funded trial into the effects of autologous adult stem cells on patients with progressive multiple sclerosis
A team at the Department of Clinical Neurosciences entered this area of research in 1991, and has since continued to study Campath-1H by painstakingly investigating its effects in multiple sclerosis. Building up from single case studies in individual patients, a large Phase II international multi-centre trial was completed in 2007. Interim results at the end of two years were announced in September 2006, and confirmed what the Cambridge-based investigators had recognised for several years.
Given early in the course of relapsing-remitting multiple sclerosis, Campath-1H causes a significant reduction in the occurrence of new episodes – by more than 90% in this trial. Campath-1H appears to stop the development of multiple sclerosis in its tracks, by inhibiting new tissue injury in the central nervous system. Remarkably, these long-term effects are achieved following only one week of exposure to Campath-1H every 12-18 months. But as with all potential new advances, treatment is not uncomplicated. Surprisingly, in this context, although the autoimmune process of multiple sclerosis seems to be suppressed, a range of other conditions – also autoimmune in their mechanisms – emerge as a complication of treatment; nevertheless the patients still consider the benefits of Campath-1H to outweigh the risks of these treatable disorders. Phase III studies of alemtuzumab (as Campath-1H is now known) are due to be launched in 2007, highlighting how coordinated and interactive research within a university environment can lead to the development of effective clinical treatments.
Cambridge researchers have simultaneously been exploring other avenues of potential therapy for patients with multiple sclerosis, by developing techniques that may enable the brain to repair damaged myelin and nerve cells itself. Using adult stem cells, which are derived from a patient’s own tissues – not necessarily of brain origin – scientists at the Cambridge Centre for Brain Repair (Department of Clinical Neurosciences) have recently begun a MRC funded trial into the effects of autologous adult bone marrow stem cells in patients with multiple sclerosis.
Showing that obesity in humans can be biologically driven and amenable to therapy
Researchers at the Institute of Metabolic Science have played a world-leading role in identifying genes that can influence human body weight.
Obesity is a major public health threat.
While recent changes in the patterns of obesity in the population are certainly driven by environmental changes, the heritability of obesity is extremely strong. Thus, identical twins who are brought up in different families, will usually have very similar amounts, and distribution, of body fat in adult life, bearing little resemblance to the families into which they were adopted.
Researchers at the Institute of Metabolic Science have played a world-leading role in identifying genes that can influence human body weight. By focusing on a cohort of children with extreme obesity from an early age, they have discovered a number of gene mutations that lead directly to obesity. Thus far, all of the genes discovered have had their normal function in the hypothalamus, the area of the brain concerned with control of appetite and energy expenditure. These genes have been shown to influence the drive to eat, as well as feeding behaviour. In particular, one genetic defect, though rare, is dramatically curable with a daily injection of a recombinant protein called leptin. This condition is a graphic demonstration that obesity in humans can be purely biologically driven and amenable to mechanism-based therapy. Researchers in the Department of Pharmacology study hypothalamic anatomy and function in an effort to determine how defects in neurocircuitry lead to excess food consumption beyond metabolic need. In particular, hypothalamic neurons – both in isolation and inside their native neural networks – are assessed to explore how they generate their electrical signals, how these signals are communicated to other brain areas, and how they are altered by physiological and pharmacological stimuli.
Cambridge scientists are gaining novel and exciting insights into the interactions between the homeostatic and hedonic control of food intake
Another obesity disorder, known as melanocortin 4 receptor deficiency, is one of the most common Mendelian disorders in humans. It is present in 5- 6% of severely obese children and 0.5- 1% of obese adults. Remarkably, the functional properties of the mutant receptor in vitro can predict spontaneous food intake behaviour at a test meal in individuals carrying these genetic defects. Further research at Cambridge has also clearly implicated the neurotrophin system in the regulation of human appetite and body weight. Collaborative research with the MRC Epidemiology Unit in Cambridge and the Sanger Institute at Hinxton is currently exploring the genetic basis of more common forms of obesity in the population, using large-scale population resources and high throughput genomics combined with expertise in functional biology.
A programme of research sponsored by the Woco Foundation has brought researchers from the Institute of Metabolic Science and the Department of Psychiatry together to explore the biology underlying higher cognitive processes involved in food seeking behaviour. Using a combination of psychometric and functional imaging studies applied to individuals with known genetic lesions in the appetitive pathways, Cambridge scientists are beginning to gain novel and exciting insights into the interactions between the homeostatic and hedonic control of food intake.
Improving diagnosis and treatment for patients with degenerative disorders
Cambridge scientists were part of the collaborative team that discovered the Huntington’s disease gene
Degenerative brain diseases have an enormous impact on our aging society. Alzheimer’s disease progressively robs its victims of their memory. Parkinson’s disease leads to impairments in movement. Frontotemporal dementia causes bewildering changes in a person’s thoughts and behaviour. Huntington’s disease painstakingly deprives a person of their ability to walk, talk, think and reason, often as early as in their mid 30s and 40s.
In all of these degenerative brain diseases, the time from the onset of symptoms until death can be as many as ten or twenty years, with many sufferers’ lives characterised by a total loss of independence in their final years. The staggering emotional toll that these diseases have on their victims and their families, as well as the economic cost to society, has led neuroscientists all over the world to strive to identify effective prevention and treatment strategies.
Addenbrooke’s Hospital in Cambridge is the only place in the UK to provide genetic testing for the tau gene
Local scientists are investigating Alzheimer’s disease, Parkinson’s disease, fronto-temporal dementia and Huntington’s disease from the genetic level to clinical symptoms.
In Alzheimer’s disease, work done in Cambridge was the first to show that the microtubule-associated protein tau is the major component of the filaments that form the neurofibrillary tangles in this disease and other tauopathies.
Cambridge neuroscientists discovered that alphasynuclein is the major component of Lewy bodies, the characteristic aggregates of Parkinson’s disease. One of the most useful models to study the mechanisms of deposition of alphasynuclein in Parkinson’s disease was produced in Cambridge.
The link between tau and neurodegeneration was established in Cambridge, with the identification of one of the first genetic mutations in the tau gene as the cause of some familial forms of fronto-temporal dementia. Cambridge scientists were part of the collaborative team that discovered the Huntington’s disease gene.
The first genetic animal model of Huntington’s disease was characterised behaviourally here. Scientists at the University showed recently that novel and important cellular and physiological processes, such as autophagy and circadian rhythm deficits, contribute to the molecular neuropathology of Huntington’s disease.
Cambridge neuroscientists have characterised the nature of cognitive dysfunction in Huntington’s disease and were amongst the first to identify specific changes in presymptomatic cases, devising a battery of tests to assess cognitive decline that is now used worldwide. Moreover, Cambridge neuropsychologists also invented a cognitive test that predicts the diagnosis of Alzheimer’s disease in patients with mild cognitive impairment.
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https://clubalthea.com/2016/10/14/your-complete-dna-sequence-will-help-shape-the-future-of-medicine/
