Simon Mead
Simon Mead
Clinical Research Programme

Simon is a consultant neurologist and Clinical Lead of the UK National Prion Clinic based at the National Hospital for Neurology and Neurosurgery.

Also working as a Programme Leader at the UK Medical Research Council’s Prion Unit, his research interest includes work alongside patients with prion disease towards better clinical trials, the discovery of genetic factors that cause or influence prion disease and the development of treatments for prion disease based on antibodies.

He trained at Oxford and Cambridge Universities, and was made a Professor of Neurology at UCL in 2014.

Human Genetic research
The MRC Prion Unit Human Genetics Group investigates why some people, but not others, get prion diseases such as Creutzfeldt-Jakob disease (CJD). We know that variant CJD (vCJD) was caused by human transmission of BSE (bovine spongiform encephalopathy or mad cow disease), a prion disease of cattle. Other people develop a prion disease spontaneously as they get older (called sporadic CJD) while others are accidentally infected with prions as a result of medical or surgical procedures.

We all have over three billion letters in our DNA code, and we are different from one another by a several millions of these letters. These genetic differences in populations lead to variations in height, intelligence, but less obviously, variation in susceptibility to disease. By comparing these genetic differences between groups of people who developed CJD and healthy people who didn’t, we hope to identify the genes that influence why particular people are more susceptible to prion diseases. We will use this information to better estimate public health risks and to point the way to new tests and treatments.

We also know that the fundamental processes involved in CJD, where one of the body’s own proteins becomes misshapen and then forms large clumps of material, are very relevant to other much commoner diseases such as Alzheimer’s and Parkinson’s diseases. We hope therefore that what we learn from studying CJD in this way will have much wider relevance in helping to reduce the burden of degenerative brain diseases which are becoming ever commoner as the average age of the population increases.

Recently we described a completely new prion disease which cause diarrhoea, low blood pressure and damage to nerves in the legs . We have also developed a technology to allow for the rapid genetic diagnosis of inherited dementia using modern “next-generation” sequencing techniques, called the MRC Dementia Gene Panel.

Strong genetic susceptibility to prion disease has been demonstrated in animals and humans. The very strong and common genetic risk factor at position (or codon) 129 of the prion protein gene (PRNP), between the amino acids methionine (60% frequency in the population) and valine is an important precedent for our work. All confirmed vCJD cases have only methionine, representing the strongest association of a common genotype with any disease. Codon 129 also strongly associates with sporadic CJD, with iatrogenic CJD (that caused by contamination of medical products or surgical instruments) and early age of onset of inherited prion disease (IPD) and kuru, an epidemic prion disease of the Fore linguistic group of Papua New Guinea. An understanding of susceptibility conferred by PRNP codon 129 has had a major impact on prion biology.

Evidence in support of the involvement of non-PRNP genetic factors comes in part from work with laboratory inbred mouse strains. We are conducting international genome wide association study to develop solid evidence for the involvement of genetic variations, and possibly specific genes themselves. This work is at an advanced stage with samples from over 4000 patients involved. We are also sequencing the parts of the human genome (whole “exome” sequencing) that code for proteins to find rare changes that might be important in causing disease.

Clinical Research
The principal aims of the clinical research programme are to facilitate the translational agenda of the Unit - the development of early diagnostics and effective therapeutics for human prion infection.

Effective clinical testing of prion disease therapeutics is challenging but much has been learned from the National Prion Monitoring Cohort. The Cohort study is providing the infrastructure for the development of effective disease rating scales, selection of other outcome measures and design of future trials.

The National Prion Clinic team have developed a rating scale for prion diseases. The team have described a precise way to track how patients with prion disease are progressing. The use of the MRC Prion Disease Rating Scale or “MRC Scale” in short form, in the National Monitoring Prion Cohort has revealed there are three distinct patterns of change: 1. slow progression associated with genetic forms of disease, 2. rapid progression associated with any form of the disease, and 3. a proportion of patients that survive in a comatose state sometimes for prolonged periods of time. Some rating scales we have used in the past were poor at measuring patient progression, though questions about every-day activities seemed to match clinical reality. The new rating scale is based on interviews with 71 families, we’ve taken into account the experience of the disease from the perspective of patients, their relatives and carers to find out what are the important symptoms of the disease. Questions focus on speech, memory, continence, mobility and self-care, which are all important aspects of how the disease impacts on families. We appreciate and acknowledge the contribution of carers and relatives to this research work.