Preparing for therapeutic trials in human prion disease: clinical and laboratory approaches to improve early diagnosis and monitoring of disease progression
Clinical and scientific understanding of the human prion diseases has advanced rapidly in recent years, and the possibility of an effective therapeutic agent being found now seems a realistic prospect. Alongside the search for an effective therapy, a number of major obstacles must be overcome to ensure that clinical trials have the best possible chance of being successful, and to maximise the benefit that can be gained from any treatment that is found. This thesis presents several projects that aim to contribute to this. Improving early diagnosis is likely to be key to making the most of any agent’s therapeutic benefit. Currently most patients with prion disease are diagnosed at a late stage of disease, when there is likely to be substantial irreversible damage to the brain. Chapters 2, 3 and 4 present work using the recently developed Direct Detection Assay in blood and cerebrospinal fluid, with the aim of improving accurate early diagnosis. Past prion disease clinical trials have suffered from the lack of a validated outcome measure to monitor disease progression. Chapter 6 presents a project carried out in the context of large prospective clinical studies of prion disease in the UK, in which a bespoke clinical rating scale has been developed and validated for use in prion disease clinical trials. Chapter 5 presents a comprehensive study of the complex psychiatric and behavioural features of prion disease, including detailed clinical characterisation, observational study of symptomatic management, and investigation of factors underlying heterogeneity in these clinical features, including a genome-wide association study looking for genetic modifiers. It is hoped that these different avenues of clinical and laboratory research will all help to establish a solid groundwork for upcoming clinical trials in prion disease, maximising the chances that they will be able to demonstrate a real and meaningful benefit for patients
