Investigation of the genetic and functional determinants of disease progression in Progressive Supranuclear Palsy

Progressive Supranuclear Palsy (PSP) is a brain disease that shares common features with Alzheimer's disease and Parkinson's disease. PSP affects around 5000 people in the UK. PSP is a rapidly progressive disorder that leads to impaired balance, eye movements, decision making and speech and swallowing problems later in the disease course. The average disease duration from diagnosis to death is typically 6-8 years. As with many other brain diseases, to date, there have been no effective disease modifying therapies for treating PSP. In cancer medicine, effective therapies are directed against specific biological pathways whose dysfunction drives the progression of the particular cancer.

We feel that the same principle should be applied to neurodegenerative disorders, in particular, studying genetic variation that drives disease progression. Whilst PSP is a sporadic (non-inherited) disorder, we think that some common gene variants may increase the risk of developing PSP and influence the rate of disease progression. The original study comparing patients with PSP with people unaffected by the illness (genome wide association study (GWAS)) identified that common variation in 4 genetic areas increased the risk of developing PSP (MAPT, STX6, EIF2AK3 and MOBP). The functional consequences of these GWAS 'hits' have not yet been fully characterised. Upcoming anti-tau antibody clinical trials offer hope for PSP patients. However, the limitation of such drugs is that they are not targeting the underlying dysfunctional biological mechanisms that lead to the aggregation of pathological tau protein and drive the progression of disease.

Our project aims to be the first to both discover the genetic drivers of disease progression in PSP and to also stem cell models to assess the functional implications of identified genes. We hope that this will lead to the development of effective drugs that slow down, or even stop, the progression of PSP.

Progressive Supranuclear Palsy (PSP) is a rapidly progressive neurodegenerative disorder. As in many other neurodegenerative diseases, to date, there have no effective disease modifying therapies for treating PSP. In cancer medicine, effective therapies are directed against specific biological pathways whose dysfunction drives the progression of the disease. We feel that the same principle should be applied to neurodegenerative disorders, in particular, studying genetic variation that drives disease progression. Whilst PSP is a sporadic disorder, it is likely that an accumulation of common genetic variants alter the risk of developing PSP and influence the rate of disease progression.

Our project aims to be the first to discover the genetic determinants of disease progression in PSP. We will achieve this through single nucleotide polymorphism (SNP) genotyping of ~1000 PSP cases. Clinical and genetic data from pathologically diagnosed cases will be obtained from the Queen Square Brain Bank and our collaborators. Clinical and genetic data from clinically diagnosed cases will be obtained from a UK wide, prospective study of atypical parkinsonian subjects (PROSPECT study), for which Prof Morris is the chief investigator. This data will be used to carry out a genome-wide association study (GWAS) to identify genetic predictors of PSP phenotype and the rate of disease progression. We will then use our GWAS data, along with summary data from the original PSP case-control GWAS, to conduct transcriptome wide association studies (TWAS) to discover SNP-gene expression-disease risk and SNP-gene expression-disease progression associations. Finally, we will study the functional implications of progression GWAS 'hits' using CRISPR/Cas-9 technology in induced pluripotent stem cell models.

We hope that this project will eventually lead to the development of drugs that directly target dysfunctional biological pathways to slow down, or even stop, the progression of PSP.

Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative disease with an estimated UK prevalence of 5-7 per 100,000 of the population which equates to approximately 5000 patients at one time. Whilst, in comparison to Alzheimer's and Parkinson's disease, this is a rare neurodegenerative disease, the early symptoms of classical PSP (falls and visual problems) are non-specific such that the diagnosis is often missed until the latter stages of the disease. In addition, the diagnosis of PSP is made more challenging by the high degree of clinical overlap with other neurodegenerative conditions such as Parkinson's disease such that PSP can be misdiagnosed for another condition. Therefore, the prevalence of PSP is likely to be higher than previous estimates.

Aside from academics (see Academic Beneficiaries section), patients will be the main beneficiaries from this research project. PSP is a brutal and rapidly progressive disease that has a significant impact on the lives of patients and their families. To date, there have been no successful therapeutics for modifying the rate of disease progression. Drug companies have realised that this is an unmet need and so the emerging era of anti-tau antibody clinical trials offers hope. My proposed research project aims to discover the functional consequences of genetic determinants of disease progression. By doing this, we hope to identify "druggable" targets that can slow down or even stop disease progression. This is something that will be achieved within the 3 year timescale of this project and has the potential to transform the management of a condition that is currently incurable.

There are also economic factors to consider. PSP, like all neurodegenerative diseases, is an economic burden to the National Health Service - estimated at £43,000 per patient/per year (see Case for Support for reference). Aside from the cost of frequent hospital admissions (most often due to falls and their resulting complications), as the disease progresses, patients require extensive multi-disciplinary team input from physiotherapists, occupational therapists and speech and language therapists. This frequently results in the provision of mobility aids (zimmer frames, wheelchairs etc.), home adaptations (stairlifts, hospital beds etc.) and artificial feeding methods such as percutaneous endoscopic gastrostomy. Therefore, the findings from this research project may have indirect impacts on healthcare policy makers and budgets through the potential future development of treatments that reduce the need for costs associated with the progression of PSP and other neurodegenerative diseases.