Approved research

Validating targets and optimizing development of therapies for rare Mendelian Disorders using UK BioBank dataset

Lay summary

There are more than 7,000 Mendelian disorders; however, only about 5% of these have approved therapies, leaving many patients with serious unmet need. BridgeBio's goal is to use the information in the UK Biobank to understand which diseases might be ripe for intervention, and how best to develop treatments for these conditions. Mendelian disorders are caused by specific genetic variants with large effects (by contrast, many common disorders are associated with several variants, each having small effects). These Mendelian variants cause alterations in the function of the protein that the gene codes for, and the functional changes lead to physiological disruptions which cause disease symptoms in patients. The distinction between common and Mendelian disorders is not always clear, because the relationship between genetics and symptoms is difficult to study without access to lots of high-quality data. A person with a causal Mendelian variant does not always exhibit traits of the associated disorder; and genome-wide association studies (GWAS) often show Mendelian mutations in those identified as having common disorders, while some rare disorders have shown multiple common mutations in several genes. All of this is to say that the causal relationship between genetic mutation and patient symptoms (the 'genotype-phenotype' relationship) requires careful study in the case of each Mendelian disorder so that therapies can be developed to have the greatest possible patient impact. In order to better serve our patients, we aim to address the following questions using the information in the UK Biobank: 1. What are the causative mutations for a given Mendelian disorder? Does the same mutation cause similar symptoms in all individuals? When different symptom profiles occur within a disorder, can causal differences in genetic mutation be identified? 2. Based on the mechanism of action of a given therapy, which patient population could potentially benefit from the therapy? 3. Is the causative mutation of a Mendelian disorder implicated in common disorders? If so, would we be able to use the same therapy to treat a broader population? We hope that by addressing these questions, we are better able to identify, design, develop and deliver effective therapies that can target diseases at their source; and that we can accelerate the speed with which we can safely bring these treatments to patients