Bringing the Promise of Precision Medicine to Rare Disease

Bringing the Promise of Precision Medicine to Rare Disease

Date: December 7, 2020

Precision medicine is a form of medicine that uses information about a person’s own genes or proteins to prevent, diagnose, or treat disease.1 When we think of precision medicine, we often focus on cancer and the recent efforts to specifically target treatment based on the genetic composition of a tumor (somatic) or the person’s germline. While it is early days, the health gains of this approach are quite significant with better outcomes shown in multiple studies2 and even data showing lower overall health costs.3 However, the point of precision medicine is not only to optimize treatment for cancer, but also to target health interventions generally for all conditions. In fact, we see the application of precision medicine to high volume diseases such as diabetes and heart disease and even lifestyle interventions such as diet and exercise.

Nowhere is this more challenging than for patients suffering from a rare disease. Ironically it is common to have a rare disease. More than 25 million Americans and more than 400 million people worldwide suffer from one of over 7000 rare conditions, defined as those conditions having an incidence of 1 in 200,000 or less. Precision medicine has focused on big data approaches to studying more common conditions, thereby leaving out those with rare conditions. Lacking a diagnosis, most of these patients and their families are on a “diagnostic odyssey.” These patients typically spend more than five years seeking accurate diagnosis and might see up to eight doctors, often receiving many misdiagnoses and differing opinions on their journey. Along the way, they may be exposed to harmful treatments and invasive testing. It is clear that comprehensive genetic testing gives the best possibility of getting to the exact diagnosis efficiently. Still, historically, genetic data have been available to a minority of patients: only those referred to a clinical geneticist for testing.

With the scaling of next-generation sequencing and the increasing availability of whole exome and whole genome sequencing, we are seeing a dramatic democratization of genetic data initiated at the intersection of rare disease research and clinical care. Country-level projects such as the 100,000 Genomes Project in the UK and All of Us and the Million Veterans Program in the US are pushing the edge of the envelope to bring diagnoses to thousands of patients. The 100,000 Genomes Project, run by Genomics England, is a UK National Health Service study aimed at identifying disease-causing genetic variants in patients with rare genetic diseases using a Whole Genome Sequencing (WGS) approach.4 Fabric Genomics is a clinical interpretation partner with Genomics England using our enterprise software platform for this project. Fabric identified candidate causal variants in 49.8% of cases (Learn more in this case study). In thousands of cases, a multi-year odyssey is ended with a single, thorough, genomic test. The ability to do this through leveraging a scalable software platform is exciting – proving the practicality of this approach.

Of course, diagnosis is just the beginning. While we don’t have proven treatments for most rare genetic diseases, the specific disease causative variant knowledge is critical even to begin that process. Furthermore, the knowledge of the gene and its protein-encoding, or metabolic, role gives essential clues to help researchers target treatments. With advances in computational biology and recent successes in identifying druggable genomic targets in the human genome, we are seeing more rapid, target-based drug discovery (Erder et al., 2014).5 Additionally, advanced approaches such as stem cell-based therapies are being used with more confidence to offer the opportunity for long-term correction. Such treatments are now under investigation for a diverse range of rare diseases6 and human clinical trials of stem cell therapies for rare diseases have started (Thomsen et al., 2014).7  At a sociological level, identifying the genetic cause allows patients to find others in similar situations. Genetic testing helps us find the patients, which leads to finding the populations. Small patient subgroups have successfully used social media to develop their communities at a global level, strengthening advocacy for research funding and actually facilitating such research by gathering potential subjects. Finding and growing the recognition of these patient populations increases interest and investment in potential therapeutics.

Clearly, without a specific genetic diagnosis, none of this could take place. Genomics is unlocking the potential for precision medicine for the hundreds of millions of people with a rare disease. Thanks to the dramatic gains in NGS scalability and increasingly accurate interpretation algorithms, we can turn this potential into reality. The time for this is now.



2. The growing role of precision and personalized medicine for cancer treatment 



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Nat Rev Drug Discov. 2014 Aug; 13(8):577-87.

6. Sun W, Zheng W, Simeonov A. Drug discovery and development for rare genetic disorders. American Journal of Medical Genetics Part A. 2017; 173: 2307–2322.

7. Thomsen G M, Gowing G, Svendsen S, Svendsen C N. The past, present and future of stem cell clinical trials for ALS. Experimental Neurology. 2014. 262: 127–137.