Clinical Research: Phase 1 - Phase 4

At the Intersection of Rare Disease and Precision Medicine: A Road to Growth

Individually, rare diseases by definition have a low prevalence, but collectively, the societal burden and impact of these uncommon conditions is significant. The majority of rare diseases are genetic in origin, and advances in genomic sequencing tools and technologies have driven an increase in the identification of rare disorders. Currently, one out of every 10 people is living with one of the more than 10,000 diseases characterized as rare.1

A key challenge of rare diseases is the time required for diagnosis. For known rare diseases, it takes an average of 4-9 years to reach an accurate diagnosis. For rare diseases that have not yet been characterized, the undiagnosed period can be even longer. Even when a diagnosis has been made, therapeutic options are often limited. With the emergence of precision medicine and its focus on customizing treatment to individual patients and tracing diseases back to their root molecular cause, it may be possible to reduce the time to diagnosis for rare conditions, enabling identification and intervention at earlier stages of the disease.2

Precision starts at our roots

With rare genetic disorders, where the root molecular cause is a pathogenic genotype, it may be easier to apply precision medicine principles than in diseases where the mechanisms of pathogenesis are more complex and heterogeneous. Moreover, in rare genetic diseases, targeting and correcting the root molecular cause with a precision therapeutic may be sufficient for providing patients with symptomatic—or even curative—relief. Consequently, for rare genetic disorders, the path from root cause identification to targeted therapy discovery and development may be more straightforward than for common diseases and could be used more broadly as a template for precision medicine.1

Our roots grow into models, building the precision story

Identification of the root molecular cause of a rare disease enables development of a disease model that can be used to test potential therapies. This may be a cellular model, a modified cell line, or a genetically modified model organism.1 Certain model organisms may be suitable for drug-repurposing screens. For example, the family of a child with congenital disorder of glycosylation type Ia (PMM2-CDG) commissioned a disease model and drug screen which identified epalrestat, a noncompetitive and reversible aldose reductase inhibitor, as a potential treatment. This drug was used to treat the child in single-patient clinical studies, with success, and is now being studied in a larger trial for others with PMM2-CDG.1,3 

The discovery of potential targeted therapies can also be driven by deeper understanding of the downstream impact of a molecular alteration and how that impact can be reversed. A National Institutes of Health (NIH) program called the Biomedical Data Translator aims to structure all biomedical data as computable knowledge that can be interrogated and analyzed via artificial intelligence. The Biomedical Data Translator may be able to identify previously undiscovered ways to alter the activity of a gene or mechanism and predict potential treatments.1

What can precision medicine in rare diseases teach us in common diseases?

The precision medicine methodologies developed within rare diseases will help to advance precision medicine for common diseases in a variety of ways:

  • Deeper understanding of the genetic, cellular, and molecular drivers of disease. While common conditions rarely arise from monogenic causes, they are often tied to individual molecular drivers that can be traced to individual genes or gene networks. Understanding the gene, the protein it encodes, and the function of that protein provides insights into molecular pathways and biological processes. Study of rare genetic diseases advances our understanding of the impact of single genetic alterations and their associated molecular pathways.
  • Better characterization of the human genome. Most of the human genome remains poorly characterized and it is estimated that we currently have pharmacological influence over only 15% of it.1,4 Applying precision medicine to rare diseases can accelerate our understanding of—and influence over—the remainder.
  • Identification of targets or drugs that may be applicable to common diseases. Rare and common diseases may share the same molecular drivers, and targeted therapies that are shown to be effective in rare diseases may also demonstrate efficacy in common conditions. A classic example of this was the discovery that cholesterol is regulated through the low density lipoprotein (LDL) receptor, which came out of the research of Dr. Michael Brown and Dr. Joseph Goldstein in the 1970s when they were studying familial hypercholesterolemia, a rare metabolic disorder. This discovery was the foundation of our understanding of the pathway of cholesterol metabolism, which led to the development of statins, the world’s most prescribed class of drugs.5

An avenue to accelerate personalized medicine

Over the past 50 years, rare disease research has led to the discovery and development of medical breakthroughs, from allogeneic stem cell transplantation to gene therapy, that have paved the way for new therapeutic options for more common diseases.6 In this era of precision medicine, the study of rare diseases is now accelerating the fulfillment of the promise of personalized medicine. By helping to link genes with molecular diagnoses and phenotypes, rare disease research helps to elucidate cellular and molecular pathways, identify potential drug targets, and inform the development of new therapies which have potential applications to common diseases.

[1] Might M, Crouse AB. Why rare disease needs precision medicine—and precision medicine needs rare disease. Cell Rep Med. 2022;3(2):100530.

[2] Isono M, Kokado M, Kato K. Why does it take so long for rare disease patients to get an accurate diagnosis?-A qualitative investigation of patient experiences of hereditary angioedema. PLoS One. 2022;17(3):e0265847,

[3] Ligezka AN, et al. Sorbitol is a severity biomarker for PMM2-CDG with therapeutic implications. Ann Neurol. 2021;90:887-900.

[4] Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov. 2002;1:727-730.

[5] Raconteur. How rare disease research benefits everyone, January 11, 2022.

[6] Klein C, Gahl WA. Patients with rare diseases: from therapeutic orphans to pioneers of personalized treatments. EMBO Mol Med. 2018;10(1):1-3.