Opportunities for developing therapies for rare genetic diseases: focus on gain-of-function and allostery

Abstract

Background: Advances in next generation sequencing technologies have revolutionized our ability to discover the causes of rare genetic diseases. However, developing treatments for these diseases remains challenging. In fact, when we systematically analyze the US FDA orphan drug list, we find that only 8% of rare diseases have an FDA-designated drug. Our approach leverages three primary insights: first, diseases with gain-of-function mutations and late onset are more likely to have drug options; second, drugs are more often inhibitors than activators; and third, some disease-causing proteins can be rescued by allosteric activators in diseases due to loss-of-function mutations.

Results: We have developed a pipeline that combines natural language processing and human curation to mine promising targets for drug development from the Online Mendelian Inheritance in Man (OMIM) database. This pipeline targets diseases caused by well-characterized gain-of-function mutations or loss-of-function proteins with known allosteric activators. Applying this pipeline across thousands of rare genetic diseases, we discover 34 rare genetic diseases that are promising candidates for drug development.

Conclusion: Our analysis has revealed uneven coverage of rare diseases in the current US FDA orphan drug space. Diseases with gain-of-function mutations or loss-of-function mutations and known allosteric activators should be prioritized for drug treatments.

Keywords: Allosteric; Drug discovery; Drug targets; Gain-of-function; Genetic diseases; Orphan drugs; Rare diseases.

Fig. 1

Texting mining algorithm to search for targetable rare diseases. We filtered all Mendelian diseases with known mutated genes in the OMIM for gain-of-function and late clinical onset related terms for the fist step of filtering to determine our disease targets. In a parallel branch of the pipeline, we filtered for diseases due to loss-of-function mutations with known allosteric activators. All candidates must have a solved protein structure. We manually verified the final disease list to ensure each disease mechanism and onset match our computationally generated label

Fig. 2

Overlap diagrams for the current approved or designated orphan drug space with the rare disease space. Each FDA approved and designated orphan drug was linked to a disease and potential OMIM ID based on the CTD table. 243 and 597 rare diseases are covered by the approved (a) and designed (b) orphan drugs. The current treatment space covers a small fraction of the rare disease space

Fig. 3

Disease category of approved or designated orphan products ranked by disease numbers. Each approved (a) and designated (b) orphan product was assigned to a disease and sequentially disease categories based on the CTD table. Numbers of diseases in the 10 most common disease category were plotted to show the distribution. Genetic diseases, the most common rare disease type, are the second most common diseases after cancer targeted by approved orphan drugs

Fig. 4

Diseases with gain-of-function mutations have higher chance to have treatment under development. Percentages of rare diseases covered by at least one FDA-designated orphan drug were plotted across categories. Mendelian diseases with a gain-of-function mutation and late clinical onset has the highest chance to be readily covered by a orphan drug (16 vs. 8% for all rare diseases)