Opportunities for developing therapies for rare genetic diseases: focus on gain-of-function and allostery
Open accessAbstract
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.
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A number of GARDs have shown a close link to specific genetic abnormalities, where mutant or misfolded proteins are expressed and lead to disease symptoms.
“A number of genetic and rare diseases (GARDs) have shown their close link to specific genetic abnormalities, where mutant or misfolded proteins are expressed as a result and lead to disease symptoms.[1]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [1]
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- Authors
- Chen, B., & Altman, R. B.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Altman, Russ B.
- Venue
- Orphanet Journal of Rare Diseases
- Published
- 2017-04-17
- Volume
- 12
- Issue
- 1
- Pages
- 61-61
- ISSN
- 1750-1172 (ISSN-L)
- PMC
- PMC5392956
- OpenAlex
- W2597836507
- Cited by
- 28
- References
- 31
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 5 · 2019: 4 · 2017: 3
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (T32 GM 7365-40)
- Paul and Daisy Soros Fellowships for New Americans
- Stanford University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biomedical Text Mining and Ontologies
- Keywords
- rare genetic disorders, orphan drugs, drug discovery targets, gain-of-function mutations, loss-of-function mutations, allosteric activators, allosteric inhibitors, late-onset disease, natural language processing, drug repurposing
- MeSH terms
- Humans, Orphan Drug Production, Genetic Diseases, Inborn, Rare Diseases, Drug Discovery, High-Throughput Nucleotide Sequencing
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