ArticleOrphanet journal of rare diseases2017
Opportunities for developing therapies for rare genetic diseases: focus on gain-of-function and allostery.
Article in Orphanet journal of rare diseases, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Developing therapeutics for rare cardiovascular diseases.American heart journal · 2026Review
- Development of a human genetics-guided priority score for 19,365 genes and 399 drug indications.Nature genetics · 2024Article
- A universal deep-learning model for zinc finger design enables transcription factor reprogramming.Nature biotechnology · 2023Article
- Lateral thinking in syndromic congenital cardiovascular disease.Disease models & mechanisms · 2023Article
- Using reported pathogenic variants to identify therapeutic opportunities for genetic diseases.Molecular genetics & genomic medicine · 2023Article
- Clinical variants inGenetics in medicine open · 2023Article
- Translational potential of base-editing tools for gene therapy of monogenic diseases.Frontiers in bioengineering and biotechnology · 2022Review
- Rational Small Molecule Treatment for Genetic Epilepsies.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Modulating gene regulation to treat genetic disorders.Nature reviews. Drug discovery · 2020Review
- Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression.Nature communications · 2020Article
- Recent advances suggest increased influence of selective pressure in allostery.Current opinion in structural biology · 2020Review
- Drug Repositioning for Noonan and LEOPARD Syndromes by Integrating Transcriptomics With a Structure-Based Approach.Frontiers in pharmacology · 2020Article
- RNA delivery biomaterials for the treatment of genetic and rare diseases.Biomaterials · 2019Review
- Exploiting machine learning for end-to-end drug discovery and development.Nature materials · 2019Article
- Substrate reduction therapy for inborn errors of metabolism.Emerging topics in life sciences · 2019Article
- Pressing diseases that represent promising targets for gene therapy.Discovery medicine · 2017Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAdvances 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.
resultsWe 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.
conclusionOur 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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