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Authors:Katerina Trajanoska, Claude Bhérer, Daniel Taliun, Sirui Zhou, J. Brent Richards & Vincent Mooser.

review paper

From target discovery to clinical drug development with human genetics

Nature - Published online: 23 August 2023


- Investments in human genetics and genomics have resulted in innovative therapies. - 40 genetic observations were identified that led to new therapies for 36 rare diseases and 4 common ones. - Most therapies for rare diseases compensate for loss-of-function mutations. - Therapies for common conditions are inhibitors that mimic the protective effects of rare loss-of-function variants. - Genetics can assist in drug development, selecting individuals who are likely to respond to experimental therapies. - A robust framework for benefit sharing is needed to capture the full potential of human genetics and genomics.

Disease or phenotype selection

Discovery (5-15 years)

Phase II–III clinical trials

Life-cycle management

Tractable hit to candidate

Target identification

Candidate selection to first-in-human studies

Development (5-10 years)

Steps along the drug discovery and clinical development pipeline

Target validation

First-in-human to proof-of-concept studies

Genetically driven therapies

Exclusion Criteria: The study excluded hormonal therapies, antimicrobial agents, vitamins, and minerals, and focused on approved drugs for which direct genetic evidence had been established between the target gene and the indication of interest. Genetic Evidence and Drug Approval: Genetic evidence was reported for 619 triplets (corresponding to 346 different drugs). For 98 triplets (corresponding to 80 drugs), such evidence was reported more than five years before drug approval. Types of Therapies: Half of the first-in-class therapies were biologicals (monoclonal antibodies, enzymes, or proteins), 36% were gene or RNA therapies, and 15% were small molecules. Targets and Indications: Most targets led to approved therapies belonging to a single class. The vast majority of indications represented rare, monogenic conditions. Impact of Genetics on Drug Discovery: The study acknowledges that these criteria captured only a fraction of the impact of genetics on drug discovery and development.

) Therapeutic Areas

) Year of First Genetic Evidence vs. Year of First Approval

) Types of Therapies

Correction of monogenic diseases

Compensation for Genetic Loss of Function: Most first-in-class therapeutic agents approved for rare diseases were designed to compensate for disease-causing loss-of-function mutations. Gene and RNA Therapies: These therapies represent a rapidly growing category that shows considerable promise for treating a variety of diseases. Gene Replacement Therapy: This therapy involves the insertion of a functional gene copy into the cell, enabling transient or persistent production of a protein. Gene Editing: Gene editing is performed using programmable nucleases, such as CRISPR. Several gene-editing modalities are in development and carry high expectations.

Mimicry of loss-of-function variants

CCR5 inhibitors: Medications that mimic the genetic deficiency in CCR5, providing protection against AIDS.SOST inhibitors: Treatments for osteoporosis that mimic the high bone mass resulting from mutations in the SOST gene. ANGPTL3 inhibitors: Treat hypercholesterolemia, mimicking the condition of low plasma lipid levels caused by mutations in the ANGPTL3 gene. Gene editing: Technologies that prevent heart diseases by reducing LDL cholesterol, blocking the production of PCSK9. Treatments for lipoprotein(a): People with genetic low blood levels of lipoprotein(a) have a lower risk of developing coronary artery disease. Treatments such as ASO pelacarsen and the small interfering RNA olpasiran are being developed to reduce lipoprotein(a) levels.

CCR5 inhibitors


The emerging role of common variants

- Common variants have an impact on drug repurposing and the discovery of new therapies. - GWAS technology helps to detect associations between diseases and common variants. - Mendelian randomization analyses explore causal relationships between risk factors and diseases. - Post-GWAS studies are necessary to identify causal variants and understand their functional effects. - Common and rare variants help anticipate potential safety issues in drug development.


Priorities for future investments in human genetics and genomics

Drug Discovery

Drug Development

- Using large databases to find new drug targets. - Investing in population diversity for genomic studies. - Identifying protective genetic variants to develop new inhibitors. - Expanding studies to identify early safety signals for investigational drugs. - Developing tools to identify causal genes in GWAS. - Conducting functional genomics studies to validate new drug targets. - Conducting studies to identify determinants of penetrance of disease-causing rare variants. - Considering factors such as duration, cost, and risks in drug development.

- Establishing an ethical, legal, and societal framework for recall-by-genotype studies. - Developing diverse cohorts for future recall-by-genotype studies.- Conducting pilot tests to demonstrate the feasibility of genetically assisted clinical development trials. - Integrating standards of equity, diversity, and inclusion in studies.- Promoting global and equitable access to innovative therapeutics.