Unlocking the Secrets of Our Genes: How Human Genetics is Revolutionizing Drug Safety
For years, the development of new medicines has been a complex and often frustrating process. Many promising drugs fail during clinical trials, either because they don't work as expected or because they cause harmful side effects. But what if we could predict these problems before they happen? That's where human genetics comes in. Scientists are now using our genetic code to understand how drugs interact with our bodies, paving the way for safer and more effective treatments.
The Power of Human Genetics
Our DNA contains the instructions for building and operating our bodies. Variations in our genes can affect how we respond to medications. Some genetic variations can increase or decrease the activity of proteins targeted by drugs. By studying these variations, researchers can gain valuable insights into potential drug safety issues.
* Genome-wide association studies (GWAS) and studies of Mendelian diseases have helped scientists identify thousands of proteins associated with diseases. These studies also help us understand the roles of genes in the body.
* Pharmacogenetics, the study of how genes affect a person's response to drugs, is an important area of research that has led to more personalized medicine.
* By looking at genetic variants that mimic the effects of a drug, researchers can predict potential side effects before a drug is even tested in humans.
* These "experiments of nature" can reveal the potential for adverse events after long-term drug exposure.
How Genetics Improves Drug Safety
Traditionally, drug safety has been evaluated in animal models. However, there are significant differences between animal and human biology. This makes it difficult to predict how a drug will behave in people. Human genetic data offer a way to overcome this limitation.
* Identifying Potential Drug Targets: Human genetics can help researchers identify and validate new drug targets. If a gene is linked to a disease, it may be a good target for a new drug.
* Predicting Side Effects: Genetic variants can mimic the effects of a drug, revealing potential side effects before clinical trials. For example, if a gene variant causes a particular side effect, a drug targeting that gene might also cause that effect.
* Assessing Carcinogenicity: Genetic data can help researchers identify if a drug target may increase the risk of cancer.
* Improving Clinical Trial Design: Genetic information can be used to design more effective clinical trials, helping to ensure the safety of participants.
* Understanding Off-Target Effects: Human genetics can help predict which unintended targets a drug might interact with, causing adverse effects.
Examples in Action
The article highlights several examples of how human genetics has been used to improve drug safety:
* Diarrhea from a diabetes drug: A drug targeting DGAT1 to treat diabetes caused severe diarrhea in trials, but researchers found that children with a genetic mutation in DGAT1 also experienced severe diarrhea, confirming the drug's effect.
* Neurological issues from a pain drug: A drug targeting SPR for neuropathic pain was discontinued after causing neurological issues in animal studies, which were linked to genetic mutations in SPR that also cause neurological problems.
* Immune-related side effects: Researchers have found that genetic variants in the CTLA4 gene, which is targeted by some cancer drugs, are associated with autoimmune diseases that are also seen as side effects of these drugs.
* Stevens-Johnson syndrome from an anti-seizure medication: Genetic testing for HLA-B*1502 in certain populations has been adopted to prevent the severe skin reaction Stevens-Johnson syndrome caused by the anti-seizure medication carbamazepine.
* PCSK9 inhibitors for lowering cholesterol: Genetic studies showed that individuals with loss-of-function mutations in PCSK9 have lower cholesterol levels and a reduced risk of heart disease. This finding provided support for the development of PCSK9 inhibitors as a safe and effective way to lower cholesterol, despite some inconsistencies with other genetic studies.
* Off-target effects of BACE1 inhibitors: BACE1 inhibitors, developed for Alzheimer’s disease, caused retinal damage that was similar to the symptoms of a genetic disorder caused by mutations in a related protein, cathepsin D (CTSD). This finding showed that BACE1 inhibitors were also affecting cathepsin D.
* Thalidomide's harmful effects: Research has shown that thalidomide causes birth defects by degrading the SALL4 protein, and mutations in the SALL4 gene cause similar birth defects.
Tools and Techniques
The article discusses several tools and techniques used in this field:
* Phenome-wide association studies (PheWAS): These studies look at how a genetic variant affects a broad range of traits and conditions, which can help identify potential side effects.
* Mendelian Randomization (MR): MR uses genetic variants as a tool to determine the causal link between a trait and an outcome, like between a drug target and a disease.
* Expression Quantitative Trait Loci (eQTLs) and Protein Quantitative Trait Loci (pQTLs): These are genetic variants that affect the expression levels of genes or proteins, which can help understand how genetic variants influence the effects of a drug.
* Databases of genetic information: There are many publicly available databases that researchers use to explore genetic variants and their effects.
Challenges and the Future
While the potential of human genetics is enormous, there are challenges to overcome:
* Causal Inference: It can be difficult to prove that a genetic variant is the direct cause of a particular effect.
* Translation to Drug Effects: Genetic variations might not perfectly mirror the effects of a drug.
* Diversity: Most genetic studies have been conducted in people of European ancestry, making it harder to generalize findings to other populations.
* Disease Context: The effect of a drug may differ in people with different diseases.
Despite these challenges, the application of human genetics to drug safety is a rapidly evolving field. As our understanding of the human genome grows and more diverse populations are included in research, we can expect even more significant advancements in the development of safer and more effective medicines.
In conclusion, human genetics is revolutionizing drug development by offering a powerful way to predict potential safety issues before they arise. This approach promises to make drug development faster, safer, and more effective, ultimately benefiting patients around the world.
References:
Carss, K.J., Deaton, A.M., Del Rio-Espinola, A. et al. Using human genetics to improve safety assessment of therapeutics. Nat Rev Drug Discov 22, 145–162 (2023).
