It is questioning the wisdom behind the old gold standard of randomised populations used for trials. While large randomised trials avoid bias, personalised medicine trials are limited by their small size, but could be more focussed and effective based on the genetics of the patient, informs Dr Suresh Subramani, Global Director, Tata Institute for Genetics and Society and Distinguished Professor, University of California San Diego
How is genetics improving the sphere of drug discovery and development? In what ways has it helped in clinical research, target identification, drug safety testing, etc.? Give us a few real-world examples.
Genomics and genetics have allowed high-throughput, molecular and target-based screens for both small molecule drug and biologics (like antibodies, enzymes, peptides, recombinant proteins, gene therapies, etc.).
In the past decade, the size and diversity of commercially-available chemical compound collections have grown exponentially. Screening of millions of compounds for lead compound identification for a single drug target is now a routine because genetics has identified many new targets.
There are many examples of libraries of small molecule compounds whose molecular targets are known and that are being repurposed or repositioned. Approved drugs that are repurposed have the advantages that they have often been used in patients, and their toxicity and safety are known. One example is the drug remdesivir, which had anti-viral activity against the SARS and MERS coronavirus RNA polymerase, and is now being repurposed against SARS-CoV2.
The identification of potential druggable genomic targets in the human genome, coupled with the development of high-throughput biochemical or reporter assays, as well as genetically-engineered reporter cell lines, has accelerated the drug discovery process to arrive at leads much faster.
Genetics has also made available many animal models of human diseases making it faster and cheaper to test for toxicity, dosing and efficacy. A good example is that with the COVID-19 pandemic, scientists are scrambling to obtain reliable animal models (trying mice, hamsters, ferrets and monkeys), where the more controversial viral challenge assays can be done with much lower risk, rather than trying these assays out on human volunteers, at a time when no alternative therapy is available should a volunteer’s life be placed at risk as a result of the viral challenge.
Elaborate on the best approaches to integrate and enhance the role of genetics in clinical drug development and clinical trial designs. What are the challenges in doing so and how can they be mitigated?
The field of companion diagnostics, which is showing promise, is based on the measurements of the levels of proteins, genes, or specific mutations to design a specific and efficacious therapy for an individual.
The Personalized Medicine Coalition in the USA, highlighted a few years ago, four major challenges to the widespread adoption of a personalised approach in patient care – regulatory oversight, reimbursement strategies for the associated costs, education of both patients and clinicians regarding the adoption of personalised medicine, and finally health information technology, which would include data privacy, confidentiality, security and avoidance of data exploitation for profit. Additional issues for many countries include the per capita cost and affordability.
The concept of personalised medicine has not been used so widely outside of oncology yet. For example, there are over 250 genes affected in retinal dystrophy, but hardly any gene-based therapies are in current use. Further, its therapeutic applications in complex, polygenic disorders remain uncertain.
Genetics has also revolutionised patient selection for clinical trials and is throwing into question the wisdom of the old gold standard of randomised populations used for trials. While large randomised trials avoid bias, personalised medicine trials are limited by their small size, but could be more focussed and effective based on the genetics of the patient.
How are genetics-driven approaches crucial to enabling precision medicine?
Various genome projects, particularly the human genome project, when coupled with disease cohorts, genome-wide association studies (GWAS) and population studies have given birth to the con...
(All Rights Reserved)