Genomics in Precision Medicine

Precision medicine can be described as treatment options optimised to take into account the patient’s genetic information and lifestyle. traditional model of drug development assumes that a drug will show a similar response in all patients afflicted with the same disease. But it is seen that most drugs show a positive response on a subset of the population. Another subset may develop adverse reactions to the drugs, while others may not show any response at all. The underlying reason for this variability is the differences in genetic makeup between individuals. Precision medicine aims to understand and utilise these genetic differences to provide more effective therapies, which improve treatment outcome & prevent adverse effects while excluding the need of unnecessary treatments or diagnostic testing.

The first reference for precision medicine can be found in 1892 writing of Dr. William Osler, “It is more important to know what kind of patient the disease has, than to know what kind of disease the patient has.” In more recent times, the term personalised medicine was first described in 1999 as performing a simple blood test to find out which patients will show positive response to a drug and which ones might show an adverse response. The basis of the diagnostic test would be the minute differences in the genetic makeup of individuals.

Applications of precision medicine

The field of oncology has been the earliest adapter of targeted treatment. The first drug prescribed on the basis of a genetic test was Trastuzumab, approved by USFDA in 1998, which is used for treatment of patients with metastatic breast cancer whose tumours overexpress the HER-2 protein. his was followed by regulatory approval of Imatinib, which inhibits the BCR-ABL protein tyrosine kinase, which is present in BCR-ABL gene fusion positive chronic myeloid leukaemia (CML). Later on, drugs targeting ALK, ROS1, BRAF V600E mutant melanoma and MET-mutant lung cancer were also developed. Multigene panels for diagnostic testing in several types of cancers have been approved by FDA.

In 2017, US Food and Drug Administration (FDA) approved the chimeric antigen receptor T-cell (CAR-T) for treatment of refractory pre-B cell acute lymphoblastic leukaemia and diffuse large B-cell lymphoma. Chimeric antigen receptors (CAR) are patient’s own T-cells that are engineered to express fusion proteins, which directs the T-cells to cancer-specific antigens, causing destruction of cancer cells. In 2020, 28 targeted therapies were approved by the FDA in patient populations defined by specific molecular biomarkers.

Cystic fibrosis is caused by one of several defects in the CFTR gene. Majority of cystic fibrosis patients have F508del mutation. Ivacaftor, which works on 5 per cent of patients who carry the G551D mutation, is ineffective for the majority of patients, for whom a combination of Lumicaftor with Ivacaftor is prescribed. In 2021, Evinacumab was approved by USFDA as an add-on treatment with cholesterol lowering agents (for example, Statins) for homozygous familial hypercholesterolemia (HoFH). HoFH patients have two mutations in genes responsible for clearing excess cholesterol from the body. Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) inhibitor. ANGPTL3 slows the function of certain enzymes that break down fats in the body.

Role of genomics in precision medicine

In precision medicine, sequencing and analysis of the patient’s genetic data play a crucial role in disease diagnosis and tailoring treatment. Technologies like Sanger sequencing, real-time PCR and Microarrays were the pioneering techniques utilised for DNA sequencing. Next generation sequencing technologies have enabled fast and efficient DNA sequencing, leading to more biomarkers being identified, which can help to classify patients into different subtypes and provide treatment accordingly.

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