Clinical Uses of Genetics

Pharmacogenomics is the science of how genetic characteristics affect the response to drugs. One aspect of pharmacogenomics is how genes affect pharmacokinetics Overview of Pharmacokinetics Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body—the time course of its absorption, bioavailability, distribution... read more . Genetic characteristics of a person may help predict response to treatments. For example, metabolism of warfarin is determined partly by variants in genes for the CYP2C9 enzyme and for the vitamin K epoxide reductase complex protein 1. Genetic variations (eg, in production of UDP [uridine diphosphate]-glucuronosyltransferase 1A1) also help predict whether the anticancer drug irinotecan will have intolerable adverse effects.

Another aspect of pharmacogenomics is pharmacodynamics Overview of Pharmacodynamics Pharmacodynamics (sometimes described as what a drug does to the body) is the study of the biochemical, physiologic, and molecular effects of drugs on the body and involves receptor binding... read more (how drugs interact with cell receptors). Genetic and thus receptor characteristics of disordered tissue can help provide more precise targets when developing drugs (eg, anticancer drugs). For example, trastuzumab can target specific cancer cell receptors in metastatic breast cancers that amplify the HER2/neu gene. Presence of the Philadelphia chromosome in patients with chronic myeloid leukemia Chronic Myeloid Leukemia (CML) Chronic myeloid leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of mature and immature... read more (CML) helps guide chemotherapy.

Gene therapy can broadly be considered any treatment that changes gene function. However, gene therapy is often considered specifically the insertion of normal genes into the cells of a person who lacks such normal genes because of a specific genetic disorder. The normal genes can be manufactured, using polymerase chain reaction (PCR) methodology, from normal DNA donated by another person. Because most genetic disorders are recessive, usually a dominant normal gene is inserted. Currently, such insertion gene therapy is most likely to be effective in the prevention or cure of single-gene defects Single-Gene Defects Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more , such as cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more .

Viral transfection is one way to transfer DNA into host cells. The normal DNA is inserted into a virus, which then transfects the host cells, thereby transmitting the DNA into the cell nucleus. Some important concerns about insertion using a virus include reactions to the virus, rapid loss of (failure to propagate) the new normal DNA, and damage to the virus by antibodies developed against the virus, viral vector, or transfected protein, which the immune system recognizes as foreign. Another way to transfer DNA uses liposomes, which are absorbed by the host cells and thereby deliver their DNA to the cell nucleus. Potential problems with liposome insertion methods include failure to absorb the liposomes into the cells, rapid degradation of the new normal DNA, and rapid loss of integration of the DNA.

With antisense technology, rather than inserting normal genes, gene expression can be altered. Modified RNA can be used to target specific parts of the DNA or RNA to prevent or decrease gene expression. Antisense technology is currently being tried for cancer therapy and some neurologic disorders but is still very experimental. However, it seems to hold more promise than gene insertion therapy because the success rates may be higher and complications may be fewer. Antisense oligonucleotides are available for clinical use for the treatment of spinal muscular atrophies Spinal Muscular Atrophies (SMAs) Spinal muscular atrophies include several types of hereditary disorders characterized by skeletal muscle wasting due to progressive degeneration of anterior horn cells in the spinal cord and... read more and Duchenne muscular dystrophy Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Duchenne muscular dystrophy and Becker muscular dystrophy are X-linked recessive disorders characterized by progressive proximal muscle weakness caused by muscle fiber degeneration. Becker dystrophy... read more .

Another approach to gene therapy is to modify gene expression chemically (eg, by modifying DNA methylation). Such methods have been tried experimentally in treating cancer. Chemical modification may also affect genomic imprinting, although this effect is not clear.

Gene therapy is also being studied experimentally in transplantation surgery. Altering the genes of the transplanted organs to make them more compatible with the recipient’s genes makes rejection (and thus the need for immunosuppressive drugs) less likely. However, thus far this process works only rarely.

CRISPR-CAS9 (clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 9) uses a versatile RNA guided DNA gene editing platform adapted from bacterial biology to manipulate and modify an organism's genetic make-up. While still experimental, CRISPR-CAS9 is rapidly moving toward human therapeutics.