special subjects
Clinical Uses of Genetics
Treatment
Understanding the genetic and molecular basis of disorders may help guide therapy. For example, dietary restriction can eliminate compounds toxic to patients with certain genetic defects, such as phenylketonuria or homocystinuria. Vitamins or other agents can modify a biochemical pathway and thus reduce toxic levels of a compound; eg, folate (folic acid) reduces homocysteine levels in people with 5,10-methylene tetrahydrofolate reductase polymorphism. Therapy may involve replacing a deficient compound or blocking an overactive pathway. Pharmacogenomics is the science of how genetic characteristics affect the response to drugs. One aspect of pharmacogenomics is how genes affect Overview of Pharmacokinetics . Genetic characteristics of a person may help predict response to treatments. For example, metabolism of Another aspect of pharmacogenomics is Overview of Pharmacodynamics (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, 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 , such as Viral transfectionis 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. 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 (SMAs) and 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 (clusteredregularlyinterspacedshortpalindromicrepeats–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. 