Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Chapter 20 Genetic Testing, Genetic Counseling, and Gene Therapy

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Genetic Testing Identifies newborns with genetic diseases Allows early treatment or monitoring Screening for 50 conditions using tandem mass spectrometry is less than $100 Some conditions may be very rare but the costs of NOT testing are very high, some children may not receive early treatment and have large medical bills or die

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Newborn Screening Table 20.1

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Uses of Genetic Testing Table 20.2

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Genetic Counselors are trained in genetics and psychology.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Genetic Counseling 2 Major reasons… people seek genetic counseling are (1) prenatal diagnosis and a (2)disease in the family Issues –Shortage of counselors –Confidentiality within society and family –“Duty to Warn” (Examples in Table 20.3) Must provide nondirective information Insurance issues New role within the health care profession

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Treating Genetic Disease Replacing missing proteins Obtaining pure proteins using recombinant DNA Delivering replacement genes Treatments are still experimental

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Enzyme Replacement Therapy Table 20.4

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Gene Therapy Altering genes hopefully can provide a longer- lasting treatment Treatments have been focused on inherited disorders with a known disease mechanism Ex vivo gene therapy alters cells outside of body In situ gene therapy occurs in a localized area In vivo gene therapy vector is introduced directly into the body; most invasive

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Figure 20.2

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Germline vs. Somatic Germline gene therapy alters the DNA of a gamete or fertilized ovum Somatic gene therapy corrects only the cells that an illness affects. Ex: clearing lungs from CF w/ nasal spray

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display In the future, artificial genes synthesized in microchips by picoarray gene synthesis may reduce the cost of gene therapy by 100-fold or more

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Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Some Gene Therapy Targets Endothelium - can secrete needed proteins directly into bloodstream Skin - skin grafts can secrete therapeutic proteins Muscle - accessible, comprises ½ body mass and has a good blood supply Liver - many functions and can regenerate Lungs - are easily accessed with aerosol spray Nervous tissue - many illnesses and injuries affect the nervous system Cancer - about ½ of current trials target cancer

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Gene Therapy for Cancer Treatment Suicide gene therapy involves expressing a protein in cancer cells that will kill them Cancer vaccines allow tumor cells to produce proteins activating the immune response

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Gene Therapy Examples: ADA, Adenosine Deaminase Deficiency Severe combined immune deficiency can be caused by ADA deficiency Lack of ADA blocks the breakdown of metabolic toxins to uric acid Toxins destroy T cells and causes susceptibility to infections and cancer

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Gene Therapy: ADA Deficiency Injections of PEG-ADA given to first child in 1986 –Increased ADA levels and T cell survival –Improved immune function White blood cells from a patient receive a functional copy of ADA and the cells are returned –Increased T cells present with functioning ADA gene Stem cells from umbilical cord blood are isolated –Cells are treated to replace mutated ADA allele with normal allele and returned –T cells with normal allele accumulate in patient

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Gene Therapy: OTC Ornithine Transcarbamylase Deficiency of OTC is inherited as an X- linked recessive mutation OTC normally breaks down amino acids present in protein Lack of OTC allows buildup of ammonia, which damages brain function Low-protein diets and ammonia-binding drugs are used to treat OTC deficiency

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Gene Therapy: OTC Jesse Gelsinger had a mild OTC deficiency When he turned 18, Jesse volunteered for the OTC gene therapy trial and was accepted as the 17th volunteer Four days after gene therapy Jesse died of massive immune reaction and associated complications Figure 20.8a

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Gene Therapy: Canavan Disease Disrupts the interaction b/t neurons & oligodendrocytes which produce the fatty myelin that coats neurons, enabling them to transmit impulses fast enough for the brain to function.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display Gene Therapy: Canavan Disease Causes brain degeneration in children First observed as inability to stand or sit, poor muscle control, poor vision, and lack of reaction to surroundings Good gene therapy candidate because: Gene and protein are well known Window of time exists for treatment Only the brain is affected Brain scans can be used to monitor treatment No existing treatment