Human Genetics

1. Human Genetics Concepts and Applications Eighth Edition Powerpoint Lecture Outline Ricki Lewis Prepared by Dubear Kroening University of Wisconsin-Fox Valley

2. Chapter 20Genetic Testing and Treatment

3. Genetic Counselors • Only about 3,000 in the US • Health care professionals trained in genetics and psychology • Evaluate patient’s risk of genetic disease based on personal and family history • Determine when specific biochemical, gene, or chromosome tests are appropriate • Help with prenatal diagnosis and family diseases

4. Genetic Counselors • Interpret test results • Help patient and family choose among medical options • Act as a resource for referral or support group information • Educate public about genetic information

5. Figure 20.1

6. Table 20.1

7. Genetic Testing • Founded on screens for newborns • Direct-to-consumer tests on the internet • 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

8. Newborn Screening • Started with Guthrie test for PKU • Tandem mass spectrometry to ID defects • PCR to amplify specific mutations • 2005, US mandated testing for 29 treatable and recommended testing for 25 untreatable (to help doctors in diagnosis) • Economically advantageous

9. Table 20.2

10. Table 20.3

11. Direct-To-Consumer Genetic Testing • Company websites  $200  $2,000 • Lacks professional counseling • Uninformed decisions • Questionable “nutrigenetics” companies

12. Direct-To-Consumer Gene Tests Table 20.4

13. Genetic Privacy • Confidentiality vs. potential harm to others • Duty to warn • More harm from keeping confidentiality • Relatives at risk can be identified • Failure to warn has increased risk of harm • HIPAA concerns

14. Treating Genetic Disease • Replacing missing proteins • Obtaining pure proteins using recombinant DNA • Delivering replacement genes

15. Enzyme Replacement Therapy Table 20.6

16. Enzyme Replacement Therapy Figure 20.2

17. Gene Therapy • Altering genes hopefully can provide a longer-lasting treatment • Treatments have been focused on inherited disorders with a known disease mechanism • Germline gene therapy – gamete or zygote alteration, heritable, not done in humans, transgenic organisms • Somatic gene therapy – specific cells, not heritable

18. Gene Therapy Concerns Table 20.7

19. Gene Therapy Trial Approval Requirements Table 20.8

20. Invasiveness of Gene Therapy • Ex vivo gene therapy alters cells outside of body • In situ gene therapy occurs in a localized area • In vivo gene therapy vectoris introduced directly into the body; most invasive

21. Figure 20.3

22. Gene Delivery • Physical methods – electroporation, microinjection, and particle bombardment • Chemical methods – liposomes • Biological approaches - a vector (modified viral genomes)

23. 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 nervous system, hard to change neurons • Cancer  about ½ of current trials target cancer

24. Sites of Gene Therapy Figure 20.4

25. Gene Therapy Examples: ADA, Adenosine Deaminase Deficiency • Severe combined immune deficiency (SCID) 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 • Replacement of ADA in individuals genetically deficient was attempted

26. Gene Therapy for ADA Deficiency Figure 20.5

27. 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

28. First Gene Therapy Patient Ashanthi DeSilva • Other patients have had complications from the treatment including a rare form of leukemia • Stalled other gene therapy trials

29. 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

30. Gene Therapy: OTC • Clinical trials to treat OTC deficiency were established using adenovirus as a vector for the normal OTC gene • Jesse Gelsinger had a mild OTC deficiency, volunteered for the OTC gene therapy trial and was accepted • Four days after gene therapy Jesse died of massive immune reaction and associated complications

31. OTC Gene Therapy Figure 20.6

32. Gene Therapy: Canavan Disease • An aspartoacylase enzyme deficiency • Neurons release N-acetylaspartate (NAA) • NAA is normally broken down by the enzyme aspartoacylase to harmless components • Enzyme deficiency creates NAA buildup, which destroys oligodendrocytes. • Lack of oligodendrocytes prevents myelin formation and neurons cease functioning

33. Gene Therapy: Canavan disease Figure 20.7

34. 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

35. Perspective on Gene Therapy • Great promise, but slower than expected • More complex than expected • Gene interactions • Appropriate vectors • Adequately targeting and sustaining therapeutic effects • Safety issues