医学遗传学遗传疾病的治疗精.ppt

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1、医学遗传学遗传疾病医学遗传学遗传疾病的治疗的治疗第1页，本讲稿共49页1.What is gene therapy?Genes,which are carried on chromosomes,are the basic physical and functional units of heredity.Genes are specific sequences of bases that encode instructions on how to make proteins.第2页，本讲稿共49页 Although genes get a lot of attention,its the pr

2、oteins that perform most life functions and even make up the majority of cellular structures.第3页，本讲稿共49页 When genes are altered so that the encoded proteins are unable to carry out their normal functions,genetic disorders can result.第4页，本讲稿共49页 Gene therapy is a technique for correcting defective ge

3、nes responsible for disease development.第5页，本讲稿共49页 Researchers may use one of several approaches for correcting faulty genes:1.A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene.This approach is most common.2.An abnormal gene could be swapped

4、 for a normal gene through homologous recombination.3.The abnormal gene could be repaired through selective reverse mutation,which returns the gene to its normal function.4.The regulation(the degree to which a gene is turned on or off)of a particular gene could be altered.第6页，本讲稿共49页2.How does gene

5、therapy work?In most gene therapy studies,a normal gene is inserted into the genome to replace an abnormal,disease-causing gene.第7页，本讲稿共49页 A carrier molecule called a vector must be used to deliver the therapeutic gene to the patients target cells.Currently,the most common vector is a virus that ha

6、s been genetically altered to carry normal human DNA.第8页，本讲稿共49页 Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner.第9页，本讲稿共49页 Scientists have tried to take advantage of this capability and manipulate the virus genome to remove disease-causi

7、ng genes and insert therapeutic genes.第10页，本讲稿共49页 Target cells such as the patients liver or lung cells are infected with the viral vector.The vector then unloads its genetic material containing the therapeutic human gene into the target cell.第11页，本讲稿共49页 The generation of a functional protein prod

8、uct from the therapeutic gene restores the target cell to a normal state.第12页，本讲稿共49页To reverse disease caused by genetic damage,researchers isolate normal DNA and package it into a vector,a molecular delivery truck usually made from a disabled virus.Doctors then infect a target cell usually from a

9、tissue affected by the illness,such as liver or lung cellswith the vector.The vector unloads its DNA cargo,which then begins producing the missing protein and restores the cell to normal.第13页，本讲稿共49页A.Some of the different types of viruses used as gene therapy vectors(1)Retroviruses A class of virus

10、es that can create double-stranded DNA copies of their RNA genomes.These copies of its genome can be integrated into the chromosomes of host cells.Human immunodeficiency virus(HIV)is a retrovirus.第14页，本讲稿共49页(2)Adenoviruses A class of viruses with double-stranded DNA genomes that cause respiratory,i

11、ntestinal,and eye infections in humans.The virus that causes the common cold is an adenovirus.(3)Adeno-associated viruses A class of small,single-stranded DNA viruses that can insert their genetic material at a specific site on chromosome 19.(4)Herpes simplex viruses A class of double-stranded DNA v

12、iruses that infect a particular cell type,neurons.Herpes simplex virus type 1 is a common human pathogen that causes cold sores.第15页，本讲稿共49页第16页，本讲稿共49页第17页，本讲稿共49页第18页，本讲稿共49页 Besides virus-mediated gene-delivery systems,there are several nonviral options for gene delivery.The simplest method is th

13、e direct introduction of therapeutic DNA into target cells.This approach is limited in its application because it can be used only with certain tissues and requires large amounts of DNA.第19页，本讲稿共49页 Another nonviral approach involves the creation of an artificial lipid sphere with an aqueous core.Th

14、is liposome,which carries the therapeutic DNA,is capable of passing the DNA through the target cells membrane.第20页，本讲稿共49页 Therapeutic DNA also can get inside target cells by chemically linking the DNA to a molecule that will bind to special cell receptors.第21页，本讲稿共49页 Once bound to these receptors,

15、the therapeutic DNA constructs are engulfed by the cell membrane and passed into the interior of the target cell.This delivery system tends to be less effective than other options.第22页，本讲稿共49页 Researchers also are experimenting with introducing a 47th artificial human chromosome into target cells.Th

16、is chromosome would exist autonomously alongside the standard 46-not affecting their workings or causing any mutations.第23页，本讲稿共49页 It would be a large vector capable of carrying substantial amounts of genetic code,and scientists anticipate that,because of its construction and autonomy,the bodys imm

17、une systems would not attack it.A problem with this potential method is the difficulty in delivering such a large molecule to the nucleus of a target cell.第24页，本讲稿共49页3.The current status of gene therapy research3.The current status of gene therapy research Current gene therapy is experimental and h

18、as not proven very successful in clinical trials.第25页，本讲稿共49页 Little progress has been made since the first gene therapy clinical trial began in 1990.In 1999,gene therapy suffered a major setback with the death of 18-year-old Jesse Gelsinger.第26页，本讲稿共49页 Jesse was participating in a gene therapy tri

19、al for ornithine transcarboxylase deficiency(OTCD).He died from multiple organ failures 4 days after starting the treatment.His death is believed to have been triggered by a severe immune response to the adenovirus carrier.第27页，本讲稿共49页 Another major blow came in January 2003,when the FDA(USA)placed

20、a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells.第28页，本讲稿共49页 FDA(USA)took this action after it learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition.第29页，本讲稿共49页 Both this child and another who had develope

21、d a similar condition in August 2002 had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease(X-SCID),also known as bubble baby syndrome.第30页，本讲稿共49页 FDAs Biological Response Modifiers Advisory Committee(BRMAC)met at the end of February 2003 to discuss poss

22、ible measures that could allow a number of retroviral gene therapy trials for treatment of life-threatening diseases to proceed with appropriate safeguards.FDA has yet to make a decision based on the discussions and advice of the BRMAC meeting.第31页，本讲稿共49页4.Factors kept gene therapy effectiveA.Short

23、-lived nature of gene therapy Before gene therapy can become a permanent cure for any condition,the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable.第32页，本讲稿共49页 Problems with integrating therapeutic DNA in

24、to the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits.Patients will have to undergo multiple rounds of gene therapy.第33页，本讲稿共49页B.Immune response Anytime a foreign object is introduced into human tissues,the immune system is designed t

25、o attack the invader.第34页，本讲稿共49页 The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a potential risk.第35页，本讲稿共49页 Furthermore,the immune systems enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in p

26、atients.第36页，本讲稿共49页C.Problems with viral vectors Viruses,while the carrier of choice in most gene therapy studies,present a variety of potential problems to the patient-toxicity,immune and inflammatory responses,and gene control and targeting issues.第37页，本讲稿共49页 In addition,there is always the fear

27、 that the viral vector,once inside the patient,may recover its ability to cause disease.第38页，本讲稿共49页D.Multigene disorders Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy.第39页，本讲稿共49页 Unfortunately,some the most commonly occurring disorders,

28、such as heart disease,high blood pressure,Alzheimers disease,arthritis,and diabetes,are caused by the combined effects of variations in many genes.第40页，本讲稿共49页 Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy.第41页，本讲稿共49页5.Some

29、 recent developments University of California,Los Angeles,research team gets genes into the brain using liposomes coated in a polymer call polyethylene glycol(PEG).The transfer of genes into the brain is a significant achievement because viral vectors are too big to get across the blood-brain barrie

30、r.This method has potential for treating Parkinsons disease.第42页，本讲稿共49页 RNA interference or gene silencing may be a new way to treat Huntingtons.Short pieces of double-stranded RNA are used by cells to degrade RNA of a particular sequence.If a siRNA is designed to match the RNA copied from a faulty

31、 gene,then the abnormal protein product of that gene will not be produced.第43页，本讲稿共49页第44页，本讲稿共49页 New gene therapy approach repairs errors in messenger RNA derived from defective genes.Technique has potential to treat the blood disorder thalassaemia,cystic fibrosis,and some cancers.第45页，本讲稿共49页 Gen

32、e therapy for treating children with X-SCID(sever combined immunodeficiency)or the bubble boy disease is stopped in France when the treatment causes leukemia in one of the patients.第46页，本讲稿共49页 Researchers at Case Western Reserve University and Copernicus Therapeutics are able to create tiny liposom

33、es 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.第47页，本讲稿共49页6.Some of the ethical considerations6.Some of the ethical considerations What is normal and what is a disability or disorder,and who decides?Are disabilities diseases?Do they need to be cured or

34、prevented?Does searching for a cure demean the lives of individuals presently affected by disabilities?第48页，本讲稿共49页Who will have access to these therapies?Who will pay for their use?Is somatic gene therapy more or less ethical than germline gene therapy(which is done in egg and sperm cells and prevents the trait from being passed on to further generations)?第49页，本讲稿共49页