GENE THERAPY

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Slide 1: 

GENE THERAPY, GENETICS DISORDERS AND BEHAVIOUARAL GENETICS Submitted To: Dr. Dijee Bastain Dr. R. m. francies Dept. of PB&G Submitted By: Pawan Saini 2010-11-153

GENES : 

GENES Segment of DNA that contains a definite information. Biological unit of heredity Are present on a chromosome Encode how to make a protein DNA RNA Proteins Proteins carry out most of life’s function Genetic disorders results from mutation in the genome.

GENE THERAPY : 

GENE THERAPY An experimental treatment that involves introducing genetic material(DNA or RNA) into a person’s cells to fight diseases.(National Cancer Institute) GT is used to correct a deficient phenotype so that sufficient amounts of a normal gene product are synthesised To imprve to genetic disorder.

HOW TO FIX IT : 

HOW TO FIX IT

TYPES OF GENE THERAPY : 

TYPES OF GENE THERAPY Sometic gene therapy Germ-line gene therapy

SOMETIC GENE THERAPY : 

SOMETIC GENE THERAPY Transfer of a gene or genes into body cells other than germ cells with effect only on the patient. The new genetic material can’t be passed on to offspring.

THREE CATEGORIES OF SGT : 

THREE CATEGORIES OF SGT Ex vivo – Cells removed from body, incubated with vector & gene engineered cells returned to body. In situ – Vector is directly placed into the affected tissues. In vivo – Vector injected directly into the blood stream.

EXAMPLES OF ex-vivo SGT : 

EXAMPLES OF ex-vivo SGT Usually done with blood cells Eg. Sickle cell anemia

EXAMPLE OF in-situ SGT : 

EXAMPLE OF in-situ SGT Infusion of adenoviral vectors into trachea & bronchi of cystic fibrosis patients. Injection of a dystrophin gene directly into muscle of muscular dystrophy patients.

THE BEGINNING………. : 

THE BEGINNING………. In the 1980, scientist began to look into gene therapy. They would insert human genes into a bacteria cell. Then the bacteria cell would transcribe and translate the information into a protein Then they would introduce the protein into human cells

Slide 11: 

“Father of Gene Therapy” W. French Anderson

THE FIRST CASE : 

THE FIRST CASE September 14th , 1990 @ NIH Clinical Centre, USA, Dr. W. French Anderson and Dr. R. Michael Blaese perform the 1st GT trial. Patient: Ashanti De Silva( 4 year old girl) Treated for SCID (Severe combined immunodeficiency ) Problem:WBC are short-lived, therefore treatment must be repeated regularly. Doctors removed her WBC, inserted the missing gene into the WBC & then put them back into her blood stream. As of early 2007, she was still in good health, and she was attending college.

GENE DELIVERY SYSTEMS : 

GENE DELIVERY SYSTEMS Viral Vectors Non viral

Slide 14: 

VIRAL VECTORS NON-VIRAL VECTORS Retroviruses Adenoviruses Adeno-associated viruses Herpes Simplex virus Lentivirus Liposomes Gene gun 47th chromosome Ormosil

RETROVIRUS : 

RETROVIRUS

Slide 16: 

Advantages: Randomly integrates into genome Infected cells are not killed Wide host range Long term expression of transgene Disadvantages: Capacity to carry theropeutic genes is small Insertional mutagenesis Expression transient

ADENOVIRUS : 

ADENOVIRUS Non-enveloped particle Contains linear double stranded DNA Does not integrate into the host genome Replicates as an episomal element in the nucleus

Slide 18: 

Are double stranded DNA genome that cause respiratory, intestinal, and eye infections in humans The inserted DNA is not incorporate into genome Not replicated though  Has to be reinserted when more cells divide Ex. Common cold

Slide 19: 

A new gene is inserted into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is succesfull, the new gene will make a functional protein)

Slide 20: 

Advantages: Accepts larger insertions of DNA Useful in tumour treatment (GENDICINE) Disadvantages: Re-administration of viruses needed Cell-specific targeting difficult to achieve Virus uptake is ubiquitous

ADENO-ASSOCIATED VIRUS : 

ADENO-ASSOCIATED VIRUS Small viruses with a genome of single stranded DNA Insert genetic material at a specific point on chromosome 19 From parvovirus family- non-pathogenic Low information capacity Two genes (cap and rep) sandwitched between the inverted terminal repeats(ITR). Cap- encodes viral capsid proteins Rep- viral replication and integration

HERPEX SIMPLEX VIRUS : 

HERPEX SIMPLEX VIRUS Double stranded DNA viruses that infect neurons Ex. Herpes simplex virus type 1 http://www.ucmp.berkeley.edu/alllife/virus.html

LENTIVIRUS : 

LENTIVIRUS Lentivirus (lenti-, Latin for "slow") is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period. Lentiviruses can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.

Liposomes : 

Liposomes Lipids in water produces liposomes DNA containing liposomes can deliver DNA No immune response, no viral components Efficiency is lower than for viral vectors

GENE GUN : 

GENE GUN DNA on microscopic gold particles “fired” into cells Efficient delivery Expressed only temporarliy

THE 47th CHROMOSOMES : 

THE 47th CHROMOSOMES Introduce an artificial chromosome into cells by microinjection Could replicate and segregate like any chromosome : stable Could carry large amounts of DNA So far, done only in mice

ORMOSIL : 

ORMOSIL Ormosil have been used as DNA vectors and can deliver DNA loads to specifically targeted cells in living animals. (Ormosil stands for organically modified silica or silicate)

DISEASES CAUSED BY DEFECTIVE GENES : 

DISEASES CAUSED BY DEFECTIVE GENES Cystic fibrosis – defective chloride channel protein Muscular dystrophy – defective muscle protein Sickle cell anemia – defective beta globin Hemophilia – absence of clotting factor IX SCID- genes fail to make a protein essential for T & B cell function Familial hypercholesterolemia- defective cholesterol receptors on liver cells Lesch-Nyhan diaease- defect in producing HGPRT enzyme Gaucher’s disease- glucocerebrosidase gene defect Parkinson’s disease

Slide 29: 

CURRENT STATUS AND SET BACKS OF GENE THERAPY

CURRENT STATUS OF GENE THERAPY : 

CURRENT STATUS OF GENE THERAPY No human gene products for sale Little progress Set backs FDA lifts ban Majority of projects don’t make it to human trials Only 2 projects have reached the market - Genedicine - Rexin-G

SET BACKS : 

SET BACKS Jesse Gelsinger French Trial

JESSE GELSINGER(JUNE18,1981-september17,1999) : 

JESSE GELSINGER(JUNE18,1981-september17,1999) 1st person publicly died in a clinical trial for gene therapy Suffered from Ornithine transcarbamylase deficiency Urea cycle disorder (1/10,000 births) Encoded on X chromosome Urea cycle = series of 5 liver enzymes that rid the body of ammonia (toxic breakdown product of protein) If enzymes are missing or deficient, ammonia accumulates in the blood and travels to the brain (coma, brain damage or death) Case of genetic mutation

Slide 33: 

Joined a clinical trial run by University of Pennsylvania On Monday, September 13th , 1999: injected with adenoviruses Coma on sept. 14th , 1999 Brain dead and life support terminated on Sept.17th ,1999 at 2:30 PM. Died 4 days after receiving treatment Cause of death: multiple organ failure and brain death

FRENCH X-SCID TRIAL : 

FRENCH X-SCID TRIAL 11 children with “Bubble Boy disease” 1 child did not respond to treatment 8 children cured 2 children came down with leukemia

RESURGENCE FOR GENE THERAPY : 

RESURGENCE FOR GENE THERAPY Small successes in gene therapy Treatment for fatal brain disease Treatment for eye disease FDA allows treatment for all life threatening diseases April,2003 FDA eased the ban on gene therapy using retroviral vectors in blood stem cells.

FACTORS HOLDING GENE THERAPY BACK : 

FACTORS HOLDING GENE THERAPY BACK Short-lived nature of gene therapy Immune response Problems with viral vectors Multi-gene disorders

SHORT LIVED NATURE OF GT : 

SHORT LIVED NATURE OF GT Must remain functional and long lived Patients will have to undergo multiple rounds of therapy

IMMUNE RESPONSE : 

IMMUNE RESPONSE Immune system designed to attack invader Hard for repeated treatments

PROBLEMS WITH VIRAL VECTORS : 

PROBLEMS WITH VIRAL VECTORS Potential threat to patient -Can cause toxicity, immune and inflammatory responses, gene control and targeting tissues. Could regain virulence

MULTI-GENE DISORDERS : 

MULTI-GENE DISORDERS Single gene mutations are best candidate for gene therapy Multi-gene disorders much more difficult to treat - Heart disease - Alzheimers disease - High blood pressure

Slide 41: 

gene therapy in news

GENE THERAPY IN THE NEWS : 

GENE THERAPY IN THE NEWS Gene therapy may boost success of Lung Transplants-Los Angeles Times Thursday, October 29th,2009

GENE THERAPY IN THE NEWS : 

GENE THERAPY IN THE NEWS Gene therapy gets closer to a cure – The Boston Globe Tuesday, March 3rd , 2009 Eight-year-old Corey Haas of Hadley, N.Y., received gene therapy for a rare disease called Leber's congenital amaurosis. Corey asked his parents when two of his friends changed their hair color. He could finally tell they were blonde, not brunettes. Gene therapy helped Corey Haas, 8, regain some sight. He has a rare disease that was causing him to go blind.

GENE THERAPY IN THE NEWS : 

GENE THERAPY IN THE NEWS Two monkeys get the gift of colour – New York Times Article, Wednesday, September 23rd , 2009 The photo on the left shows how Dalton, a male squirrel monkey, saw the world when he only had two color pigments; the photo on the right shows how he sees things after being given the gene for the missing red pigment

Slide 45: 

Dalton and Sam are male squirrel monkeys, about a foot tall. Dalton and Sam lead a more protected life in the laboratory of Jay and Maureen Neitz at the University of Washington, Seattle. Recently, the Neitzes endowed them with a new genetic gift: the ability to see the world with full color vision. Male squirrel monkeys have only two of the color pigments known as opsins. The Neitzes, with Katherine Mancuso and other colleagues, used the technique of gene therapy to introduce the gene for the missing red pigment into the cone cells of the monkeys’ retinas. Jay Neitz said Dalton was named for John Dalton, who not only invented modern atomic theory but in 1794 was also the first person to describe color blindness his own.

GENE THERAPY IN THE NEWS : 

GENE THERAPY IN THE NEWS Severe adverse event in clinical trial of gene therapy for X-SCID-BBC News, Tuesday, December 18th, 2007 One of the boys with no immune system being treated with pioneering gene therapy at Great Ormond Street has developed leukaemia, his doctors say. A trial in France of a similar therapy was halted in 2002 after four of eleven children developed leukaemia. Ten children with X-SCID have so far been treated at the London hospital.

Slide 47: 

X-SCID is caused by mutations in the IL2RG gene, which governs the behaviour of a protein involved in the development of a number of immune system cells. Without the protein, the cells cannot develop normally, and are unable to protect the body.

GENE THERAPY IN THE NEWS : 

GENE THERAPY IN THE NEWS ‘Slimming Gene’ discovered that regulates body fat. (Science Daily, Nov. 22, 2009) Scientists at the University of Bonn have discovered a previously unknown fruit fly gene that controls the metabolism of fat. Larvae in which this gene is defective lose their entire fat reserves. Researchers called the gene 'schlank' (German for 'slim'). The scientists therefore have hopes in new medicines with which obesity could be fought.

GENE THERAPY IN THE NEWS : 

GENE THERAPY IN THE NEWS Genetic Information Nondiscrimination Act (GINA) The President has signed into law the Genetic Information Nondiscrimination Act (GINA) that will protect Americans against discrimination based on their genetic information when it comes to health insurance and employment. (Washington, Wed., May 21 2008) The bill had passed the Senate unanimously and the House by a vote of 414 to 1. The long-awaited measure, which has been debated in Congress for 13 years. Pave the way for people to take full advantage of the promise of personalized medicine without fear of discrimination.

GENE THERAPY USES AIDS VIRUS TO FIGHT AIDS : 

GENE THERAPY USES AIDS VIRUS TO FIGHT AIDS In the study, immune cells were removed from the patients' bodies, modified with a disabled AIDS virus known as a lentivirus, and then intravenously returned. The genetically altered cells disseminated anti-HIV material and prevented HIV from reproducing( 07 November, 2006).

BRAIN DISEASE TREATED BY GT : 

BRAIN DISEASE TREATED BY GT Researchers have halted a fatal brain disease by delivering a therapeutic gene to the stem cells that mature into blood cells. The gene was transferred using a virus derived from HIV. Together with his colleagues, paediatric neurologist Patrick Aubourg at INSERM — France's main biomedical research agency and at the Saint-Vincent de Paul Hospital in Paris, developed the system to treat X-linked adrenoleukodystrophy (ALD), a neurodegenerative disease that affects young males.

Slide 52: 

ALD results in severe degeneration of the myelin sheath, a structure that is crucial for brain-cell function. The disease is caused by mutations in a gene encoding the ALD protein. The mutations lead to a deficiency of ALD protein and a subsequent loss of myelin, which begins affecting cognitive function in boys aged 6 to 8 years; most die before reaching adolescence. Nature News, 5 November 2009

GENE THERAPY IN NEWS (FEB, 2009) : 

GENE THERAPY IN NEWS (FEB, 2009) The journal Nature Medicine, reporting on a trial of 74 HIV patients, said gene therapy had modest but promising effects. A study in the journal Human Gene Therapy reported that two patients with rheumatoid arthritis saw a reduction in pain and swelling with gene therapy.

SOME MORE NEWS ABOUT GT : 

SOME MORE NEWS ABOUT GT Using Gene Therapy to Prevent Heart Failure-Science Daily (Nov. 15, 2010) New Therapy Offers Hope to Spinal Muscular Atrophy Patients – Science Daily (June 9, 2010) Gene Therapy for Metastatic Melanoma in Mice Produces Complete Remission – Science Daily (Nov. 18, 2010) First Clinical Trial of Gene Therapy for Muscular Dystrophy Lends Insight Into the Disease – Science Daily (Oct. 7, 2010) Breakthrough Gene Therapy Prevents Retinal Degeneration – Science Daily (Aug. 18, 2010)

Slide 57: 

BIOETHICIS BIOETHICIS

Slide 58: 

“A thing is right when it tends to preserve the integrity, stability, and beauty of the biotic community. It is wrong when it tends otherwise.” - Aldo Leopold, 1949, A Sand County Almanac ALDO LEOPOLD THE FIRST BIOETHICIST

WHAT ARE THE ETHICAL ISSUES SORROUNDING GENE THERAPY? : 

WHAT ARE THE ETHICAL ISSUES SORROUNDING GENE THERAPY? How can “good” and “bad” uses of gene therapy be distinguished? Who decides which traits are normal and which constitute a disability or disorder? Will the high costs of gene therapy make it available only to the wealthy? Could the widespread use of gene therapy make society less accepting of people who are different? Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?

WHO SHOULD PAY? : 

WHO SHOULD PAY? “The one thing that could bankrupt America is out of control healthcare cost” - Dr. John Biok (60 Minutes Interview Nov 22, 2009)

CONT….. : 

CONT….. Are we at risk of creating a greater divide between the rich and poor. If the cost of gene therapy is the sole responsibility of the individual will only the wealthy have access to gene therapy. Will the wealthy become healthier, smarter, and better looking than the poor?

CONT…. : 

CONT…. Gene therapy currently cost up to $200,000 per treatment. While that is a lot, it pales in comparison to cost of treating someone with a chronic condition for their entire life. Some people might say that with the difficulty the government is having passing the current Health Care Bill it is unlikely that they will be paying for gene therapy anytime in the foreseeable future. But fortunately we have time. 40.5 Million people on medicare

UNFORESEEN CONSEQUANCES : 

UNFORESEEN CONSEQUANCES Is it possible that eliminating defects from our genome may have unforeseen consequences

Slide 64: 

Flu vaccine ‐ 1976 vaccine caused five hundred cases of Guillain–Barré syndrome and 25 deaths. There was a small risk of GBS following influenza (swine flu) vaccination (approximately 1 additional case per 100,000 people who received the swine flu vaccine). That number of GBS cases was slightly higher than the background rate for GBS

Slide 65: 

ATTEMPTING ON MOST DISABLING DISEASES

LESCH-NYHAN SYNDROME : 

LESCH-NYHAN SYNDROME Defect in producing HGPRT enzyme(hypoxanthine-guanine phosphoribosyl transferase) Defective metabolism of hypoxanthine and guanine results in uric acid accumulation. Gout, kidney disease,cerebral palsy, mental retardation, head banging, profanity, spitting,mutilation of fingers LNS is transmitted as and X-linked recessive trait. Female carriers do not show the symptoms.

SUCCESSFUL ONE YEAR GT TRIAL FOR PARKINSON’S DISEASE : 

SUCCESSFUL ONE YEAR GT TRIAL FOR PARKINSON’S DISEASE Neurologix a biotech company announced that they have successfully completed its landmark Phase I trial of gene therapy for Parkinson's Disease. This was a 12 patient study with four patients in each of three dose escalating cohorts. All procedures were performed under local anesthesia and all 12 patients were discharged from the hospital within 48 hours of the procedure, and followed for 12 months. Primary outcomes of the study design, safety and tolerability, were successfully met. There were no adverse events reported relating to the treatment

RELIGIOUS OBJECTION : 

RELIGIOUS OBJECTION Madeline Kara Neumann, 11, had Type I Diabetes. Her disease went untreated and she died on March 23, 2008. Her parents did not believe in modern medicine and prayed for her instead of getting her treated. Convicted of second‐degree reckless homicide. Father was sentenced to 25 years in jail.

RELIGIOUS OBJECTION : 

RELIGIOUS OBJECTION Majority of the world believes in some type of higher power. The majority of religions states that everyone should be happy with what they have. Do we have the right to play GOD?

Slide 70: 

BEHAVIOURAL GENETICS

Slide 71: 

It is field of study that examined the role of gene in animal/human behaviour. Sir Francis Galton – 1st Behaviouaral Genetician He studied the heritability of human ability focussing on mental characteristics as well as emenesses among close relative in the English upper class. In 1869,Galton published his results in Hereditary Genius. Theodosius Dobzhansky was elected the first president of the Behavior Genetics Association in 1972. BGA bestows the Dobzhansky Award on researchers for their outstanding contributions to the field.

Slide 72: 

Genetics and molecular biology have provided some significant insights into behaviors associated with inherited disorders. Down Syndrome Klinifelter Syndrome Cri Du Chat

LIST OF GENETIC DISORDERS : 

LIST OF GENETIC DISORDERS Alkaptonuria Alzheimer’s Disease Bloom Syndrome Cri Du Chat Cystic Fibrosis Di-George Syndrome Down Syndrome Duchene Muscular Syndrome Galactosomia Goucher’s Disease Haemophilia Joubert Syndrome Klinifelter Syndrome Lesch-Nyhan syndrome Marfan Syndrome Phenylketonuria Sickle Cell Anemia Tay-Sachs Disease Turner Syndrome Wilson’s Disease

REFERENCES : 

REFERENCES http://ghr.nlm.nih.gov/handbook/illustrations/therapyvector.jpg http://cmbi.bjmu.edu.cn/cmbidata/therapy/about/images/TIGHE2.GIF http://www.wesleyjsmith.com/blog/uploaded_images/bubbleboy-736662.jpg http://singularityhub.com/wp-content/uploads/2009/09/gene-therapy-color-blind-monkey-216x300.jpg http://images.ctv.ca/archives/CTVNews/img2/20091028/470_ap_lung_transplant_0910.jpg http://beta.images.theglobeandmail.com/archive/00231/monkey17lf2_231084a.jpg http://cache.boston.com/resize/bonzai-fba/Globe_Photo/2009/02/27/1235793129_4657/300h.jpg

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http://www.accessexcellence.org/RC/VL/GG/images/diagram.gif http://www.accessexcellence.org/RC/VL/GG/ecb/ecb_images/06_39_retrovirus.gif http://nobelprize.org/nobel_prizes/medicine/laureates/1993/illpres/big-adenovirus-v3.gif http://www.nanolifenutra.com/images/image_liposome_01.jpg http://hordeum.msu.montana.edu/Bio102/Transformation/plants/Gene%20Guns_files/gun_schematics.gif http://www.nysaes.cornell.edu/hort/faculty/reisch/Image1.gif http://i.acdn.us/image/A5595/55959/300_55959.jpg http://biologia.uab.es/biocomputacio/treballs02-03/N_Salvador/El%20moderno%20Prometeo/ADA.jpg http://www.jesse-gelsinger.com/images/jesseportrait.jpg

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http://romancatholicworld.files.wordpress.com/2010/08/the-jackson-lab-gene-therapy-breakthrough-not-around-the-corner-naples-daily-news-august-04-2010-by-dr-bryan-hanypsiak-director-of-medical-education-at-arthrex-inc.jpg?w=630&h=362 http://romancatholicworld.files.wordpress.com/2010/08/the-jackson-lab-gene-therapy-treatment-is-still-in-realm-of-science-fiction-naples-daily-news-august-08-2010-by-arthrex-president-reinhold-schmieding.jpg http://en.wikipedia.org/wiki/List_of_genetic_disorders http://en.wikipedia.org/wiki/Genetic_disorder http://en.wikipedia.org/wiki/Behavioural_genetics http://www.ornl.gov/sci/techresources/Human_Genome/elsi/behavior.shtml http://4.bp.blogspot.com/_ROxmhDMSsJI/SYKhd74A4UI/AAAAAAAAALc/UEAURXQCX9k/s400/down+syndrome+effects.jpg http://1.bp.blogspot.com/_AL7GK_3BsMM/SIKzXusC0EI/AAAAAAAAFHo/zt6AappSMcY/s400/Klinefelter%2Bsyndrome.jpg

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http://www.sciencedaily.com/releases/2010/10/101006175630.htm http://www.sciencedaily.com/releases/2010/11/101116122903.htm http://www.sciencedaily.com/releases/2010/11/101118124206.htm http://www.sciencedaily.com/releases/2010/08/100816110411.htm http://www.sciencedaily.com/releases/2010/06/100609142253.htm http://www.genetherapynet.com/breaking-news.html http://en.wikipedia.org/wiki/Gene_therapy http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml http://www.accessexcellence.org/RC/AB/BA/Gene_Therapy_Overview.php http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/G/GeneTherapy.html

Slide 78: 

THANKS

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