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Chapter 11 Medical Biotechnology and Gene Therapy

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Title: Chapter 11 Medical Biotechnology and Gene Therapy


1
Chapter 11 Medical Biotechnology and Gene Therapy
BTEC 3301
2
How is biotechnology used in Medicine?
  • Biotechnology is responsible for hundreds of
    medical diagnostic tests that detect disease
    earlier, enduring a more accurate, beneficial and
    cost-effective outcome to disease.

3
How is biotechnology used in Medicine?
  • There are more than 350 biotechnology-based drug
    products and vaccines currently in human trials
    and more than 100 therapeutic drug products
    already on the market, with many more in
    development.
  • Some of these drugs are designed to treat cancer,
    heart disease, diabetes, multiple sclerosis,
    HIV-AIDS and obesity.

4
Therapeutic proteins
  • Proteins made by genetic engineering processes
    that patients cannot make themselves due to
    defective genes
  • Therapeutic proteins can be produced by
  • Bacteria
  • Animals
  • Plants

5
  • With genetic manipulation, pigs, cows, goats, and
    other animals can produce human proteins in its
    milk
  • Proteins can also be engineered in eggs
  • Drug delivery is simple and inexpensive

6
Why Hunt for Human Gene Disorders?
  • 6 dysfunctional genes per person
  • 30 pediatric admissions to hospital due to
    genetic problems
  • 12 adult admissions to hospital due to genetic
    problems
  • 70-75 of products, prevention and gene therapy
    goes for human species
  • There are 4000 known genetic disorders and of
    these gt200 are enzymatic defects

7
Few common examples of human diseases caused by
defective genes
Disease Genetic defect
hemophilia A absence of clotting factor VIII
cystic fibrosis defective protein
muscular dystrophy defective muscle protein
sickle-cell disease defective beta globin
hemophilia B absence of clotting factor IX
severe combined immunodeficiency (SCID) cell-mediated immune responses nor is able to make antibodies.
8
Genetic Engineering of a Milk Protein
9
What is Gene Therapy?
  • It encompasses repairing or replacing defective
    genes and making tumors more susceptible to other
    kinds of treatment. Thus, gene therapys
    potential for preventing and curing disease is
    vast

10
What is Gene Therapy?
  • Gene therapy is the insertion of genetic material
    into cells to prevent, control, or cure disease,
    especially genetic disorders.
  • Gene therapy is "a therapeutic technique in which
    a functioning gene is inserted into the somatic
    cells of a patient to correct an inborn genetic
    error or to provide a new function to the cell"

11
What is Gene Therapy?
  • There have been many human gene therapy clinical
    trials, involving over 700 patients world-wide
    (by 1996), for several different diseases
    including several cancers.
  • In the USA the trials must be approved by the
    Recombinant DNA Advisory Committee (RAC) and the
    FDA

12
What is Gene Therapy?
  • Gene therapy is a technique for correcting
    defective genes responsible for disease
    development. Researchers may use one of several
    approaches for correcting faulty genes
  • Carriers of therapeutic genes include

13
What is Gene Therapy?
  • Carriers of therapeutic genes include
  • harmless viruses that have undergone genetic
    alteration and can carry selected genetic
    material into human cells and
  • liposomesinjectable microscopic fatty globules
    that can enclose and protect DNA segments (e.g.,
    a "suicide gene" for insertion into cancer
    cells.)
  • Genes, which are carried on chromosomes, are the
    basic physical and functional units of heredity.

14
What is Gene Therapy?
  • Carriers of therapeutic genes include
  • Genes are specific sequences of bases that encode
    instructions on how to make proteins.
  • Although genes get a lot of attention, its the
    proteins that perform most life functions and
    even make up the majority of cellular structures.
  • When genes are altered so that the encoded
    proteins are unable to carry out their normal
    functions, genetic disorders can result.

15
How it done?
  • A normal gene may be inserted into a nonspecific
    location within the genome to replace a
    nonfunctional gene. This approach is most common.
  • An abnormal gene could be swapped for a normal
    gene through homologous recombination.
  • The abnormal gene could be repaired through
    selective reverse mutation, which returns the
    gene to its normal function.
  • The regulation (the degree to which a gene is
    turned on or off) of a particular gene could be
    altered.

16
Two types of Gene Therapy "platforms"
  • 1. Ex vivo therapies
  • Ex vivo therapies involve treating cells that
    have been removed from a patient with a
    functional gene to restore protein activity. The
    cells are then returned to the patients to have a
    therapeutic benefit. (ADA, sickle cell disease -
    blood cell diseases or immune system diseases)

17
Two types of Gene Therapy "platforms"
  • 2. In vivo therapies
  • The use of in vivo therapies generally involves
    injection or inhalation of a product that
    contains a therapeutic gene together with some
    sort of gene delivery system.

18
How does gene therapy work?
  • Gene Delivery System
  • Therapeutic genes and
  • an efficient gene delivery system
  • a way to get the correct genes into the correct
    cells .

19
How does gene therapy work?
  • Gene Delivery System
  • Viruses attack their hosts to insert their
    genetic material into the genetic material of the
    host.
  • This genetic material contains instructions to
    produce these viruses. The host cell will carry
    out these instructions and produce the viruses.
    This is how viruses spread, in general.

20
How does gene therapy work?
  • Gene Delivery System
  • In addition to the instructions producing the
    components of the virus itself, viruses can carry
    additional genes containing instructions for
    creating other kinds of proteins.
  • In theory, if we insert a gene that is missing
    from a patient in a virus, and infect that
    patient with the virus, the virus will spread the
    missing gene in all the cells of the patient.
  • The missing gene is now replaced and the disease
    is cured

21
How does gene therapy work?
  • The 7 requirements of a successful gene delivery
    system
  • A practical gene delivery system (the vector)
    must meet seven characteristics
  • Efficient in introducing the genes to recipient
    cells
  • Capable of achieving long term expression or
    short term expression (depending on use)
  • Flexible with respect to the target tissues it
    can deliver to

22
How does gene therapy work?
  • The 7 requirements of a successful gene delivery
    system
  • A practical gene delivery system (the vector)
    must meet seven characteristics
  • Harmless to the patient
  • Able to handle a wide range of therapeutic genes
  • Able to demonstrate a dose-response relationship
  • Supplied in a form familiar and comfortable to
    the medical community.
  • The biggest hurdle to overcome (still) of gene
    therapy is finding effective, safe vectors

23
Types of vectors
  • Types of viruses are currently used as vectors in
    gene therapy
  • retroviruses,
  • adenoviruses
  • adeno-associated viruses and
  • Herpes simplex viruses
  • They differ in their mechanisms of action and
    results

24
Types of vectors
  • viruses are currently used as vectors in gene
    therapy
  • Retroviruses
  • A class of viruses 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

25
Types of vectors
  • Three types of viruses are currently used as
    vectors in gene therapy
  • Adenoviruses
  • A class of viruses with double-stranded DNA
    genomes that cause respiratory, intestinal, and
    eye infections in humans. The virus that causes
    the common cold is an adenovirus.

26
Types of vectors
  • Three types of viruses are currently used as
    vectors in gene therapy
  • Adeno-associated viruses
  • A class of small, single-stranded DNA viruses
    that can insert their genetic material at a
    specific site on chromosome 19.

27
Types of vectors
  • Three types of viruses are currently used as
    vectors in gene therapy
  • Herpes simplex viruses
  • A class of double-stranded DNA viruses that
    infect a particular cell type, neurons. Herpes
    simplex virus type 1 is a common human pathogen
    that causes cold sores eye infection

28
  • Non-virus-mediated delivery system
  • Direct introduction
  • There are several nonviral options for gene
    delivery.
  • The simplest method is the 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.

29
  • Non-virus-mediated delivery system
  • Artificial lipid
  • Another nonviral approach involves the creation
    of an artificial lipid ,a liposome, which carries
    the therapeutic DNA which delivers the DNA
    through the target cell's membrane.

30
  • Non-virus-mediated delivery system
  • Special cell receptors as chemical links
  • Therapeutic DNA also can get inside target cells
    by chemically linking the DNA to a molecule that
    will bind to special cell receptors.
  • Once bound to these receptors, the therapeutic
    DNA constructs are engulfed by the cell membrane
    and passed into the interior of the target cell
    (Less effective).

31
What is the current status of gene therapy
research?
  • The Food and Drug Administration (FDA) has not
    yet approved any human gene therapy product for
    sale.
  • Current gene therapy is experimental and has not
    proven very successful in clinical trials.
  • Little progress has been made since the first
    gene therapy clinical trial began in 1990

32
What is the current status of gene therapy
research?
  • In 1999, gene therapy suffered a major setback
    with the death of 18-year-old Jesse Gelsinger.
    Jesse was participating in a gene therapy trial
    for ornithine transcarboxylase deficiency (OTCD)
    also known as Urea cycle.
  • Jesse 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.

33
  • The urea cycle is the sole source of endogenous
    production of arginine and it is the principal
    mechanism for the clearance of waste nitrogen
    resulting from protein turnover.
  • http//www.ornl.gov/sci/techresources/Human_Genome
    /medicine/genetherapy.shtml

34
What is the current status of gene therapy
research?
  • Another major blow came in January 2003, when the
    FDA placed a temporary halt on all gene therapy
    trials using retroviral vectors in blood stem
    cells.
  • Gene Therapy X-SCID Poses Substantial Cancer
    Risk

35
What is the current status of gene therapy
research?
  • FDA took this action after it learned that a
    second child treated in a French gene therapy
    trial had developed a leukemia-like condition.
  • Another child developed leukemia-like conditions
    (August 2002 ) when tested for combined
    immunodeficiency disease (X-SCID), also known as
    "bubble baby syndrome
  • http//www.medicalnewstoday.com/articles/42339.ph
    p

36
What factors have kept gene therapy from becoming
an effective treatment for genetic disease?
  • Short-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.

37
What factors have kept gene therapy from becoming
an effective treatment for genetic disease?
  • Short-lived nature of gene therapy
  • Problems with integrating therapeutic DNA into
    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.

38
What factors have kept gene therapy from becoming
an effective treatment for genetic disease?
  • Immune response
  • Anytime a foreign object is introduced into human
    tissues, the immune system is designed to attack
    the invader.
  • The risk of stimulating the immune system in a
    way that reduces gene therapy effectiveness is
    always a potential risk.
  • Furthermore, the immune system's enhanced
    response to invaders makes it difficult for gene
    therapy to be repeated in patients.

39
What factors have kept gene therapy from becoming
an effective treatment for genetic disease?
  • 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.
  • In addition, there is always the fear that the
    viral vector, once inside the patient, may
    recover its ability to cause disease and become
    virulent

40
What factors have kept gene therapy from becoming
an effective treatment for genetic disease?
  • Multigene disorders
  • Conditions or disorders that arise from mutations
    in a single gene are the best candidates for gene
    therapy.
  • Unfortunately, some the most commonly occurring
    disorders, such as heart disease, high blood
    pressure, Alzheimer's disease, arthritis, and
    diabetes, are caused by the combined effects of
    variations in many genes.
  • Multigene or multifactorial disorders such as
    these would be especially difficult to treat
    effectively using gene therapy.

41
What are some of the ethical considerations for
using gene therapy?
  • Some Questions to Consider...............
  • What is normal and what is a disability or
    disorder, and who decides?
  • Are disabilities diseases? Do they need to be
    cured or prevented?
  • Does searching for a cure demean the lives of
    individuals presently affected by disabilities?

42
What are some of the ethical considerations for
using gene therapy?
  • Some Questions to Consider...............
  • Is somatic gene therapy more or less ethical than
    germline gene therapy?
  • Preliminary attempts of gene therapy are
    exorbitantly expensive.
  • Who will have access to these therapies? Who will
    pay for the cost ?

43
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44
Gene Therapy Links and Research Institutes
  • For more information on different types of
    genetic disease and gene therapy
  • Must visit these sites to enrich your knowledge
    about what are being done around you, if not for
    the present but for our children

45
  • Reading Materials
  • It is a MUST that you read the rest of the slides
    which gives more examples of gene therapies and
    disasters
  • What are some recent developments in gene therapy
    research?

46
What are some recent developments in gene therapy
research?
  • Some Questions to Consider...............
  • 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 barrier."
    This method has potential for treating
    Parkinson's disease. See Undercover genes slip
    into the brain at NewScientist.com (March 20,
    2003).

47
What are some recent developments in gene therapy
research?
  • Some Questions to Consider...............
  • RNA interference or gene silencing may be a new
    way to treat Huntington's. Short pieces of
    double-stranded RNA (short, interfering RNAs or
    siRNAs) are used by cells to degrade RNA of a
    particular sequence. If a siRNA is designed to
    match the RNA copied from a faulty gene, then the
    abnormal protein product of that gene will not be
    produced. See Gene therapy may switch off
    Huntington's at NewScientist.com (March 13, 2003).

48
What are some recent developments in gene therapy
research?
  • Some Questions to Consider...............
  • 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. See Subtle gene therapy tackles blood
    disorder at NewScientist.com (October 11, 2002).

49
What are some recent developments in gene therapy
research?
  • Some Questions to Consider...............
  • Gene 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.
    See 'Miracle' gene therapy trial halted at
    NewScientist.com (October 3, 2002).

50
What are some recent developments in gene therapy
research?
  • Some Questions to Consider...............
  • Researchers at Case Western Reserve University
    and Copernicus Therapeutics are able to create
    tiny liposomes 25 nanometers across that can
    carry therapeutic DNA through pores in the
    nuclear membrane. See DNA nanoballs boost gene
    therapy at NewScientist.com (May 12, 2002).

51
What are some recent developments in gene therapy
research?
  • Some Questions to Consider...............
  • Sickle cell is successfully treated in mice. See
    Murine Gene Therapy Corrects Symptoms of Sickle
    Cell Disease from March 18, 2002, issue of The
    Scientist.
  • Do not ignore
  • Know how it happens

52
Additional Notes
  • Breast cancer
  • The discovery of the gene BRCA1 was reported in
    September 1994 after an intense and competetive
    search, by a team of researchers led by Mark
    Skolnick of the University of Utah and Myriad
    Genetics Inc. (Science, 26666-71 and 120-2,
    1994).
  • BRCA1 (and the related BRCA2) are tumor
    suppressor genes that, when working normally,
    keep cell growth in check.
  • When one copy of the tumor suppressor gene is
    damaged or lost, uncontrolled cell growth occurs.
  • Women who inherit the faulty gene may have up to
    an 85 percent risk of developing breast cancer.

53
Additional Notes
  • Xenotransplantation
  • There is a worldwide shortage of organs for
    clinical transplantation and, sadly, many
    patients due to receive new organs die on the
    waiting list.
  • Recent advances in understanding the mechanisms
    of transplant organ rejection have brought us to
    a stage where it is reasonable to consider that
    organs from other species, probably pigs, may
    soon be engineered to minimize the risk of
    serious rejection and used as an alternative to
    human tissues, possibly ending organ shortages.
  • Other procedures, some of which are being
    investigated in early clinical trials, aim to use
    cells or tissues from other species to treat
    life-threatening illnesses such as cancer, AIDS,
    diabetes, liver failure and Parkinson's disease

54
Gene Therapy Links and Research Institutes
  • For more information on different types of
    genetic disease and gene therapy
  • Must visit these sites to enrich your knowledge
    about what are being done around you, if not for
    the present but for our children

55
Gene Therapy Links and Research Institutes
  • Genetic Disease Information
  • http//www.fortunecity.com/victorian/orwell/1133/l
    inklife.html
  • http//www.ornl.gov/sci/techresources/Human_Genome
    /medicine/genetherapy.shtml
  • www.geneclinics.org
  • MEDLINEplus Genes and Gene Therapy - Access
    news, information from the National Institutes of
    Health, clinical trials information, research,
    and more.
  • Recombinant DNA and Gene Transfer - National
    Institutes of Health Guidelines
  • Questions and Answers about Gene Therapy - A fact
    sheet from the National Cancer Institute.
  • Introduction to Gene Therapy - An overview by
    Access Excellence.
  • A Gene Therapy Primer - Introduction to gene
    therapy from the bio.com.
  • Gene Therapy and Your Child - From KidsHealth for
    Parents.
  • Pioneering gene treatment gives frail toddler a
    new lease of life
  • Gene Transfer - An overview of gene therapy
    science issues, ethical concerns, and regulation
    and policy from the Genetics Public Policy
    Center.
  • Cures - An introduction to gene therapy provided
    by discoveryhealth.com.
  • Delivering the Goods - An article describing the
    different types of gene therapy approaches. From
    October 2, 2000, issue of The Scientist.
  • How to Turn on a Gene - An article from Wired
    Magazine.
  • How Viruses Are Used in Gene Therapy - From The
    DNA Files, a series of radio programs from Sound
    Vision Productions.
  • Human Gene Therapy Present and Future - A Human
    Genome News article.
  • Gene Therapy - A News Hour with Jim Lehrer
    transcript covering the death of gene therapy
    patient, Jesse Gelsinger (February 2, 2000).
  • Animations from the Tokyo Medical University
    Department of Pediatrics Genetics Study Group

56
  • Therapeutic protein
  • www.icr.org/article/428/
  • www.marketresearch.com/product/display.asp?product
    id1118842g1

57
Gene Therapy Links and Research Institutes
  • Gene Therapy Research Institute
  • The Institute for Human Gene Therapy (IHGT) -
    University of Pennsylvania Philidelphia
  • Virtual Lecture on gene therapy with James M.
    Wilson
  • Gene Therapy Courses at U Penn
  • (Some very sad news September 17, 1999 - patient
    Jesse Gelsinger dies while receiving gene
    therapy)
  • The Pittsburgh Human Gene Therapy Center (PHGTC)
  • UCSD Program in Human Gene Therapy
  • University of North Carolina Chapel Hill (UNC-CH)
    Gene Therapy Center
  • And of course, lets not neglect IUPUI -
  • Riley Hospital Wells Center (Children's cancer
    research)
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