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Molecular Biology > Gene Therapy > Flashcards

Gene Therapy Flashcards

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1
Q

What is gene therapy?

A

Treatment of a disease by genetically modifying the cells of a patient.

-usually involves the insertion of a normal gene (DNA) directly into a cell

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2
Q

Why gene therapy?

A

Done to correct or prevent a pathological process

  • Acquired diseases
  • Genetic diseases
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3
Q

How is gene therapy done?

A
  1. Normal (therapeutic) DNA isolated
  2. Gene therapy
    - (a) therapeutic DNA is packaged into a vector
  • (b) vector unloads its DNA into target cell and
  • (c) faulty or damaged cell restored to normal
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4
Q

What is somatic gene therapy?

A
  • Modification introduced into somatic (non-reproductive ) cell implicated in the disease
  • Confined to a patient
  • Changes are not heritable
  • may have to be repeated in future generations
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5
Q

What is germline gene therapy?

A
  • Modification in gamete or fertilized egg (zygote or early embryo)
  • Changes are heritable
  • prevents the diseas/trait from being passed on to future generations

Ethical implications:
-technology is not perf3ct

  • no right to decide
  • therefore not currently performed in humans
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6
Q

What are strategies for transecting human cells?

A

In vivo gene therapy

Ex vivo gene therapy

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7
Q

What is gene augmentation therapy?

A

Insert a normal gene into a nonspecific location within the genome to replace a nonfunctional gene. A most common approach

  • to treat inherited disorders caused by loss of function of a gene
  • effect of disorder must be reversible
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8
Q

What is gene replacement therapy?

A

Swap an abnormal gene for a normal gene through homologous recombination

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9
Q

What is gene inhibition therapy?

A

Silencing a gene: exogenous gene inhibits gain of function caused by mutation, or a pathogen

Antisense RNA or DNA hybridized to normal mRNA. Protein synthesis is blocked

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10
Q

What is gene repair therapy used for?

A

Repair an abnormal gene

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11
Q

What is gene alteration?

A

Alater the regulation (the degree to which a gene is turned on or off) of a particular gene

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12
Q

What is viral mediated gene therapy?

A

Also called transduction

  • Therapeutic DNA is delivered to the cell using a “vector” (virus)
  • Viruses can recognize and insert their DNA into certain cells
  • Most protocols have used mammalian viral vectors because of their high efficacy
  • The viral vectors are modified:
    • So they are unable to cause disease
    • to increase their ability to deliver specific genes to a patient’s cells
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13
Q

Why choose a particular viral vector for viral-mediated gene therapy?

A
  • ability to recognize and infect certain cells
    • targeted gene therapy e.g. a strain of Herpes virus (HSV-1) primarily infects cells of central nervous system

-ability to transfer the genes to cells

  • Ability to alter DNA:
    • permanently
    • temporarily
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14
Q

What are common viral vectors used for gene therapy ?

A

Integrating viral vectors:

Retroviruses- single stranded RNA viruses e.g. Maloney murine leukemia virus (Mo-MLV)

Lentiviruses- specialized retroviruses that can infect both dividing and non-dividing cells (e.g. human immunodeficiency virus)

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15
Q

What are the non-integrating viral vectors of common viral vectors used for gene therapy?

A

Adeno-associated viruses: nonpathogenic single stranded DNA viruses, capable of infecting both dividing & non dividing cells, e.g. human parvovirus

-Adenovirus- non-enveloped viruses containing a linear double stranded DNA genome (e.g. the viruses causing common cold)

Poxviruses

Herpes viruses- have a linear double stranded DNA molecule in its genome (e.g. Herpes simplex virus type 1) a human neurotropic virus

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16
Q

Describe Non-viral mediated gene therapy

A

Safety concerns of recombinant viruses have prompted increasing interest into non-viral vector systems including:

Transfection (chemical, liposome mediated, lipofection, electroporation, and receptor mediated)

Direct transfer (microinjection t& particle bombardment)

Bacterial gene transfer involves live invasive bacteria (salmonella and shigella) or those who transfer DNA through their pilus eg Agrobacteria tumefaciens

17
Q

What is In vivo liposome gene delivery ?

A

Used of artificial lipid here with an aqueous core

Liposome carries therapeutic DNA and is capable of passing the DNA through the target cell’s membrane when injected or sprayed into the tissue

18
Q

What is receptor mediated endocytosis ?

A

Viral coat protein binds a specific receptor on the plasma membrane of cells, followed by endocytosis

19
Q

Explain the introduction of a 47th (artificial human chromosome into target cells)

A

47th chromosome would be a large vector

  • capable of carrying substantial amounts of genetic code
  • would exist autonomously alongside the standard 46
  • wouldn’t cause any mutation

Hopefully, the body’s immune systems wouldn’t attack it because of its construction and autonomy

-Difficulty to deliver such a large molecule into the nucleus of a target cell

20
Q

Give the example of the first human gene therapy

A

1990- Ashanti DaSilva

Ex vivo gene therapy strategy used in a 4 year old severe combined immunodeficiency (SCID) patient with a deficiency in adenosine deaminase (ADA) gene

21
Q

What are the challenges facing human gene therapy?

A
  • human immune system may fight off viral vector
  • appropriate vectors
  • gene therapy is still in its infancy
  • current therapies are primarily experimental
    • in research & human clinical trials stages
  • Gene therapy is short lived
    • Problem with adequately targeting and sustaining therapeutic effects
  • problems with viral vectors
    • gene therapy used to treat children with X-SCID (“bubble boy” disease) is stopped (2002) in France when the treatment caused leukemia in one of the patients
  • multi gene or multifactorial disorders
    • e.g. heart disease, Ahlzeimer’s disease, arthritis and diabetes -would be especiall difficult to treat effectively using gene therapy

-need for increased public funding for biomedical research

22
Q

What are the recent advances?

A
  • Gene therapy rids men of cancer
  • sickle cell disease corrected in human models using stem cell based gene therapy
  • gene therapy prevents the onset of diabetic symptoms in mice
  • gene therapy for HIV
23
Q

Give the history of the human immune system may fight off viral vector

A

E.g. gene therapy that led to death of Jesse Gelsinger in 1999

  • an 18 year old patient who suffered from orthinine transcarbamoylase deficiency,
    - an inherited disorder: commonly causes death in affected new born males from inability to properly process nitrogen in food proteins

Gelsinger’s died from immune reaction to engineered adenovirus that was infused into his liver

24
Q

How can gene therapy be used to rid men of cancer?

A
  1. Blood taken from patient
  2. T cells infected with virus to carry key genes into them
  3. DNA from genes helps cells develop receptors
  4. Modified cells injected back into patient
  5. Receptors target cancerous cells to be killed
25
Q

How can sickle cell disease be corrected in human models using stem cell-based gene therapy?

A

Combined RNA interference with globin gene transfer to create a therapeutic transgene

-The therapeutic gene was engineered into a lentiviral vector and introduced into hematopoietic stem cells to produce normal hemoglobin

  • The new gene had two functions
    • produce normal hemoglobin
    • suppress the generation of sickle shaped hemoglobin S
26
Q

How can gene therapy prevents the onset of diabetic symptoms in mice?

A

University of Pittsburgh investigators successfully prevented onset of elevated blood sugar (hyperglycemia) in diabetes-prone mice

 -by inserting a gene encoding for a cytokine (a protein that stimulates or inhibits the proliferation or function of immune cells)into their insulin-producing cells
27
Q

How did Dr. John Rossi contribute to gene therapy for HIV?

A

Study will genetically modify stem cells to carry anti-HIV genes

  • To combine three anti-HIV gene therapy targets, in addition to the use of anti-HIV drugs
  • The study will be the first triple-construct approach tested in humans with HIV
  • The hope is that by combining different approaches, resistance issues will be lessened and potency will be enhanced
28
Q

What are potential applications of gene therapy for the treatment of cancer?

A
  • artificial killing of cancer cells
  • stimulate natural killing of cancer cells
  • Protect surrounding normal tissues from effects of chemotherapy/radiotherapy
    - protect tissues from the systemic toxicities of chemotherapy (e.g. multiple drug resistance type 1 gene)
  • tumors resulting from oncogene activation
    • selectively inhibit the expression of the oncogene
  • tumors arising from inactivation of tumor suppressor
    • gene augmentation therapy. Insert wild-type tumor suppressor
29
Q

How can cancer cells be killed artificially?

A

-insert a gene encoding a toxin or a gene conferring sensitivity to a drug into tumor cells

30
Q

How can the natural killing of cancer cells be stimulated?

A
  • increase anti tumor activity of immune system cells
    • e.g. by inserting genes that encode cytokines

-induce normal tissues to produce anti tumor substances (e.g. interlocking-2, interferon)

31
Q

What are the ethical considerations ?

A

What is normal, what is a disability or a disorder: who decides?

Are disabilities diseases- do we prevent or cure them?

How do we weigh the benefits of gene therapy against assurances that the gene vectors are safe?

Does searching for a cure demean the lives of persons currently affected by the disabilities in question?

Preliminary attempts at gene therapy are highly e pensive

 - Who will have access to these therapies
 - Who will pay for the use of such therapy?

Is somatic gene therapy more or less ethical than germline gene therapy?

Debate about the method of obtaining embryonic stem(ES) cells for gene therapy
-by the destruction of an early human embryo

Molecular Biology (24 decks)

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