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MCP Unit 7 > Treatment of Genetic Disease > Flashcards

Treatment of Genetic Disease Flashcards

1
Q

mutant gene

A

-modify somatic genotype- transplantation or gene therapy

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2
Q

mutant mRNA

A

-RNAi

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3
Q

mutant protein

A
  • protein replacement

- enhancement of residual function

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4
Q

metabolic/biochemical dysfunction

A

-disease specific compensation

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5
Q

clinical phenotype

A

-medical or surgical intervention

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6
Q

family

A

-genetic counseling, carrier screening, pre natal testing

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7
Q

counseling

A
  • prenatal or carrier testing
  • provide information
  • planning and education
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8
Q

medical or surgical intervention

A
  • drug therapy- usually treats symptoms
  • surgery- transplant
  • repair
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9
Q

treatment of metabolic disorders

A
  • dietary modification/restriction
  • aa catabolic pathway disorders
  • life long
  • PKU
  • can be difficult for patient and family
  • replacement- adding back something thats missing (BH4)
  • diversion- use other pathways to avoid accumulation of metabolite
  • redirect breakdown substances to harmless compounds
  • inhibition- modifying rate of synthesis by using drug or other gent that slows or blocks critical step
  • depletion-removes excess
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10
Q

hereditarty hemochromatosis

A

-accumulation of iron can be controlled by regular phlebotomy

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11
Q

treatment at protein level

A
  • replacement-extracellular
  • VIII hemophilia and a1 antitrypsin
  • cost
  • availability
  • antibody production in patient
  • contamination

replacement- intracellular

  • must target cell type
  • gaucher- lysosomal storage, deficiency of glucocerebrosidase
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12
Q

enhancing genetic expression

A
  • protein level
  • using gene to compensate for the mutation in another
  • sickle cell anemia- treat with decitabine increases gamma globin
  • functions as replacement oxygen carrier and inhibits polymerization of HbS
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13
Q

bone marrow transplant

A
  • hematologic disorders
  • remove the disease clone and replace it with unaffected cells
  • collect bone marrow stem cells from the patient for from matched donor (autologous vs allogenic)
  • transplanted cells will re establish in the new host and hopefully cure disease
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14
Q

bone marrow transplant for lysosomal storage diseases

A
  • bone marrow is about 10% of the body’s cell mass and extracellular transfer from the normal marrow may stimulate function in the other cells
  • acts as a source of mono-nuclear phagocytes
  • can reduce the size of various internal organs
  • if done within the first 2 years of life, will limit negative neuro impact
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15
Q

stem cells

A
  • self renewing, undifferentiated cells
  • can proliferate and produce a wide variety of different types of differentiated cells
  • embryonic are pluripotent and can make all things
  • somatic stem cells are limited to tissue or origin
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16
Q

embryonic stem cells

A
  • potential therapy for parkinsons/alzheimers
  • potential source of cells for tissue grafting and organ transplants
  • source of cells?
  • should embryos be used?
  • do potential benefits outweigh other considerations?
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17
Q

problems with allogenic stem cell use

A
  • immunosuppresion

- GVHD

18
Q

induced pluripotent stem cells

A

-can take cells from adult and revert them to stem cells and transplant them back in

19
Q

cloning/nuclear transfer

A
  • take donor egg and remove nucleus
  • take nucleus from thing to be cloned and insert it into donor egg to be carried and birthed
  • potential ill effects of procedure
  • negative impact on genes, chromosomes, normal cell processes like aging
  • benefits from agriculture-improving crops, herds, etc
20
Q

donor egg

A
  1. removing mother’s nucleus
  2. removing nucleus from donors egg
  3. inserting mothers nucleus in donor egg
  4. fertilizing egg
21
Q

companies for cloning

A
  • offering nuclear transfer for other animals
  • closed in sept 2009 by parent company due to patent infringement by other entities and anomalies identified in some of their attempts
22
Q

gene therapy

A
  • deliberate introduction of genetic material into human somatic cells for therapeutic, prophylactic, or diagnostics purposes
  • correct a loss of function mutation by incorporating functional gene
  • compensate for deleterious dominant allele by replacing or inactivating mutant allele
  • adding genetic material that has a pharmacological effect
23
Q

requirements for successful gene therapy

A
  • identification of gene
  • availability of gene sequence or cloned DNA from gene of interest
  • identification of target tissue
  • ability to deliver gene to target
  • understanding of gene biochem
  • understanding of expression
24
Q

major limitation of gene therapy

A
  • delivery of gene to target
  • vector must be able to carry DNA
  • must be able to insert DNA into the target cell
25
Q

delivery of gene to target

A
  • most permanent if the therapy DNA is incorporated into the host cells own DNA
  • viral vectors
  • temporary incorporation in cytoplasm requires repeated therapy sessions
26
Q

in vivo vs ex vivo

A
  • can put man made cloned gene in patient or

- can take pt cells, fix them, and put them back

27
Q

first successful gene therapy

A
  • 1990
  • ADA deficiency
  • immunodeficiency disorfer
  • 15% of SCIDs
  • pathway thats disrupted causes increase in dATP and lymphocyte cell death
  • ashanti de silva and cindy kisik
  • took cells, corrected them, and put them back
28
Q

clinical trials

A

-1999- Jesse Gelsinger, 18 dies from liver complications- he had OTC and an immune response to adenovirus gene therapy
-2002- two French patients die of cancer
-retroviral vector
-insertion of therapy gene into another active gene lead to loss of function
2003- gene therapy with retroviral vectors is banned in US

29
Q

who should be subjects?

A
  • when to the benefits outweigh the risks?
  • who should participate?
  • an individual known to have a disease causing mutation but is currently not showing symptoms?
  • an individual with clinical symptoms of a disease by whom has received no standard therapies?
  • an individual who has failed standard therapies?
  • be sure that the protocol and risks are clearly described and an informed consent is executed
30
Q

2004

A

-adenovirus vector carrying CFTR gene is used in an inhaler for CF pts

31
Q

2006

A
  • clinical trials start for DMD intramuscular injection using a plasmid vector
  • possible immunity complication in 2010
32
Q

2006 2

A
  • first successful use of gene therapy to treat a melanoma

- T cells targeting to attack cancer cells

33
Q

2007

A
  • proposal for intramuscular injection for hemophilia
  • 1st ADA patient (Ashanti) doing well, treated at 4, now 20-25% normal population of T cells, attending college
  • 3 year old with X-SCID dies of leukemia- received retroviral gene therapy at birth in the UK
  • death in chicago due to immunosuppression caused by gene therapy (adenovirus)- for arthritis and died of fungal infection
34
Q

2008

A

-8 patients with rare immunological diseases were cured

35
Q

2009

A
  • 5 children with Lebers congenital amaurosis had partial restoration of sight
  • 2 kids with adrenoleukodystrophy responded to therapy and stable after 2 years- used HIV as vector
36
Q

2010

A

-gene therapy in dogs to treat color blindness

37
Q

additional approaches

A
  • antisense DNA therapy
  • useful to down regulate protein production
  • cancer characterized by overproduction of a protein
  • incorporate an antisense strand into the cells to block translation
38
Q

RNA interference

A
  • targeted degradation of mRNA
  • destroy mRNA from negative dominant mutations while leaving second allele alone
  • reduce the concentration of an mRNA that is over expressed
39
Q

other vectors

A
  • AAC- adeno associated virus
  • non-pathogenic
  • reduces likelihood of an immune reaction
  • found in many serotyoes- so proper vector can be matched to a particular cell type
  • non integrative, won’t disrupt cancer
40
Q

germ line gene therapy?

A

currently only on somatic cells

  • modification of germ line could end certain diseases
  • tampering with evolution?
  • designer babies?
41
Q

conclusions

A
  • there are many different options, and it is important to assess the disease and best choice
  • use the technology wisely
  • be aware of possible ethical issues for different treatments

MCP Unit 7 (14 decks)

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