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MS 1 Unit 7 MCP > Emerging Clinical Technologies > Flashcards

Emerging Clinical Technologies Flashcards

1
Q

Level of intervention and treatment

A
  • mutant gene- modify somatic genotype: transplantation, gene therapy
  • Mutant mRNA- RNAi
  • Mutant protein- protein replacement, enhancement of residual function
  • Metabolic or biochemical dysfunction- disease specific compensation
  • clinical phenotype- medical or surgical intervention
  • the family- genetic counseling, carrier screening, prenatal testing
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2
Q

Counseling

A
  • prenatal/carrier testing
  • provide information
  • planning and education
  • provides opportunity for patients to obtain data about potential genetic disorders or carrier status and to discuss their concerns with someone who understands genetic principles
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3
Q

Medical or Surgical intervention

A
  • Drug therapy: usually treats the symptoms

- Surgery: transplantation (heart, liver, etc); Repair (cleft lip/palate, aorta, bone fusion)

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4
Q

Treatment of Metabolic Disorders- dietary modification

A

-Dietary modification/restriction: amino acid catabolic pathway disorders (PKU), life long, can be difficult for patient and family

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5
Q

Treatment of Metabolic Disorders- Replacement

A
  • add back something that is missing

- BH4 hyperphenylalanemia

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6
Q

Treatment of Metabolic Disorders- diversion

A
  • use other pathways to avoid accumulation of a metabolite
  • redirect to breakdown substances to harmless compounds
  • example: defect in the urea pathway where the block prevents degradation of NH3 to urea which can be eliminated from the body
  • NH3 will accumulate which can be toxic
  • diet is partial solution but does not solve the entire problem
  • it was found that administering sodium benzoate will push the excess ammonia to combine with glycine, and this is converted to hippurate which can be excreted in the urine
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7
Q

Treatment of Metabolic Disorders- Inhibition/Depletion

A
  • Inhibition: modifying the rate of synthesis by using a drug or other agent that slows or blocks a critical step in the pathway
  • Depletion: Removal of a substance that is in excess, hereditary hemochromatosis- accumulation of iron be controlled by regular phlebotomy
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8
Q

Treatment at the Protein Levels- Replacement Extracellular

A
  • extracellular
  • if a protein is absent- add it back
  • Hemophilia A- factor VII
  • alpha 1 antitrypsin deficiency- treat with alpha 1 antitrypsin

-Problems: cost, availability, antibody production in patient (pigs, cows), contamination

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9
Q

Treatment at Protein Level- Replacement Intracellular

A
  • must target a specific cell type
  • Example: Gaucher disease: lysosomal storage disease, deficiency of glucocerebrosidase
  • there is modification of the glucosidase by mannose 6-phosphate. This is picked up by the macrophages. The enzyme can then cross the lysosomal membrane to begin to digest the stored macromolecules
  • response in patients has been positive, with overall improvement in function and phenotype
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10
Q

Treatment at Protein level- enhancing genetic expression

A
  • enhancing genetic expression: use of one gene to compensate for the mutation in another
  • Sickle cell anemia
  • treatment with decitabine increases levels of y-globin in the blood (hypomethylates DNA by inhibiting methyltransferase)
  • Hb F functions as a replacement oxygen carrier and inhibits polymerization of deoxyhemoglobin S
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11
Q

Transplantation- Bone Marrow for Hematologic disorders

A
  • hematologic disorders
  • remove the disease clone and replace it with unaffected cells
  • collect bone marrow stem cells from the patient (autologous) or from a matched donor (allogenic)
  • transplanted cells with re-establish in the new host, and hopefully cure the disease
  • possibility that not all of the disease related cells will be removed, and they could re-establish the disease
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12
Q

Transplantation of Bone Marrow 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 other cells
  • acts as a source of mononuclear phagocytes
  • can reduce the size of various internal organs
  • if done within the first 2 years of life, will limit the negative neurological impact of the disease
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13
Q

Stem Cells

A
  • self renewing, undifferentiated cells
  • can proliferate and produce a wide variety of different types of differentiated cells
  • Embryonic stem cells (ESC)-which are pluripotent and capable of differentiating into any cell type in the body
  • Somatic stem cells (SSC) which are self renewing but can only differentiate into the cell types present in the tissue of origin- for example hematopoetic stem cells can differentiate into lymphocytes, neutrophils, basophils, red blood cells but could not generate skin or nerve cells
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14
Q

Embryonic Stem Cells

A
  • Potential therapy for : Parkinson disease, Alzheimer disease
  • Potential source of cells for: tissue grafting, organ transplants
  • attract option because they provide the possibility of creating multiple types of cells from a single source
  • furthermore, they offer the possibility of generating normal cells from tissues that may not be normally accessible- such as brain cells
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15
Q

Downside of Embryonic Stem Cells

A
  • what about the source of cells?
  • should embryos be used in this way?
  • do the potential benefits outweigh other considerations?
  • will the embryos be destroyed during the harvesting process?
  • if ESC are an important commodity, will this become a commercial endeavor?
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16
Q

Problems with Allogenic Stem Cell Use

A
  • immunosuppression
  • graft vs host disease
  • the ideal situation is for stem cells to be collected from one individual and reimplanted in the same person which avoids the problems of immune reaction (autologous transplantation)
  • even with matched donors (allogenic transplantation), there are likely to be negative consequences of a transplant or infusion of “foreigh” cells
  • thus patients will be at risk for graft vs host disease and will require immunosuppressive drugs throughout the remainder of their lives
17
Q

Induced Pluripotent Stem Cells

A
  • cells collected from an individual are treated in vitro using reprogramming factors that have been shown to reverse the differentiation in the cells and revert them to a state of pluripotency
  • these cells are able to function in much the same way as embryonic stem cells with the capability of being stimulated to re-differentiate into any desired cell type
  • the newly established cells can be transplanted back into the patient
  • as they are his/her own cells, there should not be a problem with immune rejection
18
Q

Cloning/ Nuclear Transfer

A
  • taking a cell from one individual and growing up another identical individual
  • a single cell is obtained from a donor and a unfertilized egg (oocyte) is obtained from another individual
  • the oocyte is enucleated, and the nuclear from the donor cell is inserted into the oocyte
  • the reconstituted cell has the nuclear contents of one individual and the cytoplasm from another
  • this cell is now implanted into a surrogate mother who will carry it to term and hopefully produce a healthy newborn
19
Q

Effects of cloning

A
  • Dolly only lived 6 years of an expected 12
  • telomere shortening was evident and even as a young sheep her cells and body processes often resembled those of an older individual
  • there was also a question of inappropriate imprinting
  • positive: creating a herd of cows or other animals that display the most positive characteristics (high milk production, thick wool)
  • for crop plants, higher productivity, heat and insect resistance, my be possible
20
Q

Nuclear transfer in humans

A
  • nuclear transfer involving a diploid nucleus derived from a somatic cells does not occur in humans
  • however it is possible to transfer a nucleus (haploid) from one egg to another
  • this is useful when the patient’s egg cytoplasm carries deleterious mutations (mitochondrial disorders)
  • if a normal donor egg can be obtained, the nucleus can be removed and replaced by the nucleus from the patient’s egg
  • in vitro fertilization or ICSI with the patient’s husband’s sperm follows to create a fertilized egg that can be reimplanted into the patient
21
Q

Cloning pets

A
  • it will not be an exact duplicate
  • color might be different because of the X inactivation which is random
  • size differences are possible, because this is an environmentally related feature
  • and personality can be totally different as this is a learned behavior
22
Q

Gene therapy

A
  • the deliberate introduction of genetic material into human somatic cells for therapeutic, prophylactic or diagnostic purposes
  • general classes of therapy:
  • correct a loss of function mutation by incorporating a functional gene into the genome
  • compensate for a deleterious dominant allele by replacing or inactivating the 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 the gene of interest
  • identification of target tissue
  • ability to deliver gene to target
  • understanding of gene biochemistry
  • understand of expression
24
Q

Major limitation- Delivery of Gene to Target

A
  • vector must be able to carry the DNA
  • must be able to insert DNA into the target cell
  • viruses tend to be favored but there are other options
  • most permanent if the therapy DNA is incorporated into the host cell’s own DNA
  • temporary incorporation in cytoplasm requires repeated therapy sessions: artificial liposome that carries DNA of interest, the lipid bilayer membrane of the liposome will fuse with the cell membrane and the DNA will be released into the cytoplasm
25
Q

In vivo vs Ex vivo

A
  • in vivo: genes are incorporated into vectors and targeted to specific cells in the body
  • ex vivo: cells are extracted from the patient and genetically modified. The altered cells are returned to the patient
26
Q

ADA Deficiency

A
  • ADA Deficiency- Immunodeficiency disorder, 15% of severe combined immunodeficiency (SCID)
  • Deoxyadenosine -> Deoxyinosine (with ADA) -> Xanthine Oxidase (with PNP) -> Uric Acid (excretion in urine)
  • lack of adenosine deaminase results in a block in the metabolic pathway leading to an accumulation of dATP in the cells which prevents DNA synthesis and cell division
  • T and B cells are highly susceptibile and the immune system is compromised
27
Q

First successful gene therapy

A
  • T cells were collected, grown in vitro and stimulated to proliferate with interleukin 2 and monoclonal antibody OKT3
  • about 10 days later retroviral vectors carrying the non-mutant adenine deaminase cDNA are added to the cultures
  • some cells will be infected by the virus particles
  • the cells were sorted and amplified then reinfused into the patients
  • significant improvement was seen as measured by improved T cell function
  • First Ashanti, then Cindy, began to produce antibodies and grow tonsils
  • they no longer needed to be isolated but could go to school, play with others their age, and begin a normal life
28
Q

Who should be subjects for gene therapy

A
  • only patients who had failed conventional therapies and who had less than 3 months to live were accepted onto new protocols
  • therapies were carefully tested in other animals before being offered to human
29
Q

Back to Gene Therapy Success

A
  • an adenoviral vector was created carrying the CFTR. The vectors are suspended in solution in an inhaler often used by CF patients
  • when inhaled the solution deposits the vector in the lungs where they are incorportated into surface cells
  • the modified cells function normally, reducing the mucus in the lungs
  • unfortunately the short term fix as the benefit is lost when the cells die
  • also things used to treat DMD, melanoma, hemophilia, Leber’s congenital amaurosis (eye disease), adrenoleukodystropy
30
Q

Antisense DNA therapy

A

-useful to down regulate protein production
-cancer characterized by overproduction of a protein
-incorporate an antisense strand into the cells to block translation
by prevent binding of ribosomes

31
Q

RNA interference

A
  • targeted degradation of mRNA
  • destroy mRNA from negative dominant mutations while leaving the second allele alone
  • reduce the concentration of an mRNA that is over expressed
32
Q

Adeno-associated virus

A
  • non-pathogenic vector
  • reduces the likelikhood of an immune reaction
  • is found in many serotypes- so the proper vector can be matched to a particular cell type
  • non-integrative, so will not disrupt cancer genes

MS 1 Unit 7 MCP (15 decks)

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