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22 Cards in this Set
- Front
- Back
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siRNA |
small interfering RNA
- they induce mRNA degredation |
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Genesense |
a colon cancer antisense drug that targets bcl-2, which is thought to have apoptosis effect |
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What are the three major difficulties of antisense? |
1. Stability (easily degraded)
2. Binding (hard to ID target)
3. Target tissue (need to get to tissue of origin) |
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What are the strategies for targeting antisense? (6) |
1. Microinjection |
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What are the strategies for monitoring antisense? (5) |
1. Inhibition of gene expression |
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G3139 |
21 day antisense strategy:
1. cont. infusion of G3139 for 7 days
2. day 4 infusion of caboplatin & paclitaxel
3. cycle repeats every 21 days |
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Vitravene |
First and only approved antisense drug - for local treatment of CMV retinitis in AIDS pt, it binds to target mRNA, inhibits IE2 protein to prevent viral replication
- intra-vitreal injections were unpleasant, it has been replaced by an oral drug |
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What is the general structure of siRNA's? |
19 nt duplex
2 nt overhangs on each 3' end |
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What are the steps of siRNA interference? |
1. siRNA unwinds within cells and is incorporated into RISC, a stable protein-RNA complex
2. siRNA is directed to target mRNA
3. mRNA undergoes premature degredation, preventing protein synthesis |
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What are the steps of turning siRNA's into drugs? |
1. Choose potent and specific sequence to target
2. Stabilize against exonucleases - addition of phosphorothioate to strand
3. Stabilize against endonucleases - addition of 2'OMe, 2'F
4. Add conjugate to improve biodistribution - i.e. piggyback to cholesterol for takeup by cells |
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How many genes does ebola have? |
three for the structure three for the membrane |
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Liposome |
organized lipid nanoparticles used in pharmaceutical drug delivery - enable delivery of siRNA's into cells
- an efficient way to deliver the drug to many different cells, particularly the liver |
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Sirna-027 |
RNAi for treatment of Age Related Macular Degeneration - targets VEGFR molecule which is implicated in degeneration of eye - shown effective in animals, is still in early trials
Probably the most promising among siRNA therapy It is: - a single intravitrial injection - well tolerated - effective in improving visual acuity |
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How do miRNA work? |
MicroRNA silence by translational inhibition and mRNA degredation |
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What is the proposed anatomy of miRNA? |
8 nt "seed" with ends that match mRNA
- in the middle is a mis-match so the mRNA is much more likely to degrade |
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What was used as an early test for HIV? |
CD4 count
- untreated, CD4 count steadily decreases until there are no longer enough to mount immune defense
- CD4 count can be low for other reasons, but in early days, was useful test |
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What is the currently used (best) test for HIV? |
RNA viral load
- grows exponentially when pt first infected - the best marker of burden, amount of virus in body - used to diagnose and to make treatment decisions |
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What are the limitations of envelope body counts in HIV diagnosis? |
can't be seen until ~100 days
very specific, but can't be seen early and not reflective of severity of infection |
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Amplicor
What are the problems? |
test to measure HIV RNA by RT-PCR
- lower limit of detection is copies/mL
Clinical Issues: - contamination - technically difficult - expensive |
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21-Gene Assay |
study of breast cancer tumor to evaluate risk of recurrance
yields a "RS" (recurrance score) with weighted results for cancer and reference genes
Good genes: estrogen group, GSTM, BAG |
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What are the treatment recommendations for low RS patients?
high RS? |
low RS - hormonal treatment
high RS - hormonal treatment + chemotherapy |
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RS 11-25 |
Randomized Hormone Rx vs. Hormone + Chemotherapy Rx trial to determine recommendation for intermediated RS patients |
