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L5 Flashcards

small molecules in CF

1
Q

what are the current treatments available for CF?

A
  • treatments only aleviate symtoms and dont treat the cause
  • oral and nebulised antibiotics (e.g. tobramycin)
  • nebulised hypertonic secretion (stimulate H2O secretion)
  • steroids
  • exercise
  • bronchodilators
  • mycolytics
  • pancreatic enzymes
  • fat soluble vitamins
  • physiotherapy
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2
Q

what are the 2 small molecules that have been developed to help in the treatment of CF?

A

VX-770 - ivacaftor

VX-809 - lumacaftor

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3
Q

what is ivacaftor?

A

VX-770, a potentiator - increase channel Po (can be used on the G551D mutation)

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4
Q

what is lumacaftor?

A

VX-809, a corrector - ensure correct trafficking of CFTR to the membrane

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5
Q

what is the drug name for the combinaiton of Vx-770 and VX-809?

A

orkambe

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6
Q

where abouts on the CFTR protein are deltaF508 and G551D found?

A

In NBD1

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7
Q

how was VX-770 found to be a contendor in the treatment of G551D mutations?

A
  • drug screening
  • cell based floursescnce assay (Vm)
  • When Vm changes - cell changes flourescence - looked for cells which changed flourescence as changed Vm - looked for which one effected CFTR
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8
Q

how was VX-809 found as a contender to treat delta F508 CF mutation patients?

A
  • drug screening

- cell based immunoblot assay - looked for mature/post golgi levels - in the membrane?

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9
Q

what experiment using fisher rat thyroid cells showed the effects VX770 has on cells?

A
  • WT and G551D mutation cells used
  • showed VX77- can work to open up mutant channels in high levels of cAMP
  • channels have to be primed by cAMP (forskolin) first in order to VX770 to have an effect
  • VX770 and fsk work together to increase Isc
  • when CFTR inhibitor added - reverse effects of fsk and 770 - shows effects are due to CFTR change
  • VX770 can enhance mutant CFTR channels
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10
Q

what did the single channel CFTR current show when VX770 was added?

A
  • in fisher rat thyroid cells

- Po of mutant CFTR increases - causes mutant CFTR channels to open

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11
Q

What did experiments using human bronchial epithelial (HBE) cells show about forskolin responses?

A
  • WT fsk response - 56uA/cm2
  • G551D/F508 fsk response - 2.9 uA/cm2
  • G551D/F508 Vx770 fsk response - 27uA/cm2 (48% of WT - sufficient as only 15-20% of channel function required)
  • shows VX770 fsk enhances response of mutant CFTR channels
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12
Q

Using HBE cells how was ASL effected by CFTR mutations and vx770?

A
  • When CF cells treated with VX770 and VIP, ASL increases and moves closer to WT levels than before
  • shows could have an actual beneficial effect in patients due to this increased channel function - could increase ASL
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13
Q

How was cilia beat frequency affected with treatment of VX770 (HBE cells) ?

A

When CF cells were treated with VIP and VX770 - cilia beat frequency increased to WT levels - more functional - could clear mucous more effectively in humans in vivo?

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14
Q

how were the clinical trials for VX770 in G551D CFTR mutations carried out?

A
  • randomised double blind trials
  • placebo used
  • 50mg of drug (or placebo) given every 12 hours
  • 48 weeks
  • at least 1 G551D mutation in patients
  • start with similar parameters
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15
Q

what were the results from the VX770 clinical trial in treatment of G551D mutation %FEV1?

A
  • %FEV1 increased 10% with treatment of VX770 - maintained for 48 weeks
  • placebo FEV1% no improvement - even a slight deterioration in FEV1%
  • has potential to improve quality of life
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16
Q

what were the results from the VX770 clinical trial in treatment of G551D mutation - events?

A
  • with treatment with VX770- 67% of patients were event free - no pulmonary exaccerbations
  • with placebo - less patients were event free - only 41 event free
17
Q

what were the results from the VX770 clinical trial in treatment of G551D mutation - sweat [Cl-]?

A
  • in patients treated with VX770 - sweat chloride concentration is reduced below the clinical threshold - maintained for 48 weeks
  • In placebo - no change in sweat chloride
18
Q

what does VIP do?

A

stimulate CFTR

19
Q

is there a cost benefit for the use of VX770?

A

Yes, patients on VX770 cost less in hospital admissions and other treatments and there is a significant improvement to the quality of life - is a cost benefit

20
Q

What was shown in fisher rat thyroid cells about VX-809 treatment with F508 CFTR?

A

With increasing concentrations of VX809, there was an increase in both the maturation and function of F508 CFTR

21
Q

what usually happens to mutant f508 CFTR?

A

It remains in an immature (unglycosylated form), as it does not reach the golgi - gets to ER and then undergoes multiple rounds of the CNX cycle - as it is misfolded - gets degraded via ERAD

22
Q

what were the steps in the pulse chase exp looking at F508 CFTR in HEK cells?

A
  • RA label amino acids with 35S methionine and cysteine
  • Then any new immature made CFTR is 35S labelled
  • 35S compounds are removed and cells are left for different durations
  • some 35s is mature (glyc) and some stays immature (unglycosylated)
  • ratio of these depends on how long cells left and what pharmacological manipulation cells are exposed to (e.g. vehicle or vx770)
23
Q

what were the results from the pulse chase exp in HEK cells?

A
  • the longer WT cells were left - the more mature protein formed , and there was less immature protein
  • in F508 cells there was a decrease in the immature form (lots of it to start with) and no/ little mature protien - degradation was going on - not maturation
  • F508 exposed to VX809 - decrease in immautre form - forced to become mature - more mature form than with no VX809`
24
Q

What was shown in Po when NIH cells expressing f508 CFTR were treated with VX809

A

The Po of f508 cftr when cells were treated with vx809 increased (became closer to WT)- shows that CFTR has been trafficked to membrane and is functional when it bcomes trafficked
- with both VX809 and VX770 the response is enhanced

25
Q

What was shown when vx809 was added to HBE cells homozygous for CFTR f508

A
  • with increasing concentrations of vx809 there is increasing currents of CFTR
  • this effect was reversed by CFTR inhibitor - shows effects in current are specific to CFTR
26
Q

what happened when vx809 was used in a clinical trial to treat f508 CFTR patients?

A
  • results from clinical trial were a mess
  • placebo was best
  • was no pattern or improvement with vx809 in %FEV1
  • sweat [Cl-] did decrease but this was not significant (only decreased by 8mM, in vx770 - decreases my 55mM)
  • shows vx809 not having a significant effect
27
Q

what happened in the preliminary study looking at combination therapy of vx770 and vx809 in f508?

A

combination having more of an impact than 809 alone, but unlikely to improve the quality of life significantly
- only in very high doses of vx809 in combination there is an improvement in FEV1%

28
Q

give some of the features of the full clinical trial which looked at effects of vx809 in combination with vx770 in f508 CF patients

A
  • used 1108 patients all over 12
  • looked at people who were homozygous for f508
  • controls - placebo
  • given combination of lumacaftor and ivacaftor
29
Q

What were the results from the clinical trial which investigated the effect of combination 770 and 809 in f508 cf patients?

A
  • 3% improvement in %FEV1, when 770 and 809 combined (not great)
  • variation of effectiveness of therapy - some had a 10% improvement in FEV1%
  • although combination had a positive effect compared to control - less hospital admissions and IVABs
30
Q

what does combination therapy show?

A
  • shows that if vx809 is able to traffic f508 to the membrane, the addition of a potentiator vx770 can enhance function and relieve symptoms
31
Q

is there a cost benefit using orkambi?

A

no
- there is a significant cost, it doesnt significantly inprove the quality of life of patients, and patietns still require other forms of treatment and hospital admissions

32
Q

what is a newer combination therapy that has been proposed?

A

Terzicaftor (vx661) and ivacaftor (vx770)

- symdeko

33
Q

what were the results of clinical trials using symdeko (terzicaftor + ivacaftor) to treat f508 homozygous patients?

A
  • after full length of trials, those who completed trials had a 6.8% increase in %FEV1
  • was a signifcant reduction in hospital admissions, events and a increased quality of life
  • approved for treatment by FDA in Fed 2018
34
Q

what do gene therapy results to treat CF suggest?

A
  • there is a stabilization of lung function - no improvement or deterioration
  • heterogeneous population - some responded very welll others not so well
  • coulod be due to lipsome formation - may not be optimum for all patients - may need varying formulations to get genes into cells
  • step forward but more work needed to be done
35
Q

what was the control in the CFTR gene therapy and why was this not idea?

A

Was saline nebulised
- ideal control would have been to add in scrambled DNA to lipsomes - but this is unethical as cannot put scrambled DNA sequecnes into the body - dont know effects

36
Q

is there improved Cl- secretion with CFTR gene therapy?q

A

yes

  • there is more Cl- secretion with gene therapy
  • is also improvement in bronchial CFTR DNA score - genes getting into the cells to make WT CFTR - why getting more Cl- secretion

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