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BIOM30002: Molecule to Maladay > Cystic Fibrosis > Flashcards

Cystic Fibrosis Flashcards

1
Q

What is the leading impact to CF?

A

Abnormally thick mucus
* produced by malfunction in transporting salt ions (Cl-) across epithelial cells lining duct

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2
Q

What are the clinical features affecting the RESPIRATORY system?

A

Frequent Coughing, Chronic Infections & Lung Damage
DUE TO:
* obstruction of bronchioles by mucus
* colonisation of bacteria (antibiotic-resistant strains)
* damage by inflammatory responses

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3
Q

What are the clinical features affecting the REPRODUCTIVE system?

A

Infertility in males & SUB-infertility in females
DUE TO:
* blockage of vas deferens = leads to fibrosis or atrophy
* cervical mucus in females = barrier of passage of sperm
* females may be anovulatory

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4
Q

What are the clinical features affecting the GASTROINTESTINAL system?

A

Poor Growth & Chronic Malabsorption
DUE TO:

  • blockage of pancreatic ducts by mucus
  • poor digestion of fats & proteins
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5
Q

What chromosome is the CFTR gene on?

A

7

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6
Q

What does the CFTR gene code for?

A

Ion channel protein & CFTR protein
ALSO:
* full transporter of four canonical domains === linked to single polypeptide chain

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7
Q

What processes is the CFTR anion pore gating regulated by:

A
  • cAMP-dependent (Protein Kinase A) phosphorylation
  • ATP binding
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8
Q

What are the domains of the CFTR protein?

A

4 Canonical Domains
* Membrane Spanning Domains (MSD - 1&2)
* Nucleotide Binding Domains (NBD - 1&2)

Regulatory Domain (R)

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9
Q

What is the role of the NBDs?

A
  • bind & hydrolyse ATP
  • ATP binding → channel OPENS
  • ATP hydrolysed → channel CLOSES
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10
Q

What is the role of the MSDs?

A
  • forms channel for passage of Cl-
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11
Q

What is the role of the R domain?

A
  • Phosphorylated by cAMP
  • Phosphorylation leads to fine tuning of channel function
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12
Q

How are the 4 Canonical Domains and R Domain linked?

A

They are linked into a single polypeptide chain

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13
Q

How do interactions between the MSDs & NBDs occur?

A

Via coupling helices

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14
Q

What do the channel opening & closing require in the CFTR molecule mechanism?

A
  • Opening: Phosphorylation & Nucleotide (ATP) Binding
  • Closing: Hydrolysis
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15
Q

What is the 2-step activation process in CFTR molecular mechanism?

A
  • PKA phosphorylation
  • ATP binding

DETAILED:
1. R domain blocks channel but can disengage and allow channel to be turned on by PKA adding P group which acts as a temporary lock and allows channel to flow freely.
2. ATP binding occurs
3. Eventually, dephosphorylation of P occurs and blocks channel again & resets to allow ^^ again

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16
Q

What is the gating cycle of the fully
phosphorylated CFTR channel?

A
  1. Flow of Cl- ions = ATP-bound closed channels open to pre-hydrolytic open state
    * ATP-induced dimerisation of NBD 1&2 = conformational changes in MSD 1&2
  2. Channel closure == ATP → ADP = NBD dimer disruption
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17
Q

What happens to the NBD domains (NBD 1 & 2) in the presence of ATP?

Relates to the dimers

A
  • NBD 1 & 2 combine head-to-tail forming dimers.
  • Two ATP molecules are trapped between these dimers.
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18
Q

What are the differences between NBD1 and NBD2?

A
  • NBD1: head region has a “degenerate site” for ATP (weak binding, upper site 1)
  • NBD2: tail region has a “catalytic site” for ATP (strong binding, lower site 2)
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19
Q

Explain what the 2 ATP is used for in NBD1 & NBD2

A
  • both ATP need to bind

THEN:

  • ATP1 undergoes hydrolysis = proper gating
  • ATP2 either remain bound (for rapid opening/closing) OR dissociate (so CFTR is more stably closed)
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20
Q

How does the R domain affect the channel?

A

Interaction depends on phosphorylation state.

  • dephosphorylated = wedges itself between the two halves of the channel = prevents NBD dimerisation & channel opening.
  • phosphorylated = adopts a permissive state = allows the channel to function.
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21
Q

What part of the CFTR protein interacts with other cellular proteins?

A

C-terminus
* acts like an anchor

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22
Q

Why is the CFTR protein anchored to the cytoskeleton?

A

To be positioned near other proteins that influence its functions.

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23
Q

List some of the functions influenced by proteins interacting with CFTR.

A
  • Conductance (regulating flow of ions)
  • Regulation of other channels (e.g., ENaC channel)
  • Signal transduction (cellular communication)
  • Localisation at apical plasma membrane (positioning)
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24
Q

How does the CFTR function in NORMAL vs CF airways?

Lungs

A

Normal
* CFTR regulates movement of Cl- and Na+ ions.
* Balanced movement keeps airway surface liquid (ASL) hydrated
* Active transport: ENaC channels move Na+ into cells.
* Passive movement: Cl- follows Na+ out, maintaining hydration.

CF
* Defective CFTR disrupts ion regulation.
* Uninhibited ENaC causes excessive Na+ absorption.
* No functional CFTR for Cl- movement out of cells.
* ASL becomes depleted, hindering mucus clearance.

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25
Q

How does the CFTR function in NORMAL vs CF sweat ducts?

A

Normal

  • Cl- ions, Na+ ions & water move into cell
  • Sweat secreted in duct by gland
  • Na+ & Cl- reabsorbed by duct cells before reaching skin surface

CF

  • Cl- ions unable to enter cell == Na+ ions and water remain in sweat ducts
  • resulting in elevated Na+ & Cl- levels in sweat
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26
Q

How does CFTR function in NORMAL vs CF pancreas?

A

Normal

  • secretes bicarbonate
  • bicarbonates moves into pancreatic duct
  • mechanism: directly via CFTR & via bicarbonate chloride exchangers

CF

  • absence of CFTR-dependent bicarbonate & Cl- secretion = abnormal acidic & low volume secretions = activation of proteolytic enzyme within gland
  • == pancreatic inflammation & destruction
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27
Q

What are the CFTR gene variant classes?

A

6 classes

  • Class I: No CFTR produced
  • Class II: Defective processing - misfolds = trafficking defect
  • Class III: Defective regulation - channel gate doesnt open properly
  • Class IV: Reduced ion conductance-function of channel is faulty
  • Class V: reduced CFTR production
  • Class VI: accelerated turnover from the cell surface = decreased CFTR stability
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28
Q

What are the variant class-specific therapies?

A
  • Class I: Aminoglycoside antibiotics = allows ‘read through’ of mRNA
  • Class II: ‘Correctors’ to improve processing
  • Class III: ‘Potentiators’ to activate protein
  • Class IV: Flavonoid compounts = augment channel function == increase open probability
  • Class V: splicing variants = increase levels of correctly spliced RNA
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29
Q

What is the most common CFTR gene variant?

A

F508del

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30
Q

What class of mutation is F508del?

A

Class II - possible drug target

  • severe folding defect == premature degradation of most of translated protein in ER
  • Located in NBD 1
  • Defective processing
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31
Q

What is happening in F508del?

A
  • 508 Phenylalanine deletion
  • 1 base from 507 Isoleucine and 2 bases from 508 Phenylalanine DELETED
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32
Q

What is the inheritance pattern of CF?

A

Autosomal recessive

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33
Q

What is the carrier frequency and the most affected ethnicity?

A

1 in 25 & northern Europe

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34
Q

What is the incidence of CF?

A

1 in 2500-3000 live births

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35
Q

What are the Heterozygote (carrier) selective advantage?

A

Protection against diseases - Cholera & Typhoid fever

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36
Q

Describe the CFTR genotype-phenotype correlation

A

Limited correlation - class of CFTR variant & phenotype

  • Class I,II,III mutation = pancreatic insufficiency (strong correlation) & more severe lung disease
  • Class IV,V mutation = pancretic sufficiency & milder lung disease
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37
Q

What is the penetrance of CF?

A

Complete penetrance for severe CF-causing variant = individuals carry these disease-causing variants on BOTH CFTR alleles == develop CF
Incomplete penetrance = certain combinations of underlying causativ CFTR variants

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38
Q

What is the expressivity of CF?

A

Variable expressivity

  • phenotype associated with disease-causing variant = differs between individuals
  • genetic & environmental modifiers contribute
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39
Q

What are the genetic testing for CF?

A

Diagnostic testing

  • Confirmation of diagnosis in symptomatic individuals

Cascade testing

Newborn screening

Population carrier screening

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40
Q

What are the special groups of CFTR gene variants?

A

Incompletely penetrant variants
1. PolyT tract c.1210-12T[5_9] (intron8)
2. c.350G>A p.Arg117His (‘R117H’ in exon4)

  • penetrance depends on polyT tract variant on same allele
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41
Q

State the disease-causing CFTR gene variant

A

On allelle 1 & 2 respectively.
LP/P variant (F508del) & R117H & 5T

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42
Q

For an individual with F508del variant on one allele and an R117H variant on the other, what ‘_‘T polymorphism is more likely to symptoms of CF

A

5T polymorphism

  • maximises effect of R117H = act as disease-causing variant

NOT 9T polymorphism since:

  • minimises effect
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43
Q

Describe the sweat test

A
  • measures concentration of Cl excreted
  • pilocarpine iontophoresis induces sweating
  • pilocarpine = parasympathomimetic == acts on cholinergic receptors
  • Normal value: Cl<40mmol/L (<30 in infant)
  • CF diagnosis: Cl>60mmol/L
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44
Q

Describe Newborn screening

A
  • Identifies babies at risk of developing CF
  • Allows early and pre-symptomatic therapy
  1. RT test = heel prick onto blood spot cards (2-3 days old)
  • Elevated IRT == further testing
  1. Genetic testing using known common LP/P gene variants == only 12 common
  • both = CF
  • heterozygous = further testing = sweat test
  • none = no CF
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45
Q

Describe Cascade testing

A
  • Identification of carriers who are relatives of a diagnosed individual
  • Information can be provided about reproductive risk
  • only 12% opt-in
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46
Q

Describe Population carrier screening

A
  • Identification of carriers in the general population
  • Pre-conception carrier screening for reproductive purposes
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47
Q

Define genetic modifiers in term of CF?

A
  • influences phenotypeof CF BUT cannot cause CF
  • e.g. can influence how severe CF symptoms are
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48
Q

Why is it important to study genetic modifiers of CF?

A
  • identify new targets for therapies
  • understanding of genetic variability
49
Q

How to identify genetic modifiers of CF?

A
  • Linkage studies: track gene/markers associated with specific phenotype in families with CF
  • Candidate gene association studies: genes with known function relevant to CF features & correlate variations
  • Genome wide association studies: examine DNA markers at many positions across genome
  • Transcriptomic, proteomic and metabolomic analyses in human tissues and
    animal models
50
Q

What is the Genome Wide Association Studies (GWAS)?

A
  1. Sequences entire genome
  2. Looks for Disease associated SNPs & Non-disease associated SNPs
51
Q

What are the limitations of GWAS?

A
  • Needs a large sample size
  • difficult to replicate studies for validation
52
Q

What are the genetic modifiers in CF?

Influences severity of the disease

A

TFGB1

  • role in regulating inflammation and tissue remodelling
  • genetic modifier of lung disease in CF

MBL2

  • Encodes mannose binding lectin
  • role in innate immunity (in lungs)
  • important for P. aeruginosa immunity
  • genetic modifier of lung disease in CF
53
Q

What are the environmental modifiers in CF?

Environmental factors associated with pooerer health outcomes

A
  • Lower socio-economic status
  • Exposure to tobacco smoke – active and passive
  • Infectious exposures
  • Disease self-management
  • Female sex = poorer adherence to medical & dietary regimens that focus on high caloric intake to match
    high metabolic demand associated with CF
  • Access to healthcare
54
Q

What is meconium ileus?

To what degree is it affected by genes and environment

A
  • Blockage in ileum of babies in utero by sticky, black faeces
  • almost completely determined by genes
55
Q

What is the difference between conducting and respiratory zones?

A

Conducting: mucosa lined, no gas exchange

Respiratory: simple squamous epithelium for gas exchange

56
Q

What is the acinus?

A

Gas exchange region of the lung

Composed of:
* Respiratory bronchioles
* Alveolar ducts
* Alveolar sacs
* Alveoli

57
Q

Describe the phases of lung development

A
  1. Embryonic: lung bud appears, out pouching from foregut
  2. Pseudoglandular: branching of airways up to terminal bronchioles
  3. Canalicular: development of acinar region & type I and II pneumocytes
  4. Sacular / alveolar:
    * sacules form into alveolar ducts
    * decrease in interstitial tissue, septation
    * alveoli start to develop

Septation = septa form between alveoli = forms more alveoli

58
Q

What are the functions of the lungs?

A
  • Gas exchange
  • Defence
  • Acid-base balance
  • Metabolic
  • Heat exchange
  • Water balance
  • Phonation
59
Q

What are the lungs defence mechanism?

A

Physical (airway)
* Upper airway filter
* Reflexes= Sneeze & Cough
* Mucociliary escalator

Cellular (alveolar)
* Phagocytes e.g. alveolar macrophages
* Immunological

60
Q

Describe the function of Mucociliary Escalator

A
  • ASL present on cells in lumen
  • Mucus produced by secretory cells inc. Goblet cells
61
Q

Describe gas exchange in the lungs

A
  • Takes place at the level of alveoli
  • Alveoli filled with air upon inspiration
  • Gas diffuses in solution across the single celled wall of the alveolus into the capillary
  • Basement membrane between alveolus and capillary
62
Q

What are the parameters used to measure lung function?

A
  • Volume
  • Flow = Volume/Time (of air)
  • Pressure
63
Q

Describe how FEV and FVC are measured

A
  1. Maximal inspiration
  2. Forced expiration until residual volume

First second: FEV
Until residual volume: FVC

64
Q

When performing Spirometry, when is the most air exhaled?

A

First Second

65
Q

What happens with reversible intrathoracic airway obstruction?

A

Air cant be exhaled as quickly

66
Q

What are the pulmonary complications of CF?

A
  • Poor lung function, progressive decline
  • ↑ Cough and sputum production
  • ↑ Dyspnoea
  • Poor appetite
  • Need for transplantation; death
  • Respiratory failure
67
Q

What causes lung disease & chronic airway infection in CF?

A

CFTR Mutations/Dysfunction

68
Q

What cell types in the respiratory system express CFTR?

A
  • Serous cells of submucosal glands
  • Alveolar epithelial type II cells
  • Alveolar macrophages
  • Neutrophils
69
Q

Describe Ion Transport in Normal Lung vs CF Lung

A

Normal Lung
* CFTR coordinates modulation of ASL by
1. Na+ absorption Epithelial Na+ channel (ENaC)
2. Cl- secretion

CF Lung
* 2 functions of CFTR lost:
1. ENaC not inhibited = ↑ Sodium absorption (Water follows sodium)
2. Cl- ions not secreted = ↑ Na+, Cl-, and H2O absorption & ↓ ASL volume

70
Q

What are the consequences of reduced ASL volume?

A
  • Volume depletion of PCL = failure of ciliary beating
  • Decreased lubrication = adherent mucous plaque

→ Promotes chronic infection

71
Q

How does CFTR impact the reduced pH of ASL in CF?

A

Lack of bicarbonate secretion = reduced ASL = acidic

  • CFTR normally = secrete bicarbonate
  • CFTR in CF = bicarbonate reduced/absent & inhibits antimicrobial function

CFTR is dysfunctional in CF

72
Q

Describe Anaerobic Millieu

A

Thick mucus plaques adherent to epithelial surface & increased oxygen consumption by CF epithelia == Anaerobic environment

  • Ideal environment for growth of certain bacteria
  • Pseudomonas = converts to anaerobic biofilm mode of growth
73
Q

What can dysregulated immune pathways in CF cause?

A
  • ↑ activation of nuclear factorkappa B (NFᵏB)
  • Abnormal lipid metabolism
  • ↑ ROS production
  • ER stress
  • Defective interferon signaling
74
Q

What are Neutrophils antimicrobial function & how do they relate to CF airways?

A

Neutrophils = first & main inflammatory cell found in CF airways

Antimicrobial functions:
* Generate reactive oxygen species
* Secrete proteases
* Phagocytosis
* NET formation

75
Q

Describe the pathology of lung disease in CF

A

Infection, inflammation and obstruction of airways == Dilation and damage of airways

  • Bronchiectasis = dilation of part of bronchial tree = caused by muscle and elastic tissue damage
76
Q

What are the treatments of pulmonary complications in CF?

A
  • Daily (x1-2) Airway clearance (chest physiotherapy)
  • Mucolytics
  • Antibiotics to treat infections
  • Anti-inflammatory agents
77
Q

How to maintain lung function?

A
  • avoiding/aggressively treating infections
  • perform airway clearance
78
Q

What are the clinical features of a high salt sweat individials?

A
  • Hypoantrmic/Hypochloremic dehydration
  • Hypokalemic metabolic alkalosis = secondary to chronic salt loss = stimulates exchange of Na+ for H+ & K+

Symptoms:
* Headache/Irritability
* Muscle Cramps
* Nausea & Vomiting
* Fatigue
* Poor Concentration

79
Q

Describe the pathophysiology of Pancreatic Disease

A
  • CFTR == apical membrane of pancreatic ductal epithelial cell
  • Regulation of Chloride secretion = reduced luminal liquid
  • Regulation of Bicarbonate secretion = acidic pH of luminal liquid = also key buffer for pancreatic fluid
  • Viscous pancreatic secretions = pancreatic duct obstruction
  • Premature activation of proteolytic enzyme = inflammation & destruction of pancreas
80
Q

What is the management of pancreatic insufficiency?

A
  • Nutrition
    • High fat (35-40%) & protein diet
    • Improved growth ALSO improves lung function
  • Pancreatic Enzyme Replacement Therapy (PERT)
  • Fat-soluble vitamins = A, D, E, K
81
Q

What causes Pancreatitis?

A
  • Impaired Bicarbonate
    • Impaired control of luminal pH = tissue damage
    • ↓ luminal pH = premature zymogen activation = pancreatitis
  • PIP score = Severity of CFTR genotype = risk of pancreatitis
  • CFTR Mutation = non-CFTR modifiers = pancreatitis in CF
82
Q

What is the management of Pancreatitis?

A

Acute = supportive care
* correction of fluid & electrolyte imbalance
* Medicine = Analgesia
* Gut rest for 1-3 days

Chronic
* Environmental Factors = smoking, alcohol, hypertriglyceridemia
* Medication = antacids, PERT, analgesia
* Surgery = TPIAT
* Monitor for pancreatic cancer

83
Q

What can the pancreas (endocrine) be impacted by?

A
  • Cystic Fibrosis Related Diabetes Mellitus (CFRDM)
  • Impaired & delayed insulin secretion
  • = insulin resistance
  • Lung function decline
  • Treatment = insulin
84
Q

What is the pathogenesis of CFLD (CF Liver Disease)?

A
  • ↑ viscosity of bile
  • Blocked intra-hepatic bile ducts
  • ↑ risk in patients with alpha 1-antitrypsin Z-allele
85
Q

What is the clinical features of CFLD (CF Liver Disease)?

A
  • Prolonged neonatal jaundice
  • Raised liver enzymes = commin in CF
  • Hepatic steatosis = fatty liver
  • Cirrhosis & portal hypertension = 3:1 M:F
  • Hepatocellular failure = uncommon
  • Increased morbidity = poor nutritional status & growth, worse pulmonary outcomes, CF-related diabetes
  • Malignancy-Hepatocellular carcinoma

Juandice = yellow discolourisation

86
Q

How is CFLD diagnosed?

A

Requires two of:
1) Abnormal physical examination
* Hepatomegaly/splenomegaly
* Stigmata of chronic liver disease

2) Abnormal serum transaminases
* 3 consecutive occasions over a 12 month period

3) Ultrasound findings of CF related liver disease
4) Biopsy consistent with CF related liver disease

87
Q

What is the treatment of CFLD?

A
  • Optimise nutritional status & pulmonary function
  • Monitor for CF related diabetes
  • Immunisations: hepatitis A & B
  • Ursodeoxycholic acid
  • Monitor for complications of portal hypertension
  • Monitor for development of synthetic liver failure
  • Consideration of liver transplant
88
Q

What is Meconium Ileus?

A
  • Inspissated intraluminal meconium = causes bowel obstruction
89
Q

What are the late complications of Meconium Ileus?

A
  • ↑ DIOS risk
  • Adhesive small bowel obstruction
90
Q

What is the Distal Intestinal Obstruction Syndrome (DIOS)?

A
  • Partial or complete bowel obstruction

Symptoms:
* Abdominal pain; crampy, RIF
* Constpiation

91
Q

How can Gastro-esophageal Reflux (GERD) worsen lung disease in CF?

A
  • Aspiration
  • reflex bronchospasm
92
Q

What is the role of a CFTR modulator?

A
  • overcome basic CFTR defect
  • Restore CFTR function
93
Q

What is protein rescue therapy?

A
  • depends on class of mutation
  • uses drug to overcome dysfunctional protein
  • e.g. Ivacaftor
94
Q

Describe the function of Ivacaftor

A
  • binds channel = allows it to function properly (i.e. keep channel open)
  • potentiator = improves lung function in CF patients with class III mutation
95
Q

What class mutation is Ivacaftor for?
&
What gene mutation is required to get Ivacaftor treatment?

A

Class III mutation
* dysregulated channel = gating defect

Gene Mutation
* Gly551Asp (G551D)
* impairs the ability of CFTR at the cell surface to open

96
Q

What was used to identify Ivacaftor?

A

High Throughput Screening

97
Q

What are the pros & cons of Ivacaftor?

A

Pros
* improvement in lung function
* increased weight
* increase in time to exacerbate

  • decreased symptoms
  • delayed exacerbation
  • reduction in sweat chloride concentrations

Cons
* very expensive

98
Q

Why was Ivacaftor significant?

A
  • addresses underlying defect
  • first CF therapeutic to do so
99
Q

What were the outcome of short vs long term use of Ivacaftor?

A

Short Term
* Sustained improvements in sweat Cl, FEV1, BMI & MCC

Long Term
* Lung function declined over time
* Sustained improvements in
sweat Cl, BMI and exacerbations

100
Q

What is Lumacaftor?

Describe its function

A
  • A protein rescue therapy
  • A ‘corrector’: used for Class II mutations

Function:
* increases the amount of CFTR trafficked to the cell surface

101
Q

Can Lumacaftor function well on its on? Explain why.

A

No
* requires potentiator (e.g. Ivacaftor)
* DUE TO: drug only gets mutated CFTR to surface = doesnt functional optimally

102
Q

Describe the efficacy of Lumacaftor

transport of CFTR

A
  • Lumacaftor = CFTR transport is 15% of wild type
  • Lumacaftor + Ivacaftor = CFTR transport is 30% of wild-type
103
Q

MIGHT NOT BE IMPORTANT TO KNOW

Describe the outcome of Lumacaftor-Ivacaftor (Orkambi)

A
  • Mean change in FEV1 of 2.6 to 4.0%
  • Exacerbation rate ↓ 39%
  • ↑ weight:1.23 to 1.57kg
104
Q

MIGHT NOT BE IMPORTANT TO KNOW

Describe the outcome of Ezacaftor + Ivacaftor (Symdeko™)

A
  • Mean change in FEV1 of 4%
  • Exacerbation rate ↓ 35%
  • Improved CFQ-R of 5.1
    – Respiratory domain
  • no change in BMI
105
Q

MIGHT NOT BE IMPORTANT TO KNOW

Describe the outcome of Tezacaftor +Ivacaftor (Symdeko™)

A
  • Mean change in FEV1
    – Symdeko 6.8%
    – Ivacaftor 4.7%
  • Improved CFQ-R of 11.1
    – Respiratory domain
  • ↓ sweat Cl 9.5mmol/L
  • no change in BMI
  • No change in exacerbation
106
Q

MIGHT NOT BE IMPORTANT TO KNOW

Describe the outcome of Elexacaftor-Tezacaftor-
Ivacaftor (TrikaftaTM)

A
  • ↑ FEV1 of 14%
  • ↓ sweat Cl of 41.8mmol/L
  • Exacerbation rate ↓ 63%
  • CFQ-R RD score ↑ 20.2
107
Q

List the future therapies for CF Lung Disease

A
  • Mutation specific therapies
  • Novel symptomatic treatments
    – Anti-infective
    – Anti-inflammatory agents
    – Mucolytics
  • Genetic therapy
108
Q

Outline the phases of clinical trials

A

Phase I
* Low doses on healthy volunteers
* progressively increase

Phase II
* 100-300 patients
* Examine effectiveness
– Dose
– Delivery method
– Dosing interval
* confirm safety

Phase III
* 1000+ patients
* Confirm previous findings
* Demonstrate safety & efficacy
* Determine best dosage

109
Q

What are nonsense mutations?

A
  • Ceases production of CFTR protein
  • Class I
110
Q

What are therapies for nonsense mutations?

A
  • develop small molecules that can produce full-length functional protein
    – facilitate PTC read-through
    – impede mRNA decay
111
Q

What are PTC read-through agents?

A

allows translation to continue despite PTC

112
Q

What are mRNA stabiisers?

A
  • prevent breakdown of mRNA
  • since PTCs lead to shot lived mRNA due to nonsense mediated decay (NMD)
113
Q

List the genotype agnostic approaches

Define genotype agnostic approaches

A
  • used regardless of an individuals particular variation (genotype)
  • restores CFTR function

Approaches
* Targeting alternative ion channels to compensate for CFTR channel defect
* Gene replacement therapy
– DNA
– mRNA
* Gene editing

114
Q

How is targeting alternative ion channels a genotype agnostic approach?

Name the 2 channels

A

Inhibits / activates epithelial transporters
* ENaC (Sodium channel)
* TMEM16A (Calcium-gated chloride channel)

115
Q

How is RNA therapy a genotype agnostic approach?

A

VX-522
* delivers full-length copy of CFTR mRNA to lung cells == using nanoparticles

  • mRNA used to create functional protein
116
Q

How is gene therapy a genotype agnostic approach?

A
  • introduces normal copy of CFTR gene into cells of conducting airways
  • Majority Phase I & II
117
Q

What is gene editing?

In regards to the genotype agnostic approach

A
  • uses cells own DNA repair machinery

CRISPR
1. Enters cell nucleus
2. snips out mutated sequence
3. cell’s DNA repair machinary = uses template = fix broken DNA
4. permanently corrects mutation

118
Q

List the system in the body where CFTR protein is present in epithelial cells

List 5

A
  • Airways
  • Sweat gland
  • Pancreas
  • Gastrointestinal tract
  • Reproductive tract
119
Q

What is pulmozyme?

A
  • digests DNA released by neutrophils in mucus of lungs in CF patients

BIOM30002: Molecule to Maladay (3 decks)

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