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GENE THERAPIES > Cortical malformations > Flashcards

Cortical malformations Flashcards

1
Q

Two main types fo cortical malformations

A
  1. abnormal neuronal and glial proliferation or differentiation
  2. abnormal cortical organisation
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1
Q

Abnormal types of neuronal and glial ploferiations (6)

A
  1. Tuberous sclerosis
  2. Focal cortical dysplasia
  3. Hemimegalencephaly
  4. Periventricular nodular heterotopia
  5. Lysencephaly
  6. Subcortical band heterotopia
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2
Q

Abnormal cortical organisation types (2) :

A
  1. polymicrogyria
  2. Schizencephaly
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3
Q

Types of mTORapthies (3):

A
  1. tuberous sclerosis
  2. focal cortical dysplasia
  3. hemimegalencephaly
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4
Q

What are mTORopathies?

A

neurological diseases caused by a mutation in the mTOR signalling pathway.

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5
Q

Two divisions of mTORopathies:

A
  1. mutations that produce DIFFUSE malformations of cortical development (MCD)
  2. mutations that produce FOCAL MCD
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6
Q

Pathological effects of mutations in the mTOR pathway (6)

A
  1. Turnover of proteins
  2. Lipid and glucose metabolism
  3. Cellular growth and proliferation
  4. Cytoskeleton organisation
  5. Ribosome biogenesis
  6. Autophagy.
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7
Q

Focal cortical dysplasia

A

caused by somatic OR mosaic mutations in the neuronal progenitors.

  • 5-10% of epilepsy patients have FCD.
  • 6.3 years is the mean age of onset.
  • Most common structural brain lesion in children with drug-resistant epilepsy
  • 38% of FC patients suffer recurring seizures after surgery resection.
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8
Q

FCD II

A

involves the loss of cortical lamination, blurred gray-white matter junction.

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9
Q

What pathological alterations does FCD II introduce into the cortical layers (6)

A
  1. Balloon cells – huge cells, highly spherical, no excitability or synaptic function.
  2. Activated microglia – indicates inflammation
  3. Hypertrophic pyramidal cells – neurofilaments, twice as big as healthy pyramidal cells.
  4. Dysmorphic neurons
  5. Excessive cellular gliosis – indicates inflammation
  6. Hypomyelination of white matter and indistinct grey-white matter boundaries
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10
Q

How many types of FCD?

A

Four

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10
Q

Hallmarks of FCD I

A

Small immature neurons and hypertrophic pyramidal cells.

Heterotopic neurons

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10
Q

Hallmarks of FCD III

A

abnormal cortical laminations.

Cellular and architectural abnormalities also seen present in type I and II.

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11
Q

Animal model characterisation of FCD II - 3 steops

A
  1. Face validity
  2. Predictive validity
  3. Construct validity
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12
Q

Four steps of face validity

A
  1. Histological assays
  2. Biomolecular assays
  3. EEG assays
  4. Behavioural assays
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13
Q

Cre/lox xystem

A

Cre/lox system: cre is a protein that is expressed in transgenic mice model or injected.

Main point – cre will recognise the sites and cut them – to cut out the gene and knock down the protein of interest. So, in this case knock down identified inhibitor mTOR – to hyperactive it.

14
Q

Two systems for mouse model development

A
  1. In-utero electroporation
  2. cre/lox system
15
Q

RHEB CA ANIMAL MODEL in FCD

A
  • The RhebCA animal model shows a significant reduction of seizure frequency with rapamycin treatment > predictive validity
  • The RhebCA animal model is generated by in-utero electroporation for targeting neuronal progenitors > construct validity
  • The RhebCA animal model displays the histological and behavioural hallmarks of the disorder > face validity.
16
Q

options for gene therapy for FCD II (2)

A
  1. Restore the physiological activity of the impaired signalling pathway
  2. Rescue protein levels impaired in FCD.
17
Q

Pros (2) and cons (2) of restoring the physiological activity of the impaired signalling pathway - FCD-II

A

+ allows for easier fine-tuning of the therapeutic effect
+ the mutated gene can be specifically targetd

  • the impaired pathway needs to be well-known
  • the therapy effectiveness depends on the mutation
18
Q

pros (2) and cons (2) of rescuing protein levels impaired in FCD

A

+ targets the direct cause of the symptoms
+ is effective independently of the causing mutation

  • harder to predict the potential secondary effects
  • compensatory mechanisms may affect long-term effectivity of the therapy.
19
Q

Kv1.1 and excitability

A

reduces excitability of neurons – so it is probable that it is contributing to seizure occurrence in FCD.

20
Q

Kv1.1 and mTOR

A
  • In an active synapse – activation of NMDA receptors leads to activation of mTOR pathway > which in turn leads to synthesis of micro-interference RNA-129.
  • miRNA-129 – target Kv1.1. mRNA – induces degradation of this mRNA and therefore the preventing the translation fo the Kv1.1 channel.

mTOR activation hinders expression Kv1.1 by degrading its mRNA. So need to design a plasmid that is carrying the KCNA1 gene (that encodes for Kv1.1) that doesn’t have the region where miRNA is binding.

21
Q

Filamin A and gene therapy for FCD II

A

Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations.

22
Q

challenges of upstream targeting the mTOR pathway

A
  • Off target effects due to interconnectivity of the mTOR pathway to other key signalling pathways.
  • The effectiveness of the therapy depends on the mutation causing the mTORC1 hyperactivity.
  • The therapy needs to be fine-tuned, as the total inhibition of mTORC1 is detrimental.
23
Q

Challneges of downstream targeting the MTOR pathway

A
  • Difficult to predict the effect of the therapy.
  • Compensatory signalling mechanism may overwrite your therapy.
24
Q

RAPTOR inhibition - in MTOR pathway

A

RAPTOR inhibition - upstream in the mTOR pathway.

  • a gene therapy based on inhibiting the activation of mTORC1 by the reudction of RPTOR levels.

reduces seizure frequnecy when injected in the dysplastic focus.

25
Q

4E-BP1 overaction

A

Downstream targeting of the mTOR pathway.

the prevention of the decrease in translation through the hyper inhibition of 4EBP caused by the hyperactivation of mTORC1, leads to restoration of disease hallmarks.

therefore a gene therapy increasing 4EBP activation is good. e.g. 4EBP1 over-expression in-utero

26
Q

Four therapeutic strategies for FCD

A
  1. restoring protein levels affected in FCD
    • EXC gene therapy
    • PT-125 therapy
  2. restoring mTORC1 signalling
    - RPTOR shRNA therapy
    - 4EBPca therapy

GENE THERAPIES (16 decks)

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