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PATH3308 > 7 and 8. Molecular Therapies > Flashcards

7 and 8. Molecular Therapies Flashcards

1
Q

What type of defects can occur aberrant gene expression?

A

1) Defect in controlling region
2) Error in coding region
3) Known unknowns
- Trans-acting factors
- Modifying genes
- epigenetics

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2
Q

What therapy/intervention targets what stage of processing the code?

A

Transcription (DNA) = Gene therapy + Cell transplant

Transcription (pre-mRNA) = Conventional pharmaceuticals

Splicing (mature RNA) = Molecular therapy

Protein (translation) = Readthrough antibiotics + conventional pharmaceuticals

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3
Q

What are the two modes of treatment for inherited disorders?

A

Direct (molecular) treatments to address cause
- Mutation dependent

Indirect treatments (address impact of disease)
    - reduce inflammation etc
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4
Q

Do all diseases have a genetic component?

A

Basically yes

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5
Q

Is cystic fibrosis a monogenic inherited disease?

A

Yes

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6
Q

Does environment play a bigger role in monogenic or multiple gene diseases?

A

Polygenic diseases

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7
Q

What are some ways in which gene therapy works?

A

Replace defective genes

Deliver genes that cause destruction of cancer cells

Provide genes that impede tissue growth

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8
Q

What type of gene transfer therapy is available?

A

Somatic cell gene transfer

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9
Q

When did gene therapy begin?

A

1980s

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10
Q

How many people die in the US due to adverse drug reactions (ADR)?

A

100 000 deaths annually

  1. Stroke
  2. Heart disease
  3. Cancer
  4. ADR
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11
Q

How many people effected by rare diseases in Australia?

A

400 000

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12
Q

What is the difference between gene therapy and molecular therapies?

A

Gene therapy

  • Gene replacement
  • Gene repair

Molecular therapies

  • Modify gene output
  • Stop codon read-through
  • Use another gene
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13
Q

What are the first steps taken in any therapy?

A

1) Correct diagnosis
2) Identifying cause and mechanism
3) Rational design to replace/compensate/by - pass the problem
4) Can only be done if mutation is properly understood

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14
Q

What happens in a point mutation?

A

Single base is substituted, can result in any number of things happening to protein (truncated)

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15
Q

What occurs in a frameshift mutation?

A

A insertion of deletion of a number of nucleotides NOT divisible by three (e.g. 1) resulting in a shift in reading frame

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16
Q

What is an in-frame deletion?

A

Deletion of multiples of 3 codons

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17
Q

What are the potential molecular / genetic therapeutic approaches?

A

1) Replace missing or mutated genes
2) Repair faulty genes
3) Modify gene expression

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18
Q

How is gene expression modified?

A

1) Molecules that alter transcription
2) Alteration of pre mRNA splicing
3) Down regulate/destroy specific mRNAs
4) Enhance mRNA stability
5) Prevent transcription

Alter splicing
Down regulate
Enhance
Prevent

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19
Q

What is an antisense therapy?

A

Antisense transcripts occur naturally - contribute to cellular regulation

Synthetic antisense oligonucleotides (AOs) are used to Alter mRNA splicing
Degrade transcripts
Block translation

20
Q

How do synthetic anti-sense oligonucleotides in antisense therapies work?

A

Alter mRNA splicing
Degrade transcripts
Block translation

21
Q

How is mRNA splicing altered using anti-sense oligonucleotides?

A

Exons are skipped via splicing

Only really useful is shortened product is still functional

This is being used in Duchenne muscular dystrophy

22
Q

How are antisense sequences used to block translation?

A

Antisense translational blockade

Antisense sequences, target translation start sites

Examples are Neugene, Phosphorodiamidate morpholino oligomer (PMO)

Used to study zebrafish

23
Q

What diseases could be treated with translational blockade?

A

Bird flu
SARS
Ebola
Hep C

24
Q

How can transcript degradation be induced by AOs?

A

RNaseH - DNA antisense oligo annealed to RNA - induces RNaseH degradation of target RNA

RNA silencing

25
Q

What does siRNA mean?

A

Small interfering or Silencing RNA

26
Q

How does gene silencing work via siRNA?

A

~21 - 24 nucleotide double stranded RNA, induced degradation of mRNA:Dicer-RISK complex

27
Q

What are two case studies associated with molecular therapies?

A

Duchenne muscular dystrophy

Spinal muscular atrophy

28
Q

What are some issues associated with treating DMD?

A 
Multi-system disorder
Multiple isoforms
Effects all muscle mass
2.4 megabase gene
Many mutations
     60% frameshifting mutations
29
Q

What are the two types of muscular dystrophy and what is the severity of each?

A

DMD = fatal X-linked muscle wasting (1/3500 boys)
- Frame shifting/nonsense mutation in dystrophin
gene
- Ultimate caridac and respiratory failure
- Truncated protein

BMD = milder allelic disorder
- In fram deletion, dystrophin levels are > 3% normal
- Large deletions may be associated with
mild asymptomatic disease

30
Q

What is the dystrophin associated complex?

A

Multiprotein complex including dystrophin

31
Q

How much dystrophin do carriers of DMD begin with?

A

50% of muscle fibers

Some dystrophin is better than none

32
Q

What does MD prevent?

A

Reconstruction of muscle due to lack of dystrophin protein

33
Q

What systems do MD effect?

A

CNS

Endocrine

34
Q

What dystrophin isoforms are there?

A

Long - Skeletal, cardiac, smooth muscle, brain

Smaller - CNS, retina, kidney

35
Q

How could DMD be repaired molecularly?

A

Improve muscle repair
Put patch over gene lesion
- AVI 4658

36
Q

How is AVI 4658 treating DMD? (Eteplirsen)

A

nucelic acid analogue targeting dystrophin exon 51

Now in phase 2b

37
Q

What is the main test to diagnose DMD?

A

6 minute walk test

38
Q

What is eteplirsen a product of?

A

Sarepta therapeutics

39
Q

What does SMA mean?

A

Spinal muscular atrophy

40
Q

What causes SMA?

A

Loss of SMN1 on chromosome 5

41
Q

What is SMN?

A

Survival motor neuron

Loss of gene is incompatible with life

42
Q

What is type 1 SMA caused by?

A

SMN1 deleted

43
Q

What is SMA type 2 caused by?

A

Multiple SNM2 copies

44
Q

What is the current treatment for SMA?

A

Antisense oligomers - alter pre-mRNA processing to generate BMD like mRNA and protein

45
Q

What does BMD stand for?

A

Becker muscular dystrophy

PATH3308 (21 decks)

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