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PRECISION MEDICINE AND THERAPEUTIC GENE EDITING Flashcards

1
Q

What is the difference between precision medicine and personalised medicine?

A
  • Precision medicine is using MEDICAL INTERVENTIONS to alter molecular mechanisms that cause disease or INFLUENCE a patients response to certain treatments
  • Personalised medicine is working out which medical treatments work best for each patient.
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2
Q

What is Moore’s law?

A
  • Long term trend in computer hardware that involves the doubling of computer power every 2 years
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3
Q

What is the general term for Anti Sense Olgio nucleotides?

A
  • Small pieces of DNA that change the way DNA is expressed

- Can be shortened to ASO

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4
Q

Does it matter if introns are correctly or incorrectly splieced?

A
  • YES because we need to get the right reading frame

- IF not correctly spliced, can lead to non-functional proteins

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5
Q

What is a phase 0 intron?

A
  • When there is NO CODON shared between exons after splicing
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6
Q

What is a phase 1 and 2 intron?

A
  • When after splicing out of introns, there is a codon shared between two exons, e.g. C and G
  • phase 2 intron where there are 2 nucleotides on the first exon that are spliced with 1 nucleotide on the third intron to make one codon
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7
Q

What can happen if exons are incorrectly spliced together?

A
  • proteins can be our of reading frame and thus non functional
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8
Q

What is an approach used to work around non-functional (out of reading frame) proteins?

A
  • Therapeutic approaches using antisense oligonucleotides (ASOs)
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9
Q

What is the specific definition of antisense oligonucleotides. ( ASOs)?

A
  • Short single stranded sequence of DNA or RNA designed to target specific RNAs to modify gene expression.
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10
Q

What are three ways that ASOs exert their effects and what does this depend on?

A
  1. RNA degradation.
  2. preventing protein translocation.
  3. modifying RNA splicing.
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11
Q

What are two diseases that ASOs are used to treat?

A
  1. Spinal Muscular Atrophy

2. DMD (Duchennes Muscular Dystrohpy)

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12
Q

What is SMA caused by and characterised by?

A

Loss-of-function mutations in SINGLE gene –>SMN1 (Survival Motor Neuron 1)
- Characterized by progressive degeneration of the spinal cord motor neurons.

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13
Q

Is there a second SMN gene and how much of the normal protein is produced?

A

Yes SMN2

- But only 10-20% of the normal protein is produced

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14
Q

How do the SMN1 and SMN2 genes differ in terms of the strucutre?

A
  • Differ in 5 bases
  • C–> T transition in exon 7 means that SMN2 favors SKIPPING of exon 7 during splicing
  • This means that majority of SMN2 products are UNSTABLE and thus truncated –> SMN delta7
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15
Q

Can SMA patients with no SMN1 still produce a functional SMN protein at sufficient levels for function?

A
  • NO –> levels are insufficient for normal function so this results in degeneration of the spinal cord motor neurons
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16
Q

How can ASOs be used to treat SMA (Spinal Muscular Atrophy)?

A
  • Can try and shift the machinery so it recognises exon 7
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17
Q

How is the drug ‘Spiranza’ used to treat SMA?

A
  • Shifting machinery to recognise exon 7
  • Blocking the 15 nucleotide sequence in intron 7 SMN2 (this is crucial for splicing regulation) –> ISS-N1 (intronic splicing silencer N1)
  • ISS-N1 blocking ASOs lead to the production of exon 7 and INCREASED EXPRESSION of SMN2
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18
Q

What is the target for Spiranza to allow for a fix of SMA?

A
  • ISS-N1
  • This is the intronic splicing silencer N1 that is imprtant in splicing regulation
  • If it is blocked, then exon 7 will be recognised and integrated to produce a full length SMA2
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19
Q

What is dystrophin?

A
  • Parts of a protein complex and anchors the cytoskeleton in muscle cell with the ECM (linker between Actin and ECM).
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20
Q

What happens if we don’t have dystrophin?

A

The muscles degrade.

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21
Q

Is the dystrophin gene small or large?

A

It is the largest gene known at 2.4 mega bases and has 79 exons.

22
Q

What are the two main domains that the dystrophin gene has?

A
  • Actin Binding domain and the dystro glycan Binding domain.
23
Q

What lies between the actin binding domain and dystro glycan binding domain in the dystrophin gene and is it important for function?

A
  • A linker sequence

- It is not important for function

24
Q

What happens to the exon/s in muscular dystrophy?

A
  • They are deleted

- this interferes with the rest of the gene being pieced together

25
In muscular dystrophy can any of the exons be deleted?
- YES
26
In the muscular dysrophy EXAMPLE, which of the exons are deleted and what is the effect of this?
- Exon 52 is deleted - This means that Exon 51 and 53 join--> BUT the ORF will be disrupted from a codon mismatch (sticky ends joining) - this means the dystrophin protein will be non functional thus disease
27
How can ASOs help with Muscular Dystrophy?
- They can SKIP the exon and put the protein BACK into reading frame so exon 53 is removed and the two non-sticky ends can join - Some of the aas will be lost but protein will still be functional
28
In dmd what are the specifics for how the EXON skipped by ASOS?
- ASOs mask the splice site. | - Means the machinery moves over that exon to the splice site in the next exon
29
What is an example of an FDA approved drug that works via the mechanism of ASO skipping for DMD and what is the function?
- Exondys 51 (Eteplirsen) | - Skips exon 51
30
Is there a clinical benefit for Exondys 51 for dmd?
- NO --> increase of 0.1% after 48 weeks | - 30mg per kg twice weekly
31
With the exon skipping for Exondys 51 treatment for DMD, is there functional dystrophin produced?
- Somewhat | - Shortened functional dystrophin produced but not as functional as the full length
32
Is there any benefit for the other drug to treat DMD (Vyondys 53)?
- NO - This is for patients with a mutation that can be helped by exon 53 skipping - FDA approval not originally given BUT granted on appeal
33
What does gene therapy involve?
Viral mediated introduction of defective cells with the corrective gene - for example ADA (Adenosine Deaminase) in SCID was corrected by the retroviral gene therapy but stopped in 2002 (because of off-target effects causing leukaemia).
34
What do we choose to express viruses in now?
- AAV (recombinant adeno-associated virus).
35
Is AAV very immunogenic?
No
36
What type of virus is AAV?
- A single stranded DNA virus. | - Icosahedral capsid (protein shell).
37
What happens to the Genome of AAV for Biotechnology?
It is gutted so the proteins can be placed in and delivered.
38
Can a AAV transduce both dividing and non dividing cells?
- Yesq
39
Can AAV be integrated into the Human Genome?
- No (very rarely)
40
What is a limiting Factor with the use of AAV for biotechnology?
-The size of insertion as you can only put a certain amount of DNA in there.
41
How does the drug Zolgensma work for the treatment of SMA?
- It delivers the NORMAL copy of the gene encoding the SMN protein to patients - AAV has a transgene encoding the SMN protein (under the control of cytomegalovirus enhancer and chicken-beta actin hybrid promoter)
42
Are there multiple injections with the SMA treatment for Zolgensma or single?
- A SINGLE ONE!! - But this is very expensive---> 2.1 million per patient - throughout 2020 they are giving 100 doses for free via a lottery
43
In terms of germline therapy for mitochondrial disease, how many of the mtDNA genes are non mendelian?
-35/37 genes
44
Can mitochondrial disease change throughout oocytes?
- YES - you can have someone with a high level of mutation, or a lower level of mutation that might get disease later on in life.
45
What is an option for preventing mitochondrial disease?
- Mitochondrial donation or mitochondrial replcaement therapy
46
What are the two forms of mitochondrial donation?
- Maternal Spindle Transfer (MST) | - Pronuclear transfer (PNT)
47
What occurs in MST?
- Mitotic spindle from a woman with bad mtDNA transferred to a site with nucleus removed and healthy mtDNA - Oocyte site then fertilised with women's partners sperm - Creates an oocyte with HEALTHY mitochondria - Occurs before fertilisation
48
Does the mitochondrial manipulation in Maternal Spindle Trasnfer occur before or after fertilization?
- BEFORE
49
What occurs in Pronuclear Transfer (PNT)?
- Affected woman has oocyte fertilised by partners sperm - Zygote is created - Pronuclei removed and placed into another zygote created using donor oocyte and partners sperm (with their pronuclei removed) - Embryo developed and inserted into woman - Mitochondrial manipulation occurs AFTER FERTILIZATION
50
In PNT does the Mitochonrial manipulation occur before or after fertilization?
-After

BMS3031 (6 decks)

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