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GenGenMol > 15 Treatment of Genetic Disease > Flashcards

15 Treatment of Genetic Disease Flashcards

1
Q

How many rare diseases are there?

A

About 7,000

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2
Q

How many rare disease have a treatment option? (percentage)

A

6%

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3
Q

What are the 4 broad targets of drugs for genetic disease?

A

Target the DNA
Target the RNA
Target translation
Target the protein product

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4
Q

What are the two ways to target DNA in treatment?

A

Gene therapy.
Genome editing.

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5
Q

What are the 3 ways to target RNA in treatment?

A

Exon skipping.
RNAi (interference)
Antisense oligonucleotides

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6
Q

What is the one way to target translation in treatment?

A

Nonsense supression

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7
Q

What are the 3 ways you can target proteins in treatment?

A

Small molecules
Chaperones, mAbs (monoclonal antibodies).
Replacement therapy.

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8
Q

With some small molecules we can just _____ them like Losartan and Tipifarnib. But for others we need to _________ like Gleevac for ______ or Ivacaftor for _____

A

With some small molecules we can just repurpose them like Losartan and Tipifarnib. But for others we need to develop new ones like Gleevac for leukaemia or Ivacaftor for CF

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9
Q

What is Marfan’s syndrome cause?

A

Disorder affecting FBN1 (Fibrillin-1) affecting the connective tissue.
Usually elevated TGFb, secreted as inactive form binds to LTBP and sequestered by FBN1. But in an FBN1 mutant, TGFb gets elevated.

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10
Q

What are the symptoms of Marfan’s syndrome?

A

Tall thin figure, long limbs and fingers, dislocated lens, dilation of aorta or aortic anuerism. Can lead to sudden death.

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11
Q

What has Losartan been widely used for?

A

Treatment hypertension

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12
Q

What effect does Losartan have when repurposed to be used for Marfan’s syndrome?

A

Reduced aortic-root grwoth, decreased levels of serum TGFb. But effects are limited, and not great over a long time.

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13
Q

What are the symptoms of Hutchinson-Gilford Progeria syndrome?

A

Premature aging, and accelerated atherosclerosis.

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14
Q

What is the genetic cause of Hutchinson-Gilford Progeria syndrome?

A

LMNA (Lamin A) mutated, nuclear blebbing seen. Progerin is the name of mutant Lamin A. a C>T affects splicing so 50AA with enzyme binding site is omitted. ZMPSTE24 is unable to process the C terminus of Progerin. Progerin ends up accumulating in the nuclear membrane.

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15
Q

What is the method of treating Hutchinson-Gilford Progeria syndrome?

A

Use Farnesyl transferases inhibitors. These prevent FT from adding CAAX to ZMPSTE24, so progerin doesn’t get accumulated at the nuclear membrane.

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16
Q

What is the result of FTI’s to treat Hutchinson-Gilford Progeria syndrome?

A

Improved nuclear shape, blebbing diminishes. Prevents the onset of the cardiovascular phenotype by preventing the loss of source muscle cells in the aorta.

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17
Q

What is Loanfarnib? What does it do?

A

It is an FTI that can improve vascular stiffness, bone structure, audiological status in chrildren with Hutchinson-Gilford Progeria syndrome

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18
Q

What are most cases of Chronic Myeloid Leukaemia caused by?

A

Chr9 and 22 translocations. This creates the philadelphia chromosome where the ABL gene is activated by the BCR promoter

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19
Q

What does Gleevac/imatinib do in CML?

A

It binds to the ATP binding site of ABL to lock it in its activated form to prevent it’s Tyrosine Kinase activity, thus causing apoptosis.

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20
Q

What do chaperones do?

A

They are proteins that stabilise unfolded proteins and help fold them or unfold for translocation across membranes or degradation.

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21
Q

Chaperones help maintain what?

A

Proteostasis. The balance of competing pathways, protein levels and turnover.

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22
Q

What mutation is in 90% of CF patients in the CFTR gene?

A

F508del

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23
Q

What does F508del do in CFTR in CF patients?

A

Disrupts folding of CFTR and its trafficking to the cell surface. Instead it gets degraded.

24
Q

What does Matrine (MTR) do to F508del CF patients?

A

It downregulates the chaperone HSC70 to prevent the ubiquitinylation of CFTR so instead of getting degraded it gets folded properly and taken to the cell membrane

25
Q

There are many CFTR modulators.
Correctors ________
Potentiators _______
Amplifiers _______
Stabilisers ________

A

Correctors help fold CFTR.
Potentiators help open the defective Cl- channel.
Amplifiers enhance protein translation.
Stabilisers Increase cell surface protein stablity.

26
Q

To significantly improve lung function in CF patients you can combine what?

A

Symkevi and Kaftrio into ORKAMBI (corrector and potentiator together)

27
Q

What are mAbs (Monoclonal antibodies)

A

They have antigen binding sites at the end of their arms to bind to a specific protein and they can inhibit or activate protein function.

28
Q

How have mAbs been used in laminopathies

A

They have been designed to target just the mutant lamin proteins and modulate their function. So Lamin A R453W and R482W cause EDMD (a muscular dystrophy) and FPLD (lipodystrophy)

29
Q

How is haemophilia A caused?

A

A lack of factor VIII for blood coagulation

30
Q

What does factor VIII normally do?

A

Factor VIII is cleaved b y thrombin to become FVIIIa which binds to FIXa and FX to bring them close together

31
Q

How can mAbs treat haemophilia?

A

A bispecific antibody can bind to FIXa and FX to mimic the FVIII function to bring them into proximity. This is Emicizumab

32
Q

When do you use Enzyme replacement therapy

A

For LOF

33
Q

Lysosomal storage diseases are….

A

A heterogenous group of disorders where enzymes fail to properly degrade in the lysosome. Leading to accumulation of undigested macromolecules, which damages cell function.

34
Q

When has ERT been used to treat lysosomal storage diseases?

A

GAA has been used to treat Pompe disease

35
Q

Aminoglycosides (some antibiotics) can suppression nonsense mediated decay (this is nonsense suppression). How?

A

They incorporate a random amino acid in place of the premature stop codon to achieve read through.

36
Q

There’s been a shift away from aminoglycosides for Nonsense suppression. Explain

A

Non-aminoglyocisdes are now used as they are less toxic, like PTC124 (ataluren)

37
Q

What disease has PTC124 been used for nonsense suppression treatment?

A

CF

38
Q

When else nonsense supression been used in a mouse model, what disease?

A

Restores dystrophin function in DMD

39
Q

What are the limitations of nonsense suppression?

A

It doesn’t stop NMD altogether, so there are limited transcripts being used. The random AA can have any effect, it may be critical for protein function. And the efficiency of readthrough depends on the nature of the stop codon. readthrough of the normal stop codon could be detrimental.

40
Q

How can antisense oligonucleotides be used for exon skipping in DMD?

A

Can turn DMD into BMD by restoring the reading frame by skippin an exon. Exon 50 commonly deleted, if you skip exon 51 using Pro51 it restores the reading frame.

41
Q

PRO051 was actually rejected by the FDA and is now replaced by Eteplirsen (exondys51) why?

A

Low clinical benefits, and the toxicity

42
Q

What are the limitations of exon skipping?

A

You need efficient delivery of the antisense oligos, the effect has a short duration. There are a diversity of mutations to the target. The efficacies and toxicity need improving.

43
Q

RNAi happens naturally. What is it?

A

22nt long endogenous double stranded RNAs (miRNAs) perform sequence specific silencing by binding to the 3’UTR of transcripts to trigger degradation

44
Q

If binding is perfect in RNAi what happens, and what if the binding is imperfect?

A

Perfect - bind 3’UTR to trigger mRNA degradation.
Imperfect - Inhibit ribosome binding to the mRNA to prevent translation

45
Q

When we do artificial RNAi, we use siRNAs. How do these work?

A

siRNA uses the RISC complex to facilitate the process by binding the guide strand, then snipping the mRNA where the guide strand is once the siRNA binds to it. Then the mRNA is degraded.

46
Q

How do we deliver siRNA for RNAi?

A

Either put it directly in the cell, or use a virus to provide the sequence

47
Q

Patisiran is RNA i used to treat amyloidosis. WHat does it do?

A

It targets Transthyretin (TTR) mRNA as the TTP protein misfolds in the liver in this disease.

48
Q

What are the challenges of siRNA therapy?

A

Specificity - could have off target effects.
Deliver to target tissues is tough, unless its the liver.
Stability of the siRNA.
Duration of the silencing.

49
Q

Anitsense oligos, what are they and what do they do?

A

They are 15-25 base long synthetic oligos that bind to complementary target mRNA to form an RNA/DNA heteroduplex. This triggers endogenous cellular RNAse H cleavage which leads to no translation of that protein.

50
Q

Tofersen is an antisense oligo treatment for ALS (a MND). Explain how it works?

A

12-20% of ALS cases are due to SOD1 mutations causing misfolding and accumulation. Tofersen is a SOF1 targeting ASO enveloped in Biogen. It’s quite effective.

51
Q

What are the 3 systems for gene editing?

A

Zinc Finger Nucleases (ZFNs)
TALENs
CRISPR/Cas9

52
Q

What is the basis of gene editing?

A

Damage the DNA so either NHEJ or HDR takes place.
The NHEJ can cause insertions and deletions, leading to disruption of disease genes.
The HDR can correct a gene with a WT copy

53
Q

What are Zinc Finger Nucleases?

A

Artificial restriction enzymes. Fused zync fingers (recognise specific bases) with a cleave FokI domain (restriction enzyme). need a dimer to bind both strands of DNA, generates a DSB for either NHEJ or HDR.

54
Q

What was the first ZFN trial for HIV?

A

Aim to inactivate CCR5, teh major coreceptor for HIV infection, in CD4 cells. Results showed decreased HIV RNA in patient blood.

55
Q

What are TALENs?

A

Similar to ZFNs, artificial restriction enzymes. But it’s the TAL effector DNA binding domain. diamino acid residues can target DNA sequences more specifically.

56
Q

What has TALENs been used for that I don’t understand?

A

To treat B-Cell ALL caused by a 11;19 translocation.

57
Q
A

GenGenMol (15 decks)

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