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POM GENETICS > Emerging Treatments > Flashcards

Emerging Treatments Flashcards

1
Q

What is the largest group of genetic diseases?

A

Inborn errors of metabolism

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2
Q

What causes inborn errors of metabolism?

A

Defects of single genes that code for enzymes that facilitate conversion of substrates into products (lack that enzyme)

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3
Q

What is the main problems with the inborn errors of metabolism?

A

There is an accumulation of substances that are not converted into products that may be toxic or interfere with normal function

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4
Q

What are four examples of diseases caused by inform errors of metabolism?

A

Maple syrup urine disease
MCAD Deficiency
Phenylketonuria (PKU)
Homocystinuria

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5
Q

What pathways do inborn errors of metabolism effect?

A

carbohydrates
fatty acids
proteins

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6
Q

What happens in phenylketonuria?

A

There is no phenylalanine hydroxylase meaning phenylalanine is no longer converted into tyrosine and is converted into phenylketones instead

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7
Q

What can untreated PKU lead to?

A

Major cognitive impairment
Behavioural difficulties
Lack of melanin so fairer skin, hair and eyes
Recurrent vomiting

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8
Q

What is used to treat PKU?

A

Tyrosine supplements in diet and low protein diet

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9
Q

Why are patients with PKU advised to keep a low protein diet?

A

Phenylalanine is an amino acid found in protein, so given PKU patients are advised to have a low protein diet to avoid unnecessary buildup as they struggle to degrade it

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10
Q

What are some symptoms of Haemophillia (blood clotting disorder)?

A

Uncontrolled bleeding
Bleeding into joints and brain (excruciating pain)
Internal bleeding
If untreated it is fatal

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11
Q

What did some patients get after being treated for haemophilia?

A

HIV and Hep C

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12
Q

How is haemophillia treated?

A

By replacing the missing clotting factors isolated from human blood serum, 8 and/or 9

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13
Q

What methods did they used to use to treat haemophilia?

A

diluted snake venom then whole blood transfusion

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14
Q

What is important to know before trying to treat through diet and replacement?

A

The biochemistry behind the condition as the treatment is not mutation specific

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15
Q

What are four other conditions which can be treated by replacement?

A

Growth hormone deficiency (injection of growth hormone now recombinant)

Fabry disease (Injection recombinant alpha galactosidase A)

Pompe disease (injection of alpha glucosidase)

Lysosomal storage disease (effects lysosomal breakdown)

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16
Q

What are the five general stages of drug development?

A
  1. Discovery/preclinical
  2. Lab based testing
  3. Testing in animals
  4. Clinical testing - in 3 phases
  5. Approval by the regulatory bodies (EMA, FDA)
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17
Q

What happens in phase 1 of clinical testing?

A

Tested on healthy volunteers, with a sample size of <100

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18
Q

What happens in phase 2 of clinical testing?

A

The drug is tested to check the therapeutic effect on patients with the condition, 100-300 people

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19
Q

What happens in phase 3 of clinical testing?

A

Large scale therapeutic trials with 200-3000 patients

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20
Q

Who tests and approves drugs in England?

A

The National Institute for Health and Care Excellence (NICE)

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21
Q

What is the purpose of protein-targeting therapies?

A

They try to normalise the function of mutant proteins
These are treatments not cures
Treat the condition not symptoms

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22
Q

What is a pharmacological chaperone?

A

A drug which serves as molecular scaffolding in order to stabilize mutant proteins and cause them to fold correctly
System in ER degrades misfolded proteins

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23
Q

What condition is migalastat used to treat and what is it?

A

Fabry disease
Migalastat is a small molecule chaperone
It stabilises enzyme in correct shape
Mutation specific

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24
Q

What are pharmacological modulators?

A

They are receptor agonists / antagonists which can act as ion channel activators and blockers

They can be designed to have an effect on mutant receptor or channel

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25
Q

What condition is Ivacaftor used to treat and how does it work?

A

Cystic fibrosis

Mutation (33) causes channel not to open
Ivacaftor causes activation of channel

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26
Q

What is combination therapy?

A

When a protein chaperone and modulator is used as the problem could be fixed with both

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27
Q

What is an example of a case where combination therapy would be useful?

A

When you have a defective chloride ion channel in CF resulting from one mutations that lead to misfolding

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28
Q

What is a non-sense mutation?

A

When a stop codon is inserted into the middle of the gene, preventing the complete read-through of the instructions for a complete protein to form

premature stop codon

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29
Q

How does stop codon read through therapy work?

A

When the therapy can recognise a mutated stop signal which differs from the normal one, and encourages the cell to ignore the stop codon

Aminoglycoside antibiotics bind to ribosome cause mistranslation
Drug based on these-> read through non-sense mutations

30
Q

What condition is Ataluren used to treat and what kinda of treatment is it?

A

Stop codon read through therapy for Duchenne Muscular Dystrophy

31
Q

What are the four methods of small molecule treatment?

A
  1. Stop codon read through therapy
  2. Pharmacological Modulators
  3. Pharmacological Chaperones
  4. Combination therapy
32
Q

What does in vitro mean?

A

In Glass

33
Q

What is meant by gene therapy?

A

The therapeutic delivery of nucleic acid into a patients cells as a drug to treat disease

34
Q

What does in vivo and ex vivo mean?

A

In the living and out the living

35
Q

What are three reasons that gene therapy is very difficult to achieve in practise?

A

Achieving specificity
Getting therapy to right place
Maintaining expression once it is in the right place

36
Q

What is done in gene therapy when you have a recessive disease?

A

You replace the defective gene

37
Q

What is done in gene therapy when you have a dominant disease?

A

Delete defective gene

38
Q

What is meant by spindle transfer/ mitochondrial transfer?

A

Where the nuclear DNA is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind

requires IVF

39
Q

Does the genome have more genetic information or does mitochondrial DNA?

A

Genome, 16569 bp in mitochondria
3088269832 bp in genome

mitochondrial transfer is popularly known as 3-parent baby even though it’s just a minor transfer of DNA

40
Q

Is mitochondrially inherited disease therapy in vivo or in vitro?

A

In vitro

41
Q

What does virus gene therapy involve?

A

The use of an engineered virus to carry therapeutic genes

42
Q

Give examples of conditions that virus gene therapy has been used to treat?

A

AAV
Adenovirus
Lentivirus - HIV
Vaccinia Virus

43
Q

What does virus choice depend on?

A

Target tissue

44
Q

What depends on virus choice?

A

Amount of DNA limited

45
Q

What is SCID?

A

Severe combined immunodeficiency
Bubble baby disease
Lack both B-cell and T-cell mediated response

There are several forms
- X-linked (X-SCID 70%)
- Adenosine deaminase deficiency (ADA-SCID 15%)

46
Q

Why can virus gene therapy be useful for patient with SCID?

A

SCID can sometimes be treated using a bone marrow transplant, however it is not possible for all children (80% ADA-SCID no match) and it has its own risks

47
Q

What is the in vitro gene therapy for ADA-SCID?

A

Strimvelis
Autologous transplant
Isolate patients Hematopoietic stem cells
isolate and expand CD34+
Transfected with ADA- lentivirus
Grow transformed cells
Treat patient with busulfan (kills HSC)
Reinfused transformed cells into patient

48
Q

What are CAR-T cells?

A

Chimeric Antigen Receptor T cells

49
Q

How does CAR-T cell therapy work?

A

T cells are genetically engineered to express chimeric antigen receptors bound to MHC, which are speicifially directive towards antigens on patients tumour cells - this means the cancer cells are killed and attacked

50
Q

What thpe of antibodies recognises cancer cells using CAR-T cells?

A

scFv = single chain fragment variable

51
Q

What are some of the side effects of CAR-T cell therapy?

A

Cytokine release syndrom and neurological damage

52
Q

How does in vivo supplement therapy work?

A

When patients lack a functional copy of the gene, they can use a virus to carry a working copy into the cells

53
Q

What is gene silencing used for?

A

Used for dominant diseases- gain of function

Can be used for recessive diseases- downstream effects

Can be used for non-genetic diseases

Several potential methods
Antisense-nucleotides
RNAi

54
Q

What are anti-sense oligonucleotides?

A

Small sections of mRNA which bind to target mRNA and cause it to be degraded - preventing the protein being transcribed properly

Short modified nucleic acid complementary to target
Modification prevents degradation allow entry to cell
Binds to target
Blocks translation
Can also alter splicing
relatively cheap to make

55
Q

What is RNAi?

A

RNA interference

biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression.

56
Q

How does RNAi work?

A

dsRNA (double stranded RNA) is complementary to target
Modification prevents degradation allow entry to cell
Activated via Dicer/ Risc pathway
Targeted RNA cleaved

57
Q

What is an example of in vivo therapy gene silencing using RNAi?

A

Lumasiran-
Primary hyperoxaluria type 1
Autosomal recessive mutation in AGT
Causes excess glyoxylate build up
Broken down to oxalate
Produces calcium oxalate kidney damage

58
Q

What is in vivo therapy gene silencing used for?

A

Useful for diseases caused by gain of function

It uses ASO

59
Q

What is an example of in vivo therapy gene silencing?

A

Inotersen (an antisense oligonucleotide inhibitor)
Transthyretin-related hereditary amyloidosis
Mutation in Transthyretin (TTH)
TTH cannot form tetramers; forms aggregates
Mutation specific

60
Q

What type of diseases is in vivo known down therapy useful for?

A

In diseases caused by a gain of function

61
Q

What is exon skipping therapy?

A

Involves the use of oligonucleotides to skip disease causing exon, with the useful RNA being put back into the reading frame so active protein is still made
Generally only large proteins

62
Q

What can happen in exon skipping therapy when given to patients with duchenne muscular dystropy?

A

Removal of the mutant exon can cause DMD to become BMD

Eteplirsen- oligonucleotide cause skipping exon 51
Will result in production partially active dystrophin

63
Q

What is a future possible gene therapies?

A

CRISPR-Cas 9

64
Q

What are the disadvantages of using CRISPR-Cas9?

A

Cannot target large changes like large deletions of triplet expansions

65
Q

One form of SCID (severe combined immunodeficiency) is caused by a lack of Adenine deaminase (ADA) in haematopoietic stem cells. This condition is often treated by bone marrow ransplant. In some patients this is not possible what genetic approach could be used to treat this condition?

A

Ex vivo gene therapy

66
Q

Phenylketonuria (PKU) is an autosomal recessive disease caused by lack of phenylalanine hydroxylase (PAH). Some of the mutations in PAH prevent it from folding properly. Other mutations reduce the activity of the enzyme. Which approaches might be successful in treating the disease caused by these two types of mutation.

A

Pharmacological chaperones

67
Q

Familial Mediterranean fever is an autosomal dominant disease caused by a point mutation in FMF gene. Which approaches might be successful in treating this disease?

A

Knowndown approach

68
Q

Marsili Syndrome is an autosomal dominant disease caused by a mis-sense mutation, in this disease the mutation is the (a point mutation) in the ZFHX2 gene. What approach might be successful in treating this disease ?

A

Knockdown (antisense) approach - disease is dominant and caused by a protein with a gain of function so thr activity of this protein needs to be blocked

69
Q

McArdle Disease is an autosomal recessive condition caused by mutations in glycogen phosphorylase, muscle associated (PYGM). PYGM is small enzyme . One of the most common mutations is a nonsense mutation (a premature stop codon) caused by the change of a single nucleotide. What approaches might be useful for treating this disease ?

A

Stop codon read through therapy as it is caused by a premature stop codon

70
Q

Where can you inject locally?

A

eye, epidurally spine and brain for in vivo therapy supplementation

71
Q

What can in vivo therapy supplementation be used for example?

A

Leber congenital amaurosis type 2
Recessive disease caused by mutation RPE65
Progressive blindness- loss of retinal cells
Lucturna rAAV2 expressing RPE65
Not cure- greatly improves vision though

72
Q

What has supplementation recently been licenced for and what is ongoing?

A

Haemophilia A

on going for Haemophilia B

POM GENETICS (9 decks)

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