Treatments for genetic disorders

Question 1

What is the largest group of genetic disease?

Answer 1

Inborn errors of metabolism

Affect variety of pathways

Question 2

Give examples of diseases caused by inborn errors of metabolism?

Answer 2

Phenylketouria (PKU)

MDCAD deficiency

Question 3

Why do errors of metabolism cause disease?

Answer 3

Lack of product e.g. enzyme

Increased levels of substrate

Question 4

What does PKU result in?

Answer 4

Major cognitive impairments
Behavioural difficulties
Fairer skin, hair and eyes

Question 5

How do you treat PKU?

Answer 5

Low protein diet

Tyrosine supplement

Question 6

What does haemophilia result in?

Answer 6

Bleeding into joint, brain and internally
Excruciating pain
Fatal if untreated

Question 7

How has haemophilia been treated?

Answer 7

Dilute snake venom
Whole blood transfusions
Plasma transfusions
Freeze-dried plasma-derived factor concentrates

Question 8

How is haemophilia treated now?

Answer 8

Recombinant factor VIII treatment

Question 9

Summarise part I

Answer 9

Treatment by diet
Treatment by replacement
Need to know biochemistry 
No need to know gene involved 
Not mutation specific
Treatments follow the science

Question 10

What are the stages of drug development?

Answer 10

Discovery
Testing in animals
Clinical trials (I,II,III)
Approval (EMA, FDA)
Approval for NHS use (cost-effective)

Question 11

What’s the deal with therapies targeting proteins?

Answer 11

Treatments not cures

Try to normalise function of mutant protein

Question 12

What are pharmacological chaperones?

Answer 12

Cause misfiled proteins to fold correctly

Question 13

What disease can be treated by pharmacological chaperones?

Answer 13

Fabry disease

Question 14

How is Fabry Disease treated?

Answer 14

Mitgalastat: small molecule chaperone
Stabilises enzyme in correct shape
Expensive

Question 15

What are pharmacological modulators?

Answer 15

Receptor agonists/ antagonists

Ion channel activators/ blockers

Question 16

What disease can be treated by pharmacological modulator?

Answer 16

Cystic Fibrosis

Question 17

How is Cystic Fibrosis treated?

Answer 17

Combination therapy: chaperone and activator
Defective chloride channel
Design drug that causes activation
Mutation specific

Question 18

What is stop codon read through?

Answer 18

Some diseases caused by premature stop codon

Prevent protein production

Question 19

Can drugs prevent stop codon read through?

Answer 19

Aminoglycoside antibiotics bind to ribosome
Cause mistranslation
Drugs read through non-sense mutations

Question 20

What drugs are used to treat stop codon read through?

Answer 20

Ataluren used to treat Duchenne muscular dystrophy

Question 21

How can small molecules treat genetic disease?

Answer 21

Correct mis-folding of proteins
Increase activity
Ignore premature stop codons

Question 22

What is gene therapy?

Answer 22

Replace defective gene

Delete defective free

Question 23

Why is gene therapy difficult to achieve?

Answer 23

Achieving specificity
Getting therapy to right place
Maintain expression

Question 24

What’s the deal with mitochondrially inherited disease therapy?

Answer 24

Only effective therapy requires IVF
Take DNA from fertilised patient egg
Transfer to donor egg normal mitochondria

Approved for use in UK
Controversial
3 parent babies

Question 25

What's the deal with virus gene therapy?

Answer 25

Can engineer virus to carry therapeutic gene | Virus choice depends on target tissue

Question 26

How does in vitro gene therapy CAR-T cell work?

Answer 26

``` Chimeric antigen receptor T-cell used to treat cancer T-cell receptor antigen bound to MHC Low affinity CAR- recognise antigen directly Variable region monoclonal antibody scFv Recognises cancer cell T-cell receptor and co-receptor signalling domain ```

Question 27

How does in vitro gene therapy CAR-T cell work?

Answer 27

``` Take donor blood Isolate T-cells and expand Transfected with CAR CAR-T cell expanded Reinfused to patient ```

Question 28

Why is in vitro gene therapy CAR-T cell not often used?

Answer 28

Can cause cytokine release syndrome and neurological damage

Question 29

What are the different methods of in vivo gene therapy?

Answer 29

Use a virus to carry working copy Can inject systemically Can inject locally

Question 30

Give an example of a disease treated by in vivo gene therapy?

Answer 30

Leber kongenital amaurosis type 2 | Injected directly to back of eye

Question 31

What are anti-sense oligonucleotides?

Answer 31

``` Short modified nucleic acid complementary to target Modification prevents degradation Allows entry to cell Binds to target Block translation Can also alter splicing Relatively cheap ```

Question 32

What else can anti-sense oligonucleotides be used for?

Answer 32

``` Exon skipping During pre-RNA processing Cause exon to be skipped Useful in limited circumstances Exons skipped mustn't be vital Generally only large proteins Used in DMD- not approved in Europe ```

Question 33

What is CRISPR-Cas 9?

Answer 33

Possible future gene editing therapy