5.9 - Emerging Treatments Flashcards
1
Q
What are inborn errors of metabolism?
A
- largest group of genetic diseases
- affects various pathways including carbohydrate, fatty acid and protein metabolism
- generally caused by lack of enzyme in that pathway - means no product is formed which are vital for health
- also causes increase in substrate concentration which can cause disease symptoms
- also the substrate could be pushed to make an alternate product which can result in disease phenotype
2
Q
What are some examples of inborn errors of metabolism?
A
- PKU - phenylketonuria
- MCAD deficiency
- Maple Syrup Urine Disease
- homocystinuria
3
Q
What is PKU?
A
- phenylketonuria
- lack of phenylalanine hydroxylase which converts phenylalanine to tyrosine = less tyrosine, more phenylalanine
- this pushes phenylalanine down an alternate path to produce phenylketones which are toxic and cause disease symptoms
- untreated PKU symptoms include major cognitive impairment, behavioural difficulties, fairer skin/hair/eyes than siblings (due to lack of melanin) and recurrent vomiting
4
Q
How is PKU treated?
A
- with a low protein diet and tyrosine supplements
- 1934 - PKU identified but thought to be untreatable
- 1953 - lack of PAH identified as cause & role of dietary phenylalanine in disease found
- 1954 - low protein diet therapy introduced, to be effective needs to start before symptoms (as some are irreversible)
- 1960s - PKU screening introduced
- 1984 - PAH mutation identified
- before treatment, need to identify the cause (mutation in PAH) but not necessarily the gene involved
5
Q
What is haemophilia?
A
- blood clotting disorder, known since ancient times
- uncontrolled bleeding
- bleeding into joints - causes excruciating pain
- bleeding into brain
- internal bleeding
- fatal if untreated
6
Q
How is haemophilia treated?
A
- 1930s - diluted snake venom (contains clotting factors) used topically
- 1940s - whole blood transfusions (very large volumes required = painful)
- 1952 - factor VIII discovered
- 1955 - first infusions of factor VIII in plasma form (large volumes required)
- 1964 - cryoprecipitate discovered
- 1968 - first FVIII concentrate available
- 1970s - freeze-dried plasma-derived factor concentrates available
7
Q
What was the haemophilia treatment blood scandal?
A
- in 70s&80s, between 5k and 30k were given clotting factors contaminated with HIV and hepatitis, and so far 2500 have died from this
- there is evidence this contamination was known about at the time
- how was this solved?
- 80s - methods of heat treating to kill virus, FVIII gene cloned
- 90s - recombinant FVIII treatment, gets around the issue of blood donated FVIII
8
Q
What other diseases are treated by replacement?
A
- growth hormone deficiency - injection of growth hormone which is now recombinant (originally was cadaver-derived and caused patients to develop CJD)
- lysosomal storage disease which affects lysosomal breakdown of products in cell e.g:
- Fabry disease - injection of recombinant alpha galactosidase A
- Pompe disease - injection of alpha galactosidase
- these treatments are not mutation specific so can be given to any patient with the condition
9
Q
What are the stages of drug development?
A
- first stage - discovery/preclinical - testing in cells, longest part is lab-based
- then testing in animals
- moves on to clinical phase - 3 phases:
- phase I - check safety in healthy volunteers (<100)
- phase II - check therapeutic effect in few patients (100-300)
- phase III - large scale therapeutic trials (200-3000)
- approval by EMA (Europe) / FDA (America) needed
10
Q
How is drug approval for NHS done?
A
- by NICE in England & Wales
- by Healthcare Improvement Scotland in Scotland
- they also give guidelines for treating conditions
11
Q
What do pharmacological therapies targeting the protein do?
A
- treat the condition not the symptoms
- these are treatments not cures
- try to normalise function of mutant protein
12
Q
What are pharmacological chaperones?
A
- protein folding in cells is complex and sometimes fails
- chaperones aid in folding process
- system in ER degrades misfolded proteins
- misfolded proteins are subject to degradation by various pathways
- some mutations prevent proteins folding properly
- if correctly folded, protein is active and moved down secretory pathway –> cytoplasm / out of cell
- quality control system, ensures only correctly folded proteins end up in target
13
Q
What is Fabry disease?
A
- deficiency of alpha-galactosidase A and subsequent build up of globotriaosylceramide (glycosphingolipid)
- some mutations that cause Fabry are ones that cause protein misfolds
- treatment is with a small molecule chaperone Migalastat - similar to beta-D-galactose which is the substrate for alpha-galactosidase A
- stabilises enzyme in correct shape
- Migalastat binds to the misfolded protein and rescues the folding process = not degraded = protein can travel through ER and increases activity of enzymes in lysosome
- NICE approved in Feb 2017
- mutation specific - only treats those where cause of disease is a mutation causing misfolding
14
Q
What are pharmacological modulators?
A
- commonly used drugs
- can be receptor agonists/antagonists
- can be ion channel activators/blockers
- can be enzyme activators/inhibitors
- can design one that has these effects on mutant receptor/channel e.g. Bcl-abl Kinase inhibitors for treatment of cancers caused by Philadelphia chromosome
15
Q
How have pharmacological modulators been used to treat cystic fibrosis?
A
- CF - defective chloride channel where mutations (33) cause the channel not to open
- can design a drug which causes activation - Ivacaftor
- mutation specific - only effective where a mutation prevents channel from opening
