Hyperlipidemia

Question 1

What is hyperlipidaemia

Answer 1

High lipid count

Question 2

How are lipids circulated around the body?

Answer 2

• Exogenous sources absorbed from intestines
• Endogenous sources made in the liver and secreted as vLDL
• Lipoprotein lipase starts to remove triglycerides

Question 3

How does endogenous cholesterol synthesis happen?

Answer 3

• Made from acetyl Co-A

* HMG-CoA reductase is the rate limiting step!

Question 4

What is cholesterol inhibited by?

Answer 4

• Statins

Question 5

What are the current treatments

Answer 5

• Statins

* Fibrates

Question 6

What are fibrates?

Answer 6

• Medicine for hyperlipidaemia
• Increases lipoprotein lipase
• Increases breakdown of VLDL
• Increases uptake into tissue
• Reduces VLDL release and increases uptake

Question 7

What are LDL receptors?

Answer 7

• Recognise apoprotein b100 on LDL
• When LDL binds receptor is endocytosed
• More LDL receptors = lower blood cholesterol

Question 8

What is PCSK9?

Answer 8

• PCSK9 circulates in the bloodstream
• It binds to LDL receptors
• When LDL binds to receptors they are endocytosed as usual
• However, PCSK9 results in receptor degradation
• High PCSK9 levels = CV risk

Question 9

What are PCSK9 inhibitors?

Answer 9

• They inhibit PCSK9
• Receptor can be recycled
• And LDL can be up taken from bloodstream

Question 10

What are the limitations of current therapy?

Answer 10

• Statins and fibrates are linked to muscle aches
• Also linked to liver damage
• Reputation of statins is perhaps worse than true side effects
• PCSK9 inhibitors are currently expensive

Question 11

Example of new methods?

Answer 11

Viral vectors and RNA targeted therapeutics

• A viral particle is introduced into the cell to produce a functional protein that is useful
• For example, could be an LDL receptor
• Slightly adjust genetic code which increases expression of LDL receptors for example
• Block the amount of protein produced (e.g., PCSK9)
• E.g., via blocking translation
• Small interfering RNA reduce translation of mRNA – reduce synthesis of particular proteins

Question 12

Small interfering RNA therapeutics clinical trial

EXAMPLE - INCLISIRAN

Answer 12

• Phase 3 trial of siRNA inclisiran targeting PSCK9 maintained reductions in LDL cholesterol via injection
• Reduces amount of PSCK9 production
• No difference in severe adverse reactions compared to placebo

Question 13

What are antisense oligo therapeutics?

Answer 13

Short synthetic chemically modified chains of nucleotides that have the potential to target any gene product
• They stop translation of specific protein

Question 14

Example of antisense oligo therapeutic

EXAMPLE = MIPOMERSEN

Answer 14

• Mipomersen is an antisense oligo targeting apoliprotein b 100 – a main component of LDL and VLDL
• Currently licensed in the USA for familial hypercholesterolaemia
• Reduces ApoB100 translation
• Reduces LDL
• Reduces cardiovascular events
• Not licensed in UK due to high incidence of severe liver adverse effects

Question 15

What is CETP

Answer 15

• Cholesteryl ester transfer can break down HDL

Question 16

What is CETP inhibitor?

Answer 16

• Inhibits CETP
• Maintains HDL level
• Reduces LDL levels
• Improve reverse cholesterol transport
• Trials for hyperlipidaemia have been stopped due to excess death and insufficient efficacy
• Ongoing trials for ischaemic heart disease

Question 17

How was PSCK9 discovered as a target?

Answer 17

• Group of families with high cholesterol who had PSCK9 mutations were studied
• Noticed that people with mutation of PSCK9 being non-functional had lower cholesterol levels