Emerging Treatments Flashcards
(28 cards)
What are inborn errors of metabolism?
Largest group of genetic disease
Affect basically all pathways, carbohydrate, fatty acid and protein metabolism
Usually a result of a lack of an enzyme
Eg. PKE, MCAD deficiency, maple syrup urine disease
Decreases the levels of a useful product. Also gives an increase in the substrate. This may be pushed down a different pathway
What is PKU?
Phenylketonuria
Lack of enzyme phenylalanine hydroxylass
Means no phenylalanine —> tyrosine
Phenylalanine is instead pushed down another route to turn into phenylketones
Symptoms: cognitive imparement, behavioural difficulties, fairer skin hair and eyes, vomiting
How is PKU treated?
Treated with a low protein diet
Also tyrosine supplements
Both ideally started before symptoms develop
Screening is now available
What is haemophilia?
Blood clotting disorder
Symptoms: uncontrolled bleeding, pain from bleeding into joints, bleeding into brain
Fatal if untreated
What are treatments for haemophilia?
First diluted snake venom was used, then whole blood transfusion but this required very large volumes
Infusions of factor VIII in plasma (also needs very large volumes)
Factor VIII concentrate became available and was turned into a freeze dried plasma derived factor concentrate
Now we use recombinant factor VIII
However this led to the blood scandal where up to 30000 people were given HIV infected blood
What are some diseases treated by gene replacement?
Growth hormone deficiency - treated with recombinant growth hormone
Haemophilia - recombinant FVIII
Lysosomal storage diseases: fabry disease- injection of recombinant alpha galactosiadass A , pompe disease - injection of alpha glucosidase
What do pharmacological therapies targeting proteins do?
Treat the underlying condition not the symptoms
Are treatments not cures
They normalise the function of the mutant protein
What are pharmacological chaperones?
Protein folding is complex and sometimes fails
System in ER degrades misfolded proteins
Some mutations prevent proteins folding properly, these are subject to the degradation pathway
Pharmacological chaperones treat these
What is Fabry disease?
Deficiency in alpha galactosidase A
Causes a build up of globotriaosylceramide
Some mutations cause misfolding
Migalastat is a small molecule chaperone that stabilises the enzyme in its correct shape
Migalastat is mutation specific
What are pharmacological modulators?
Most commonly used drugs are these
They are receptor agonists or antagonists
Or ion channel activators or blockers
Eg used in some cystic fibrosis people
How are pharmacological modulators used to treat cystic fibrosis?
CF may be caused by a defective chloride ion channel
Some mutations (33) cause this channel not to open
So a drug was designed that caused this channel to open - ivacaftor
Ivacaftor is mutation specific
How is combination therapy used to treat some CF cases?
some people have a defective ion channel and a misfolding protein caused by the same mutation (f508del)
This is treated with a combination of a chaperone and an activator
Eg. Orkambi (ivacaftor/lumacaftor)
Not a cure but does improve lung function
What are drugs that treat stop codon read through?
Some diseases are caused by a non sense mutation. This introduces a premature stop codon
This stops protein production and gives unusually short proteins
Drugs can be used to prevent this
What is an example of a drug that treats stop codon read through?
Aminoglycoside anyobiotics bind to ribosome
This causes a mis translation
But drugs can be based on these so that non sense mutations are actually read through
This produces a full length protein as opposed to a truncated one
How are stop codon read through drugs used to treat duchenne muscular dystrophy?
DMD is caused by a premature stop codon that produces truncated dystrophin
Becker muscular dystrophy has dystrophin with a missing section
If a drug can cause readthrough of a premature stop codon, it can give a phenotype for DMD that is more like BMD
Ataluren does this
A treatment not a cure
Non sense mutation specific
What are some types of drugs, broad catagories?
Pharmacological chaperones
Pharmacological modulators
Prevent stop codon read through
What is gene therapy?
Conceptually:
Recessive - replace the defective gene
Dominant - dlte the defective gene
But in practice very difficult to achieve :
Specificity, getting the therapy to the right place, maintain expression
Much easier in vitro than in Vivo
How is gene therapy used to treat mitochondrial my inherited disease?
Ex Vivo
Requires IVF
Thank dna (spindle) from an unfertilised patient egg. Transfer dna to a donor egg that had normal mitochondria. Then fertilise and implant the new egg
Or take pro nucleus from fertilised patient egg, transfer this to a fertilised donor egg
What is viral gene therapy?
Ex Vivo
Can engineer a virus to carry the therapeutic gene
Wide variety of virus used: AAV, adenovirus, lentivirus - HIV, vaccinia
Virus choice depends on the target tissue (viral tropism) and the amount of DNA
What is SCID?
Severe combined immune deficiency
Patients lack both B and T cell responses
Most common is X linked (75%) also adenosine deaminase deficiency (15%)
Can now be treated with a bone marrow transplant but this isn’t always possible and comes with its own complications
How is gene therapy used to treat SCID?
In vitro
Treats ADA-SCID
Called strimvelis
Autologous transplant:
Take bone marrow from patient
Isolate haemapoietic stem cells
Isolate and expand CD34+ cells
Transfected with ADA-lentivirus and grow these cells
Treat patient with Bulfusan (kills HSCs)
Reinfuse transformed cells into patient
What is in Vivo therapy supplement?
Lack of functional gene
A virus can be used to carry in a working copy
Can be injected systemically but more effective if injected into eye or spine or brain
What is the only in Vivo therapy supplement in use?
Leber congenital amaurosis type 2
Recessive disease caused by mutation in RPE65
Causes progressive blindness due to loss of retinal cells
Treatment is called Luxturna, uses rAAV2 virus expressing RPE65 gene
Not a cure but greatly improves vision
What are anti sense oligonucleotides?
Short modified nucleic acids complementary to the target
Modification allows entry to cell and prevents degradation
They bind to target and block translation
Can also alter splicing
Cheap to make
Aka knockdown approach
