Emerging Treatments Flashcards
What are in born errors of metabolism?
Missing factors = treatments based on diet and enzyme replacement, not mutation specific
Usually lacking an enzyme
Usually affects Carbs, Fatty acid and protein pathways
What disease examples of in born errors of metabolism are there? ( 4 )
PKU
MCAD deficiency ( Medium-chain acyl-CoA dehydrogenase )
HCU ( homocystinuria )
Maple Syrup Urine disease
What are the characteristics of PKU? Disease and symptoms?
Phenylketonuria:
There are no Phenylalanine hydroxylases to create Tyrosine . decreased tyrosine and more phenylalanine turning to phenylketones
Symptoms: Major Cog-impairment, behavioural difficulties.
Fair skin, hair, eyes than siblings
Recurrent vomiting
What PKU treatment is available?
Low protein diet : Tyrosine supplements
- Can identify enzyme deficiency : Km is increases and Vmax decreased on a graph
What are the characteristics of Haemophilia?
Blood clotting disorder causing uncontrolled bleeding into joints, brain, internal bleeds.
Treatments started in 1940s and developed overtime from whole blood transfusions to Factor 8 plasma, F8 concentration
Currently use: Recombinant factor 8 treatment
What are the characteristics of Lysosomal storage diseases?
What replacement injections are there for both types?
Effect lysosomal breakdown
e.g.
Fabry disease = injection of recombinant α-galactosidase A
Pompe disease = injection of α-glucosidase
What do Pharmacological therapies do?
They treat conditions not symptoms. NOT CURE
They aim to normalise mutant protein function
What do Pharmacological chaperones do to help?
When protein folding fails due to mutation degradation can occur
Chaperones can stabilise enzyme in correct shape
What is the Pharmacological chaperone used in Fabry disease?
A deficiency of α-galactosidase A due to muatation caused misfolding
Causes build up of globotriaosylceramide
Migalastat = small molecule chaperone
Stabilises enzyme in correct shape
What do Pharmacological modulators do to help?
Act as receptor agonists/antagonists so can activate or block ion channels
( can use effects on mutant receptor or channel )
e.g. bcr abl kinase inhibitor CML
Pharmacological modulator use in Cystic Fibrosis?
Has defective chloride channel due to Mutation ( 33 ) ∴ channel does not open
Ivacaftor is a mutation specific drug : activates channel
How is combination therapy used to treat Cystic Fibrosis?
mutation : f508del, misfolded inactive channel
Chaperone ( misfolded) and activator (ion channel ) combination
Orkambi ( ivacaftor / lumacaftor )
does NOT CURE but improve lung function
How does stop codon read through help?
Pharmacological modulator
Stop codons cause premature proteins
Drugs can bind to ribosome - cause mistranslation and read pass the non-sense mutations to rescue protein
.e.g aminoglycoside antibiotics bind to ribosomes
Use DMD as an example of stop codon read through?
Duchenne muscular dystrophy = premature stop
Becker muscular dystrophy = missing section
Can turn DMD –> BMD by reading through stop codon
Drug: Ataluren
- BMD has a less severe phenotype so px can live longer
What does Gene therapy do?
Blocks genes skipping disease exons = mutation specific
May or may not be a cure
Recessive : need to replace defective gene
Dominant : delete defective gene
Why is Gene therapy easier in vitro followed by ex vivo and lastly in vivo?
In vitro : in glass
ex vivo : out of living ( virus + px stem cells = new cells which are introduced to px )
in vivo : in living ( inject viral vector )
Describe mitochondrially inherited disease therapy? And the two methods involved
Take DNA from fertilised px egg
Transfer donor egg to normal mitochondria
Method 1 - Maternal spindle transfer:
Chromosomes removed from egg which has mutated mDNA
Added to donor enucleated egg cell which is fertilised in vitro = embryo
Method 2 - Pronuclear transfer:
Mutated mDNA egg fertilised. Resulting pronucleus removed and transferred to fertilised enucleated donor egg = embryo NOT APPROVED in UK, 3 parent babies
How does virus gene therapy work?
Can engineer virus to carry therapeutic gene
e.g. AAV, Adenovirus, HIV, Vaccina depending on target tissue
What are the characteristics of SCID?
Severe combined immuno-deficiency ( bubble baby disease )
Lack T and B cell response
Mostly X linked 70%
Adenosine deaminase deficiency ( ADA- SCID ) 15%
Treatment: Bone marrow transplant
* ADA-SCID 80%x does not match for transplant
In vitro gene therapy
Describe In vitro gene therapy ADA-SCID?
Drug: Strimvelis
Autologous transplant Isolate px hemopoietic stem cells Isolate and expand CD34+ Transfected with ADA-lentivirus Grow transformed cells treat px with bulsulfan - kills HSC Reinfused transformed cells into Px
What is an example of In vivo therapy supplement?
In vitro therapy can supplement is a px is lacking a working gene, can inject systemically, or locally in eye spine brain etc
Leber congenital Amaurosis Type 2 is a recessive genes caused by mutation RPE65 = progressive blindness
Luxturna rAAV2 expresses RPE65 which improves vision
patients require sufficient remaining cells, not a cute but greatly improves vision
What are Anti-sense oligonucletotides used for?
In vivo
Short nucleic acids complementary to targets.
Once bound to target it blocks translation = can alter splicing.
- Pre-RNA processing
- can skip disease causing exon
- RNA back into reading frame
- usually for larger proteins
( - ) useful in limited situations
( + ) cheap
What are the characteristics of Transthyretin-related hereditary amyloidosis?
( in vivo knockdown therapy )
Mutation in Transthyretin ( TTH )
So cannot form tetramers : forms aggregates
Aggregate –> deposits in tissues –> damage tissue –> progressive and fatal heart, kidney, muslce weakness and pain.
Treated by Inotersen : binds to mRNA, activates RNase H1, cleaves mRNA into fragments
How can Exon skipping be applied to DMD?
Can prevent the incorporation of mutant exon so phenotype is BMD.
Drug: Eteplirsen ( oligonucleotide skips exon 51 )
Results in partially active dystrophin
Why may Gene editing be used?
Gene editing corrects relatively small errors, but can’t correct large changes -
( - ) May have off-target effects and struggles to get into the cell.
Not currently used on humans except one exception.
How is gene editing currently used on humans?
Use of CRISPR-Cas to alter genome of IVF embryos
Deleted CCR5 gene in twins
Controversial - illegal in most of the world
Could use to prevent genetic disease
( - ) Need to identify prior to conception
Used in Russia to prevent heritable deafness
in born errors of metabolism growth hormone deficiency?
Give recombinant injection
Extra missed info?
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