HD - Treatment and Animal Models Flashcards
What is tetrabenazine?
A reversible monoamine uptake and storage inhibitor
What is deutetrabenazine?
Isomer of tetrabenazine
What is the difference between tetrabenazine and deutetrabenazine?
6 H atoms replaced by 6 D atoms which slows the metabolism
What is the main concern with using monoamine uptake inhibitors?
Less DA in the brain may lead to depression
Which brain structure releases DA?
Substantia nigra
Which symptom would DA inhibition mainly treat?
Chorea
Which anti-sense oligonucleotide is currently being used?
ASO-Htt-Rx
What effect does the ASO-Htt-Rx have on mutant Htt?
Binds to the RNA so it is never transcribed/translated into protein
Approx how long does gene silencing last?
4 months
How is ASO-Htt-Rx delivered?
Via brain shuttle
Describe the concept of a brain shuttle
Epidural inject of the drug in small packets
Enveloped in other proteins so that it may cross the BBB (Niewoehner et al 2014)
How effective do rodent studies find the “brain shuttle” technique for anti-sense nucleotides?
Doesn’t reach key structures very efficiently
But does overall lower the amount of Htt
What are the main problems with gene silencing in HD?
Function of Htt not fully understood - switching off WT may have implications
Immune response problems (as per)
What is the benefit of an N-terminal transgenic?
Severe symptoms that develop early on and are quicker to research
What is an N terminal transgenic?
Mice model which carries a small portion of the 5’ end of the Htt gene
Which phenotypes can be developed with N-terminal transgenics?
Loss of co-ord
Tremor
Hypokinesia
Abnormal gait
How are N-terminal transgenics made?
Pronuclear injection (integrate of transgene into the mouse genome)
R6/2 mouse if a chromosome 4 injection
What is the benefit of using full length transgenics?
Closer to human condition
How is a full length transgenic mouse made?
Ful length Htt transgene carried in either a yeast or bacterial artificial chromosome which integrate in the genome and multiply
There is microinjection of this into a fertilised oocyte
What is the disadvantage of using full length transgenics?
Take months to develop the disease phenotype
What is a knock-in mouse?
Mice with CAG repeats introduced directly into the mouse Htt gene via recombinant techniques using a mouse embryonic stem cell
What is the benefit of using knock in mice?
No variability in tissue distribution and expression (as there isn’t an insertion site)
How is a knock-in mouse made?
Injection into a blastocyst which is then injected into a psudedopregnant female
What is the difference between knock in mice genetics and human?
Knock in mice produces homozygotes which is very rare in humans
Way more CAG repeats than average adult onset HD
Why may be geldanamycin be beneficial?
It enhances chaperone levels to there is more promotion of normal folding
But it does not penetrate BBB very well
Ross and Poirier 2004
What other methods may be used to treat protein aggregation in disease?
Stimulate increase proteasome activity Chemical chaperones (to block protein aggregation)
What is a potential danger with inhibition a single step in a pathway as treatment?
The accumulation of the intermediate step may be worse
Is tetrabenazine effective?
Shown to improve motor symptoms and reduce striatal neuron loss in full length transgenic mice
Wang et al 2010
