HD - Treatment and Animal Models

Question 1

What is tetrabenazine?

Answer 1

A reversible monoamine uptake and storage inhibitor

Question 2

What is deutetrabenazine?

Answer 2

Isomer of tetrabenazine

Question 3

What is the difference between tetrabenazine and deutetrabenazine?

Answer 3

6 H atoms replaced by 6 D atoms which slows the metabolism

Question 4

What is the main concern with using monoamine uptake inhibitors?

Answer 4

Less DA in the brain may lead to depression

Question 5

Which brain structure releases DA?

Answer 5

Substantia nigra

Question 6

Which symptom would DA inhibition mainly treat?

Answer 6

Chorea

Question 7

Which anti-sense oligonucleotide is currently being used?

Answer 7

ASO-Htt-Rx

Question 8

What effect does the ASO-Htt-Rx have on mutant Htt?

Answer 8

Binds to the RNA so it is never transcribed/translated into protein

Question 9

Approx how long does gene silencing last?

Answer 9

4 months

Question 10

How is ASO-Htt-Rx delivered?

Answer 10

Via brain shuttle

Question 11

Describe the concept of a brain shuttle

Answer 11

Epidural inject of the drug in small packets

Enveloped in other proteins so that it may cross the BBB (Niewoehner et al 2014)

Question 12

How effective do rodent studies find the “brain shuttle” technique for anti-sense nucleotides?

Answer 12

Doesn’t reach key structures very efficiently

But does overall lower the amount of Htt

Question 13

What are the main problems with gene silencing in HD?

Answer 13

Function of Htt not fully understood - switching off WT may have implications

Immune response problems (as per)

Question 14

What is the benefit of an N-terminal transgenic?

Answer 14

Severe symptoms that develop early on and are quicker to research

Question 15

What is an N terminal transgenic?

Answer 15

Mice model which carries a small portion of the 5’ end of the Htt gene

Question 16

Which phenotypes can be developed with N-terminal transgenics?

Answer 16

Loss of co-ord
Tremor
Hypokinesia
Abnormal gait

Question 17

How are N-terminal transgenics made?

Answer 17

Pronuclear injection (integrate of transgene into the mouse genome)

R6/2 mouse if a chromosome 4 injection

Question 18

What is the benefit of using full length transgenics?

Answer 18

Closer to human condition

Question 19

How is a full length transgenic mouse made?

Answer 19

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

Question 20

What is the disadvantage of using full length transgenics?

Answer 20

Take months to develop the disease phenotype

Question 21

What is a knock-in mouse?

Answer 21

Mice with CAG repeats introduced directly into the mouse Htt gene via recombinant techniques using a mouse embryonic stem cell

Question 22

What is the benefit of using knock in mice?

Answer 22

No variability in tissue distribution and expression (as there isn’t an insertion site)

Question 23

How is a knock-in mouse made?

Answer 23

Injection into a blastocyst which is then injected into a psudedopregnant female

Question 24

What is the difference between knock in mice genetics and human?

Answer 24

Knock in mice produces homozygotes which is very rare in humans

Way more CAG repeats than average adult onset HD

Question 25

Why may be geldanamycin be beneficial?

Answer 25

It enhances chaperone levels to there is more promotion of normal folding
But it does not penetrate BBB very well

Ross and Poirier 2004

Question 26

What other methods may be used to treat protein aggregation in disease?

Answer 26

Stimulate increase proteasome activity 
Chemical chaperones (to block protein aggregation)

Question 27

What is a potential danger with inhibition a single step in a pathway as treatment?

Answer 27

The accumulation of the intermediate step may be worse

Question 28

Is tetrabenazine effective?

Answer 28

Shown to improve motor symptoms and reduce striatal neuron loss in full length transgenic mice

Wang et al 2010