Ataxia

Question 1

two main groups of ataxia

Answer 1

1. Autosomal dominant spinocerebellar ataxia (SCAs)
2. Autosomal recessive ataxia (most common being Friedrich’s ataxia)

Question 2

two types of gene therapy - dependent on which cells are being treated:

Answer 2

1. Somatic gene therapy: transfer of a section of DNA to any cell of the body that doesn’t produce sperm or eggs, effects of gene therapy will not be passed onto children.
2. Germline gene therapy: transfer of a section of DNA to cells that produce eggs/sperm. Effects of gene therapy will be passed onto patient’s children and subsequent generations.

Question 3

what is ataxia

Answer 3

‘Lack of order/coordination’

• Loss of balance: with unsteady, irregular, wide-based gait.
• Irregular and fragmented limbic movements
• Disrupted eye movements: no calibrated, sometime with unstable fixation, with or without double vision.
• Slurred speech: variable speed and volume.
• Some are dominant and a few are recessive.
• Due to mendelian genes.

Question 4

Protein associated with Ataxia

Answer 4

PolyQ

Question 5

PolyQ disorders:

Answer 5

translate triplet repeat diseases.
Gain of function – the product of the gene of interest is expressed and leads to an abnormal product.

PolyQ protein – is an aberrant protein which eventually leads to inclusions that aer toxic to the cell physiology.

Question 6

what is CRAG

Answer 6

(guanosine trisphosphate named CRAG:

Question 7

RNAse H-dependent

Answer 7

RNAse H-dependent: RNAse H-dependent mRNA degradation, a portion of nucleotides in the 20 position of the ASOs molecules must remain unmodified.
- Following the formation of the mRNA: DNA (ASO) duplex and its recognition by RNAse H, the target mRNA molecule is cleaved, while the artificial oligonucleotide molecule remains intact.

Question 8

RNA H-independent

Answer 8

RNAse H-independent: RNAse H-independent RNA modulation, completely 20-modified ASOs may be used to mediate several processes where mRNA degradation is not the outcome.
- The mechanism can be employed to modulate mRNA splicing events, which in the context of PolyQ SCAs could enable skipping the exons containing the pathological mutation.

Question 9

Friedrich’s Ataxia

Answer 9

An autosomal recessive neurodegenerative disorder. More complex. Characterised by the progressive loss of voluntary movement coordination (ataxia) and heart enlargement.

Question 10

Gene in Friedrich’s ataxia

Answer 10

FXN

• Untranslated triplet GAA repeat diseases: loss of function – the product of the gene of interest is not expressed or mildly expressed.
• Downstream – low expression of the protein.

Question 11

Frataxin

Answer 11

increase the level of frataxin improve symptoms of FA.

Question 12

Gene therapy for Friedreich’s ataxia

Answer 12

AAVs in-vivo approach for neurodegenerative diseases.
- Administration? Into the spine or directly into cerebellum – lots of side effects and without great success.
- A point of major concern in gene therapy for FA is phototoxicity or the toxicity associated with overexpression of the transgene.
o Studies in cultured human cells have demonstrated that FXN overexpression causes oxidative stress and toxicity in a similar way to frataxin deficiency, underscoring important of physiological levels of FXN to confer a therapeutic effect.