Clinical Research in Ataxia

Question 1

Ataxia

Answer 1

Loss of balance, unsteady irregular gait, irregular limb and eye movements, slurred speech

Due to death of neurons involved in motor function

Can be acquired or hereditary

Question 2

Friedreich’s Ataxia

Answer 2

GAA repeat expansion in FXN gene
Most common form of AR ataxia
Characterised by loss of voluntary movement coordination and heart enlargement

Question 3

FRDA Typical Phenotype

Answer 3

Progressive gait and limb ataxia age 5-15
Dysartria
Pyramidal weakness
Babinski sign
Sensory neuropathy
Neuronal degeneration

Question 4

FRDA Genetics

Answer 4

GAA repeat expansion in Intron 1 causes inhibition of transcription and protein reduction leading to FXN silencing (96% of patients)

The more GAA copies, the earlier the onset and the quicker the decline

Question 5

FXN Function

Answer 5

FXN is in the inner mitochondrial membrane -> it helps to build iron-sulphur clusters -> iron is important for the electron transport change

Disruption causes escape of ROS and oxidative stress -> increases lipid peroxidation -> ferroptosis

Question 6

NRF2 Pathway

Answer 6

NRF2 is normally bound to Keap1 which signals it for ubiquitination

In oxidative stress, Keap1 releases Nrf2 which translocates to the the nucleus and activates antioxidants to protect the cell

In FRDA, Nrf2 is inhibited even in the presence of ROS, meaning no antioxidants are generated

Question 7

Omaveloxone

Answer 7

Omaveloxolone covalently binds to Keap1, causing Nrf2 release

Omav prevents Complex I inhibition, oxidative stress and cell death

Question 8

RT001

Answer 8

A modified lipid which is resistant to ROS induced oxidation -> counteracts lipid peroxidation

Worked well preclinically but no efficacy in phase II trials

Question 9

Nicotinamide

Answer 9

Aims to reduce heterochromatinization at FXN

FXN upregulated towards asymptomatic carrier levels

Generally well-tolerated -> nausea

Question 10

Exercise to increase NAD+

Answer 10

Using exercise to increase NAD+ to resist oxidative stress

Question 11

Spherical Nucleic Acids

Answer 11

Used to allow gene therapy to enter the right part of the cell

Increases FXN mRNA by degrading natural antisense transcript, increasing FXN mRNA half-life in cytosol and enabling more translational cycles per mRNA molecule