ALS - Potential Therapy Flashcards
What is the current therapy for ALS?
Riluzole
What are the acute effects of riluzole?
Decrease in voltage gated Na+ currents
Potentiates Ca2+ dependen K+ current
Inhibits GLU release
Where are stem cells used for therapy harvested from?
Bone marrow or umbilical cord blood
What must the stem cell be able to do to be an effective treatment
Differentiate, replace and connect with denervated muscle
How does stem cell treatment work with mouse embryos?
Treat mice embryo with retinoic acid and sonic hedgehog
With 2 weeks it grows to be a motor neuron
Is stem cell treatment a viable option?
In chicks the stem cells migrate to the anterior horn of the spinal cord
Slow the progression and increase survival in rats
But this evidence is limited just now
Why might ceftriaxone help ALS?
Increases glial cell mediated glutamate transport (via stimulation and upregulation of EAAT2 mRNA)
What is the main aim of muscle therapy?
To improve diaphragm function
How does ACE-031 work?
Inhibits negative regulators of muscle growth
(like myostatin)
(ie promotes muscle growth)
How is ACE-031 given?
Subcut
Good tolerance
How does CK-2017357 work?
Activates fast skeletal muscle troponin by increasing muscle sensitivity to Ca2+
What is the overall effect of CK-2017357?
Increase muscle force to improve pulmonary function
Which proteins are involved in protein folding and degradation?
Heat shock proteins
What does arimoclol do?
Penetrates the CSF to increase the expression of neuroprotective HSPs
This delays disease progression and increases lifespan
How is arimoclol given?
Orally
Explain why using RNA could help treat ALS
anti-sense oligonucleotides and small inhibitory RNAs
To bind to mutant RNA and stop if form being translated
This slows disease progression and increases survival in transgenic mice
What is the main issue for RNA targeted therapies?
Only work on known mutations
What does ISIS333611 do?
Intrathecally targets mSOD1 to reduce its gain of function
What is olesoxime?
Mitochondrial pore modulator which delays onset and extends survival
Does creatinine affect ALS symptoms?
Seems to in transgenic mice
What does dexpramipexole do?
Decreases the oxidative stress
Maintains mitochondrial function
Extends survival
Well tolerated
What is HUR?
An mRNA stabiliser which binds to VEGF RNA to enhance protein production
How is HUR affected in ALS?
binds competitively to mSOD1 instead of VEGF RNA
So there is less VEGF so less neuroprotection
What has intracerebroventricular VEGF been shown to do?
Increase MN survival and increase O2 supply
Which recent evidence suggests stem cells could treat ALS?
Adipose-derived stem cells can accurately reach targets and form connections in both upper and lower motor neurons
At intermediate stage ALS
Walker 2019
How does olesoxime work?
Modulates mSOD1 and Ca2+ entry to the mitochondria
