Anavex Life Sciences Corp (AVXL)

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CLN6 Batten Disease Video Notes

I wonder which S1R Agonist they were using specifically. I'd like to touch on the fact that Anavex 2-73 regularly performs better in preclinical trials against other S1R Agonists. In any case, here is some interesting data (numbers are high confidence estimates) from the data in the video.

CLN6 Batten Disease: infantile variant, nearly all die before the age of 15.

GFAP and ATP (cortical astrocytes) are effected in resting and active conditions, but especially in active conditions, showing that S1R agonists have greater efficacy against the disease-related stress. That is excellent news as it suggests S1R agonists may be disease-modifying in CLN6 Batten Disease.

GFAP = inflammatory marker
GFAP is a common hallmark of Batten Disease and is released only after CNS cellular death (https://www.sciencedirect.com/topics/neuroscience/glial-fibrillary-acidic-protein)
S1R dosing (0.3mM) during rested conditions reduced GFAP in WT by ~38% (1 to .68)
S1R dosing (0.3mM) during rested conditions reduced GFAP in CLN6 cells by ~31% (1.18 to .86)
NOTE: dosing in CLN6 cells brought GFAP levels down lower than resting normal cells, sweet!
S1R dosing (0.3mM) during active conditions reduced GFAP in WT by ~32% (1.63 to 1.18)
S1R dosing (0.3mM) during active conditions reduced GFAP in CLN6 cells by ~45% (1.59 to 1)
NOTE: extraordinary response in 'active' GFAP conditions lends credence to the researchers assessment in S1R having greater efficacy against disease-related stress conditions. Diseased cells were able to surpass even normal cells during this test.

ATP (SubC) = disease hallmark
SubC is one of a the classic hall markers of Batten disease. SubC is a protein that accumulates in NCL storage material within autophagic vacuoles and lysomes.(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774306/)
S1R dosing (0.3mM) during rested conditions reduced ATP SubC in WT by ~28% (1 to .75)
S1R dosing (0.3mM) during rested conditions reduced ATP SubC in CLN6 cells by ~18% (1.1 to 0.92)
NOTE: dosing in CLN6 cells brought ATP SubC levels down lower than resting normal cells, very promising!
S1R dosing (0.3mM) during active conditions reduced ATP SubC in WT by ~25% (1.03 to .80)
S1R dosing (0.3mM) during active conditions reduced ATP SubC in CLN6 cells by ~51%!!! (1.4 to .83)
NOTE: as demonstrated in the GFAP 'active' category, CLN6 cells performed exceptionally well while under stressed conditions, their end result dramatically passed that of even normal treated cells.

In mice, a 90 day injection test was conducted. For this test, researchers checked three areas in the brain commonly affected by Batten disease (Thalamus, Somatosensory Cortex, and the Cerebellum), as well as three pathological markers of CLN6 (ASM, CD68, and SubC). In this test, ASM (autoflourescent storage material disease hallmark) saw dramatic decrease in all three brain area, even in low doses. ASM saw decreases in the Thalamus upwards of ~115%, decreases in the somatosensory cortex by ~140%, and decreases in the Cerebellum by ~91% (low dose) and ~127% (high dose). CD68 also saw moderate decreases when comparted to untreated mice in the Thalamus and Cerebellum regions with ~40% decrease and ~61% decrease respectively. SubC saw very marginal changes in the Thalamus (possibly ~10% decrease in high dose), virtually no difference in the somatosensory cortex, and fairly substantial decreases in the cerebellum at ~33%-40% decreases. Researchers mention this is likely due to S1R effecting different brain areas differently. Researchers also say that recent western blots of CLN6 mice show "regulated S1R protein expression in different nervous tissues compared to WT mice" which will be a point of continued exploration in further S1R studies towards Batten Disease.