Tracking Signaling Pathway Activity May Be Biomarker in Testing Anavex2-73

Researchers say implications extend to most neurologic disorders with 'abnormal cell signaling'

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with Anavex2-73 (blarcamesine), an experimental therapy that Anavex Life Sciences is developing to treat fragile X syndrome led to certain signaling pathways in immune cells normalizing in mouse model experiments.

Analyzing these immune signaling pathways could help track the effect of the investigational medication in future clinical trials, according to Anavex.

“These additional biomarker findings in Fragile X Syndrome provide further evidence of potential to expand the therapeutic profile of Anavex2-73 into the largest portion of addressable market of autism spectrum disorder, Fragile X Syndrome,” Christopher Missling, PhD, president and CEO of Anavex, said in a press release. “We look forward to initiating a double-blind, placebo-controlled Phase 2/3 Anavex2-73 study in Fragile X Syndrome.”

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The findings were published in the American Journal of Genetics, in the study, “Brain cell signaling abnormalities are detected in blood in a murine model of Fragile X syndrome and corrected by Sigma-1 receptor agonist Blarcamesine.”

Lymphocytes are a group of immune cells that includes B-cells and T-cells. They are vital for defending the body against infectious invaders and their activity is governed by a number of different molecular signaling networks.

In particular, the PI3K/Akt/mTOR and MAPK/ERK pathways both play central roles in regulating lymphocyte activity. In people with fragile X syndrome, these pathways in lymphocytes are characteristically overactive. At a molecular level, this increased activation is recognizable as an uptick in levels of Akt or ERK protein that have been phosphorylated, a chemical modification involving the addition of a phosphate group.

Scientists at Anavex analyzed lymphocyte signaling pathways in mice that had been treated with Anavex2-73. This experimental therapy is designed to improve the health of synapses, the connections between nerves, by acting as an agonist (activator) of the sigma-1 receptor.

Results showed the treatment reduced phosphorylated Akt and ERK levels, indicating it helped normalize activity in the PI3K/Akt/mTOR and MAPK/ERK signaling pathways.

In line with earlier data, results also showed treatment with Anavex2-73 normalized behavior in mice with fragile X. The changes in lymphocyte signaling occurred in parallel with behavioral changes, according to Avonex, suggesting that tracking these signaling pathways’ activities may be a useful biomarker in clinical trials testing Anavex2-73.

“Evaluations of lymphocyte cell signaling in mouse models of Fragile X Syndrome are feasible and support corresponding assessments in affected individuals,” Walter E. Kaufmann, MD, chief scientific officer at Anavex and co-author of the study, said. “These analyses have the potential for monitoring response to treatment, particularly for drugs correcting multiple pathway abnormalities such as sigma-1 receptor agonist Anavex2-73. Implications of this work extend beyond [fragile X] to most neurologic disorders associated with abnormal cell signaling.”

Missling, who was also a co-author of the study, said these results are”further evidence of the potential of Anavex2-73 as a platform technology of precision medicine.”