Treatment of Psychiatric Disorders by Inhibiting Importin Alpha 5

Background and Unmet Need

Anxiety and stress-related disorders affect 10-30% of the general population and are therefore considered a major burden on public health. Current medical treatments for anxiety disorders include drugs (e.g., benzodiazepines, selective serotonin uptake inhibitors [SSRIs]) that target various synaptic mechanisms, such as uptake of neurotransmitters. However, severe side effects and suboptimal efficacy in some patients limit long-term treatment with such drugs.

The Solution

Repurposing of approved importin ?5 pathway-targeting drugs and nutraceuticals for the treatment of anxiety disorders

Technology Essence

The research team led by Prof. Fainzilber has uncovered importin ?5, a protein involved in nuclear localization of MeCP2 in hippocampal neurons, as a potential therapeutic target for treating anxiety and related disorders1. Using a series of in vivo mouse models and a panel of behavioral tests, the research team identified a positive correlation between importin ?5 expression and anxiety levels. More specifically, importin ?5 knockout led to significantly reduced anxiety phenotypes, which were associated with marked reduction of short-term synaptic plasticity. Importin ?5 knockout mouse brains exhibited a clear nuclear deficit of MeCP2 in ventral and dorsal hippocampal neurons and in increased expression of Sphk1, a gene directly regulated by MeCP2. In line with these findings, reduced anxiety was also measured in adult wild-type mice treated with importin ?5 knockdown shRNA.

Administration of fingolimod, an inhibitor of the Sphk1 receptor, and a drug approved for multiple sclerosis (MS) reversed the anxiolytic effect of importin ?5 knockout.

Similarly, intraperitoneal injection of PF-543, a selective Sphk1 inhibitor, significantly increased anxious behavior patterns in importin ?5 knockout mice. A bioinformatics-driven screen identified b-sitosterol, a widely marketed nutraceutical that could be repurposed to treat anxiety disorders. The team validated its hypothesized effect in mice (Figure 1A) and further demonstrated the synergistic anxiety-reducing effect of sub-efficacious doses b-sitosterol and fluoxetine (Prozac), an established SSRI (Figure 1B)2.

Applications and Advantages

• Reduction of anxiety levels.
• Treatment of a variety of psychiatric diseases
• Targets a novel signaling pathway with a role in various neurological disorders
• Existing drugs can be repurposed
• Potential synergistic drug combinations with a SSRIs, leading to reduced dosage and improved safety profile

Development Status

The team characterized importin ?5 as a key regulator of anxiety levels and reported the anxiolytic effect of importin ?5 knockdown. An in-depth analysis of its underlying molecular mechanisms identified Sphk1 and its receptor as downstream mediators, which, when selectively inhibited using approved drugs, validated the central role of importin ?5 in psychiatric orders. Following an in silico screen for relevant drug candidates, the team flagged bsitosterol for repurposing to treat anxiety disorders, and demonstrated its anti-anxiety effect in mice in vivo model when delivered with fluoxetine.

References

Panayotis N, Sheinin A, Dagan SY, et al. Importin ?5 Regulates Anxiety through MeCP2 and Sphingosine Kinase Cell Rep. 2018;25(11):3169-3179.e7. doi:10.1016/j.celrep.2018.1066 [1]

Panayotis N, Freund PA, Marvaldi L, et al. ?-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice. Cell Rep Med. 2021;2(5):100281. doi:10.1016/j.xcrm.2021.100281 [2]