This technology is a therapeutic strategy for neurodegenerative diseases involving the inhibition of the RhoA signaling pathway with small molecules and shRNA viral vectors to correct disrupted retromer-dependent endosome trafficking.
Current therapeutics for Alzheimer’s disease and many neurodegenerative disorders only treat symptoms and not the underlying cause. Studies have implicated the dysfunction of retromer-dependent endosome trafficking as the causal pathway in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders. Increasing levels of SORL1, a Type I integral membrane protein located inside endosomal tubules, can improve this endosomal trafficking process by stabilizing retromers to increase their recycling function. Upregulating the trafficking of SORL1 to endosomes could thus enhance retromer-dependent trafficking and be a potential therapeutic for neurodegenerative disorders.
This technology identifies ARHGEF12 and ROCK2 as druggable targets of the RhoA signaling pathway in neurodegenerative disorders, as well as their inhibitory small molecules and shRNA vectors for remedying disrupted retromer-dependent endosomal trafficking. Both proteins are differentially expressed in the brain and upregulated in either Alzheimer’s disease (AD) or AD-vulnerable brain regions. In silico structural analyses of the two proteins identified druggable sites where binding of small molecules can downregulate these proteins’ downstream inhibition of SORL1 localization to endosomes. Docking analyses further identified commercially available, including 1 FDA-approved, small molecules that bind to ARHGEF12’s most druggable site. AAV vectors for shRNA-mediated genetic knockdown of the two targets were also designed.
ARHGEF12 protein expression level was verified in mouse brain and human induced pluripotent stem cell-derived neurons.
Patent Pending
IR CU25028, CU25089
Licensing Contact: Jerry Kokoshka
