VPS35 floxed mouse model for Alzheimer's drug discovery

This technology is a genetically engineered mouse model that enables the conditional deletion of the VPS35 gene, which can be used to investigate the pathogenesis of neurodegenerative conditions, particularly Alzheimer's disease.

Unmet Need: Precise retromer disruption model for adult-onset Alzheimer’s Disease studies

Investigating the role of essential genes in adult-onset diseases, such as Alzheimer's Disease, is often hindered by the limitations of conventional knockout models. Current methods to interrogate the retromer complex in Alzheimer’s and related disorders rely on over-expression via viral transduction or constitutive knock-down of VPS35. AAV-mediated “retromer repletion” techniques often give patchy expression or fail to match endogenous gene expression across all neurons, while VPS35 knock-out can be lethal for young mice and cause confounding developmental effects, making it difficult to study a gene's specific function in adult pathology. A model that allows precise, tissue-specific, and temporally controlled disruption of VPS35 in adult animals would be a critical tool for neurodegeneration drug discovery.

The Technology: Inducible, tissue-specific VPS35 knockout mouse for neurodegeneration studies

This technology describes a mouse line in which LoxP sites have been engineered to flank exons 3 through 5 of the endogenous VPS35 gene. By breeding these mice with a line that expresses an enzyme that recognizes the LoxP sites, researchers can induce the deletion of this essential portion of the VPS35 gene. This Cre-Lox system enables the gene knockout to be targeted to specific cell types or timed to occur at a particular stage of life, offering precise experimental control over gene function.

This mouse model has been characterized and utilized in multiple published studies investigating the mechanisms of neurodegeneration in Alzheimer’s Disease.

Applications:

• Pre-clinical drug discovery for Alzheimer’s Disease and other neurodegenerative diseases
• Biomarker discovery assays for Alzheimer’s Disease and other neurodegenerative diseases
• Neurodegenerative disease modeling
• Research tool to study the function of the VPS35 gene
• Research tool for cell-specific analysis in the progression of Alzheimer's disease

Advantages:

• Temporal and spatial specificity of gene deletion
• Robust expression
• Broad experimental flexibility
• Easy to breed
• Easy to distribute and quality control
• Lower cost and variability relative to viral knockdown

Lead Inventor:

Scott Small, M.D.

Related Publications:

• Qureshi YH, Berman DE, Marsh SE, Klein RL, Patel VM, Simoes S, Kannan S, Petsko GA, Stevens B, Small SA. The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease. Cell Rep. 2022 Jan 18;38(3)

• Simoes S, Neufeld JL, Triana-Baltzer G, Moughadam S, Chen EI, Kothiya M, Qureshi YH, Patel V, Honig LS, Kolb H, Small SA. Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans. Sci Transl Med. 2020 Nov 25;12(571)

• Qureshi YH, Berman DE, Klein RL, Patel VM, Simoes S, Kannan S, et al. Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus. bioRxiv [Preprint]. 2019 Apr 26:618496

Tech Ventures Reference:

• IR CU25395

• Licensing Contact: Jerry Kokoshka