Generation of a new transgenic mouse model for assessment of tau gene silencing therapies.

Susan Fromholt,David R Borchelt,Christian Reitano,Jada Lewis,Hilda Brown

doi:10.1186/s13195-016-0202-1

Susan Fromholt, David R Borchelt + Show 3 more

Open Access

https://doi.org/10.1186/s13195-016-0202-1

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Abstract

BackgroundTargeting the expression of genes has emerged as a potentially viable therapeutic approach to human disease. In Alzheimer’s disease, therapies that silence the expression of tau could be a viable strategy to slow disease progression.MethodsWe produced a novel strain of transgenic mice that could be used to assess the efficacy of gene knockdown therapies for human tau, in live mice. We designed a tetracycline-regulated transgene construct in which the cDNA for human tau was fused to ubiquitin and to luciferase to create a single fusion polyprotein, termed TUL.ResultsWhen expressed in brain, the TUL polyprotein was cleaved by ubiquitin-processing enzymes to release the luciferase as an independent protein, separating the half-life of luciferase from the long-lived tau protein. Treatment of bigenic tTA/TUL mice with doxycycline produced rapid declines in luciferase levels visualized by in vivo imaging and ex vivo enzyme measurement.ConclusionsThis new mouse model can be used as a discovery tool in optimizing gene targeting therapeutics directed to reduce human tau mRNA levels.

Highlights

Targeting the expression of genes has emerged as a potentially viable therapeutic approach to human disease
The tau protein in the fusion protein tau-ubiquitin-luciferase (TUL) mice appears to migrate to a size that would be expected if the luciferase had been cleaved by ubiquitin processing enzymes as envisioned in the design of the construct
The iP301L model is a bigenic model similar to the rTg4510 model that is bigenic for a mutant tau responder transgene and Second, we created the possibility for very nice positive controls because the expression of the TUL construct should be suppressed by feeding the mice Dox [21, 23, 24]

Summary

Introduction

Targeting the expression of genes has emerged as a potentially viable therapeutic approach to human disease. Multiple approaches to knocking down mutant gene expression have been described in the literature including viral vector delivery of shRNAi or microRNA mimics, delivery of naked RNAi and RNAi complexed with various reagents to facilitate uptake, and delivery of modified antisense DNA oligonucleotides (ASOs) [2,3,4,5]. Preclinical testing of such therapies has met with encouraging outcomes, with examples of good to moderate efficacy [6,7,8,9]. FTD represents a attractive target for gene knockdown as it may be possible to direct such

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Conclusion