scholarly journals E2F4-Based Gene Therapy Mitigates the Phenotype of the Alzheimer’s Disease Mouse Model 5xFAD

2021 ◽  
Author(s):  
Noelia López-Sánchez ◽  
Alberto Garrido-García ◽  
Morgan Ramón-Landreau ◽  
Vanesa Cano-Daganzo ◽  
José M. Frade

AbstractAfter decades of unfruitful work, no effective therapies are available for Alzheimer’s disease (AD), likely due to its complex etiology that requires a multifactorial therapeutic approach. We have recently shown using transgenic mice that E2 factor 4 (E2F4), a transcription factor that regulates cell quiescence and tissue homeostasis, and controls gene networks affected in AD, represents a good candidate for a multifactorial targeting of AD. Here we show that the expression of a dominant negative form of human E2F4 (hE2F4DN), unable to become phosphorylated in a Thr-conserved motif known to modulate E2F4 activity, is an effective and safe AD multifactorial therapeutic agent. Neuronal expression of hE2F4DN in homozygous 5xFAD (h5xFAD) mice after systemic administration of an AAV.PHP.B-hSyn1.hE2F4DN vector reduced the production and accumulation of Aβ in the hippocampus, attenuated reactive astrocytosis and microgliosis, abolished neuronal tetraploidization, and prevented cognitive impairment evaluated by Y-maze and Morris water maze, without triggering side effects. This treatment also reversed other alterations observed in h5xFAD mice such as paw-clasping behavior and body weight loss. Our results indicate that E2F4DN-based gene therapy is a promising therapeutic approach against AD.

2020 ◽  
Author(s):  
Noelia López-Sánchez ◽  
Morgan Ramón-Landreau ◽  
Cristina Trujillo ◽  
Alberto Garrido-García ◽  
José M. Frade

AbstractAlzheimer’s disease (AD) has a multifactorial etiology, which requires a single multi-target approach for an efficient treatment. We have focused on E2F4, a transcription factor that regulates cell quiescence and tissue homeostasis, controls gene networks affected in AD, and is upregulated in the brain of Alzheimer’s patients and of APP/PS1 and 5xFAD transgenic mice. E2F4 contains an evolutionarily-conserved Thr-motif that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. Here we show that neuronal expression in 5xFAD mice of a dominant negative form of E2F4 lacking this Thr-motif (E2F4DN) potentiates a transcriptional program consistent with global brain homeostasis. The latter correlates with attenuation of both microglial immune response and astrogliosis, modulation of Aβ proteostasis, and blockade of neuronal tetraploidization. Moreover, E2F4DN prevents cognitive impairment and body weight loss, a known somatic alteration associated with AD. We propose E2F4DN-based gene therapy as a promising multifactorial approach against AD.


2015 ◽  
Vol 93 (9) ◽  
pp. 1325-1329 ◽  
Author(s):  
Yuanli Li ◽  
Junqing Wang ◽  
Shenghao Zhang ◽  
Zhaohui Liu

2006 ◽  
Vol 14 (7S_Part_12) ◽  
pp. P677-P677
Author(s):  
Michael J. Castle ◽  
Fernando Calvo Baltanas ◽  
Imre Kovacs ◽  
Alan H. Nagahara ◽  
Krystof S. Bankiewicz ◽  
...  

2021 ◽  
pp. 147264
Author(s):  
Lauren V. Owens ◽  
Alexandre Benedetto ◽  
Neil Dawson ◽  
Christopher J. Gaffney ◽  
Edward T. Parkin

2020 ◽  
Vol 21 (3) ◽  
pp. 777 ◽  
Author(s):  
Lewis E. Fry ◽  
Caroline F. Peddle ◽  
Alun R. Barnard ◽  
Michelle E. McClements ◽  
Robert E. MacLaren

RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a range of genetic diseases. For inherited retinal degenerations caused by point mutations in large genes not amenable to single-adeno-associated viral (AAV) gene therapy such as USH2A and ABCA4, correcting RNA offers an alternative to gene replacement. Genome editing of RNA rather than DNA may offer an improved safety profile, due to the transient and potentially reversible nature of edits made to RNA. This review considers the current site-directing RNA editing systems, and the potential to translate these to the clinic for the treatment of inherited retinal degeneration.


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