ATF4-Controlled BECN1 Vectors for Treatment of Huntington’s Disease in R6/2 Mice Open Access
Fogel, Lindsay (Fall 2021)
Published
Abstract
Background: Huntington’s disease (HD) is a rare genetic neurodegenerative disorder that affects approximately 2.7 people per 100,000 worldwide. The disease is characterized by a variety of motor, psychiatric, and cognitive symptoms before its ultimately fatal course. Currently, there are no therapeutic options capable of slowing or halting disease progression. Accumulation of mutant huntingtin protein has been found to activate the unfolded protein response (UPR) and contribute to endoplasmic reticulum (ER) stress, resulting in downstream effects implicated in disease progression. However, one novel therapeutic strategy that capitalizes on this dysregulation is the regulation of protein clearance via BECN1 in response to indicators of intracellular stress. Activating transcription factor 4 (ATF4) is translated according to the PERK signaling pathway in the UPR and can serve as an indicator of intracellular stress. As such, expression of BECN1 in response to translation of ATF4 represents an opportunity to modulate the delivery of BECN1 to enhance neuroprotection and halt disease progression.
Methods: R6/2 mice received bilateral striatal injections of AAV2-derived therapies (ATF4-GFP, ATF4-BECN1, GFP, BECN1) and underwent a series of behavioral assessments to measure motor skills, including climbing tests, as well as weekly weigh-ins as an indicator of disease progression. Following completion, post-mortem neuropathological assessments were conducted to understand the extent of vector spread and reduction of htt aggregates.
Results: With regard to behavioral skills, including climbing, rearing, and movement on the mesh, the treatment did not have a significant effect on motor decline and progression. There was not a significant difference in weekly weights among the treatment groups for Huntington’s mice. However, upon neuropathological analysis of ATF4-GFP and ATF4-BECN1 groups, ATF4-BECN1 mice on average had fewer htt aggregates present within striatal sections where the treatment was present.
Conclusion: While the gene therapy did not significantly alter motor skills in R6/2 mice, the decreased presence of htt aggregates suggests the therapy could be improved and offer potential for therapeutic regulation. Possible improvements include increased vector spread through the use of a different AAV serotype, as well as testing in an HD model with a slower rate of disease progression than the R6/2 model.
Table of Contents
Table of Contents
Introduction……………………………………………………….…………..…………………………………………………………1
Methods……………………………..…..………………………………………………………………………………………..…….10
Results…………………………………..……………………………………………………………………………………………..…15
Discussion………………………..……………………………………..………………………………………….………………..…18
Figures….…………………………….…………..……………………………………………………………………………...………23
Supplementary Data……………...…………..………………………………………………………….………………..………30
References………………..…...…………………………………………………………………………………...……..……..……31
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