Gene therapy-mediated enhancement of protective protein expression for the treatment of Alzheimer's disease

Owens, Lauren and Benedetto, Alex and Dawson, Neil and Gaffney, Christopher and Parkin, Edward (2021) Gene therapy-mediated enhancement of protective protein expression for the treatment of Alzheimer's disease. Brain Research, 1753. ISSN 0006-8993

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Alzheimer’s disease (AD) is the leading form of dementia but lacks curative treatments. Current understanding of AD aetiology attributes the development of the disease to the misfolding of two proteins; amyloid-β (Aβ) and hyperphosphorylated tau, with their pathological accumulation leading to concomitant oxidative stress, neuroinflammation, and neuronal death. These processes are regulated at multiple levels to maintain homeostasis and avert disease. However, many of the relevant regulatory proteins appear to be downregulated in the AD-afflicted brain. Enhancement/restoration of these ‘protective’ proteins, therefore, represents an attractive therapeutic avenue. Gene therapy is a desirable means of achieving this because it is not associated with the side-effects linked to systemic protein administration, and sustained protein expression virtually eliminates compliance issues. The current article represents a focused and succinct review of the better established ‘protective’ protein targets for gene therapy enhancement/restoration rather than being designed as an exhaustive review incorporating less validated protein subjects. In addition, we will discuss how the risks associated with uncontrolled or irreversible gene expression might be mitigated through combining neuronal-specific promoters, inducible expression systems and localised injections. Whilst many of the gene therapy targets reviewed herein are yet to enter clinical trials, preclinical testing has thus far demonstrated encouraging potential for the gene therapy-based treatment of AD.

Item Type:
Journal Article
Journal or Publication Title:
Brain Research
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This is the author’s version of a work that was accepted for publication in Brain Research. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Brain Research, 1753, 2021 DOI: 10.1016/j.brainres.2020.147264
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Deposited On:
06 Jan 2021 10:15
Last Modified:
28 Sep 2023 00:29