Work

Tuning neurodegeneration-linked gene expression, one (edited) base at a time

Year: 2022

Type: article

Abstract: Dysregulated gene expression is a frequent hallmark of neurodegenerative diseases. Thus, strategies that enable precise and targeted tuning of endogenous gene expression represent an attractive approach for neurodegenerative-focused gene therapies. In this issue, Lim et al. 1 Lim C.K.W. McCallister T.X. Saporito-Magriña C. McPheron G.D. Krishnan R. Zeballos C.M.A. Powell J.E. Clark L.V. Perez-Pinera P. Gaj T. CRISPR base editing of cis-regulatory elements enables the perturbation of neurodegeneration-linked genes.. Mol Ther. 2022; 30: 3619-3631 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar employ CRISPR base editors to modify cis-regulatory sequences that govern the expression of two key genes involved in neurodegenerative diseases - the HTT gene for Huntington’s disease (HD), and the APP gene for Alzheimer’s disease (AD). By performing a focused, tiled CRISPR interference (CRISPRi) screen, Lim et al. identify functional elements embedded within the HTT promoter, most importantly an NF-κB binding site, that tune HTT expression levels. The authors build upon these findings and show that using cytosine base editors (CBEs) at this pivotal NF-κB binding site can induce marked reduction in HTT mRNA levels and consequently, nearly a two-fold decrease in HTT protein levels in HEK293T cells. Further, by targeting the CBE to the HTT promoter in vivo using AAV1, the authors were able to reduce HTT mRNA levels by ∼50% compared to control animals in the R6/2 mouse model of HD. Finally, Lim et al. showed that combinations of different CBEs could be used to modulate neurodegenerative-associated gene expression in a synergistic manner, resulting in even greater repression. Collectively, this work highlights the rising promise and utility of base editing technologies for therapeutic intervention, particularly at endogenous non-coding regulatory elements.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2022.10.003

Authors: Rosa Selenia Guerra-Resendez, Daniel Brenner, Isaac B. Hilton

Institution: Rice University

Language: English

Topic: CRISPR and Genetic Engineering

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,900