Gene targeting techniques for Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT) is essential, involved in a variety of crucial cellular functions such as vesicle transportation, cell division, transcription regulation, autophagy, and tissue maintenance. The mutant HTT (mHTT) proteins in the body interfere with HTT's normal cellular functions and cause additional detrimental effects. In this review, we discuss multiple approaches targeting DNA and RNA to reduce mHTT expression. These approaches are categorized into non-allele-specific silencing and allele-specific-silencing using Single Nucleotide Polymorphisms (SNPs) and haplogroup analysis. Additionally, this review discusses a potential application of recent CRISPR prime editing technology in targeting HD.

Keywords: Allele-specific targeting; Huntington’s disease; Prime editing; SNPs.

Figure 1.

HTT has been experimentally linked to a variety of different cellular functions including cell division, vesicular transport, endocytosis, ciliogenesis, autophagy, and transcription regulation. The mutant allele with a CAG expansion of greater than 36 repeats has been linked to a variety of gain of function effects including toxic aggregation, mitochondria dysfunction, transcription interference, proteasome disruption, autophagy interference, and potential loss of healthy HTT function (Bates et al., 2015; Grima et al., 2017; Jones & Hughes, 2011; Schulte & Littleton, 2011).