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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.

SUBMITTER: Fields E

PROVIDER: S-EPMC8373677 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Gene targeting techniques for Huntington's disease.

Fields Eric E Vaughan Erik E Tripu Deepika D Lim Isabelle I Shrout Katherine K Conway Jessica J Salib Nicole N Lee Yubin Y Dhamsania Akash A Jacobsen Michael M Woo Ashley A Xue Huijing H Cao Kan K

Ageing research reviews 20210605

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 discus ...[more]

PMID: 34098113

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Project description:BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a novel dual-function compound, N(6)-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A(2A)R and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2A)R and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. CONCLUSIONS/SIGNIFICANCE: The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.

Dataset Information

Gene targeting techniques for Huntington's disease.

Publications

Gene targeting techniques for Huntington's disease.

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