Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease.

Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease.

Publication date: Mar 06, 2019

Huntington’s disease is caused by an abnormally expanded CAG repeat expansion in the HTT gene, which confers a predominant toxic gain of function in the mutant huntingtin (mHTT) protein. There are currently no disease-modifying therapies available, but approaches that target proximally in disease pathogenesis hold great promise. These include DNA-targeting techniques such as zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9; post-transcriptional huntingtin-lowering approaches such as RNAi, antisense oligonucleotides, and small-molecule splicing modulators; and novel methods to clear the mHTT protein, such as proteolysis-targeting chimeras. Improvements in the delivery and distribution of such agents as well as the development of objective biomarkers of disease and of HTT lowering pharmacodynamic outcomes have brought these potential therapies to the forefront of Huntington’s disease research, with clinical trials in patients already underway.

Tabrizi, S.J., Ghosh, R., and Leavitt, B.R. Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease. 06385. 2019 Neuron (101):5.

Concepts Keywords
Antisense Drug delivery
Biomarkers CRISPR
Cas9 Sense
Chimeras RNA interference
Clinical Trials Cas9
CRISPR Huntingtin
DNA Biotechnology
Huntingtin Genome editing
Huntington Immune system
Mutant RNA
Neuron Branches of biology
Nucleases Molecular biology
Oligonucleotides
Pathogenesis
Pharmacodynamic
Protein
Proteolysis
RNAi
Small Molecule
Splicing
Transcription Activator
Zinc

Semantics

Type Source Name
disease MESH development
gene UNIPROT SLC35G1
gene UNIPROT HTT
gene UNIPROT SLC6A4
gene UNIPROT RXFP2
drug DRUGBANK Zinc
gene UNIPROT ZHX1-C8orf768q24.13

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