Therapeutic strategies for Huntington’s disease.

Therapeutic strategies for Huntington’s disease.

Publication date: Aug 01, 2020

Huntington’s disease is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HTT gene, and current therapies focus on symptomatic treatment. This review explores therapeutic approaches that directly target the pathogenic mutation, disrupt HTT mRNA or its translation.

Zinc-finger transcription repressors and CRISPR-Cas9 therapies target HTT DNA, thereby preventing all downstream pathogenic mechanisms. These therapies, together with RNA interference (RNAi), require intraparenchymal delivery to the brain in viral vectors, with only a single delivery potentially required, though they may carry the risk of irreversible side-effects.Along with RNAi, antisense oligonucleotides (ASOs) target mRNA, but are delivered periodically and intrathecally. ASOs have safely decreased mutant huntingtin protein (mHTT) levels in the central nervous system of patients, and a phase 3 clinical trial is currently underway.Finally, orally available small molecules, acting on splicing or posttranslational modification, have recently been shown to decrease mHTT in animal models.

Huntingtin-lowering approaches act upstream of pathogenic mechanisms and therefore have a high a priori likelihood of modifying disease course. ASOs are already in late-stage clinical development, whereas other strategies are progressing rapidly toward human studies.

Concepts Keywords
Antisense HTT
ASOs Neurodegeneration
Autosomal Dominant RNA interference
Brain Huntington’s disease
Cas9 RNA
Central Nervous System Gene expression
Clinical Trial Huntingtin
CRISPR Branches of biology
DNA
Gene
Huntingtin
Huntington
Intrathecally
MRNA
Mutant
Mutation
Neurodegenerative Disorder
Oligonucleotides
Pathogenic
Posttranslational Modification
Repressors
RNAi
Splicing
Symptomatic Treatment
Transcription
Viral Vectors
Zinc Finger

Semantics

Type Source Name
drug DRUGBANK Zinc
pathway REACTOME Translation
disease MESH neurodegenerative disorder
disease MESH development

Original Article

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