Oligonucleotide therapeutic approaches for Huntington disease
Dinah W.Y. Sah, Neil Aronin
Dinah W.Y. Sah, Neil Aronin
Published February 1, 2011
Citation Information: J Clin Invest. 2011;121(2):500-507. https://doi.org/10.1172/JCI45130.
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Oligonucleotide therapeutic approaches for Huntington disease

Abstract

Huntington disease is an autosomal dominant neurodegenerative disorder caused by a toxic expansion in the CAG repeat region of the huntingtin gene. Oligonucleotide approaches based on RNAi and antisense oligonucleotides provide promising new therapeutic strategies for direct intervention through reduced production of the causative mutant protein. Allele-specific and simultaneous mutant and wild-type allele–lowering strategies are being pursued with local delivery to the brain, each with relative merits. Delivery remains a key challenge for translational success, especially with chronic therapy. The potential of disease-modifying oligonucleotide approaches for Huntington disease will be revealed as they progress into clinical trials.

Authors

Dinah W.Y. Sah, Neil Aronin

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Figure 1

Multiple pathogenic mechanisms of mutant huntingtin include loss of BDNF neurotrophic support for striatal neurons, impaired axonal transport, altered vesicle recycling, mitochondrial dysfunction, increased autophagy, protein aggregation, and transcriptional dysregulation.

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Multiple pathogenic mechanisms of mutant huntingtin include loss of BDNF...
No single aberrant effect of mutant huntingtin explains neuronal dysfunction and early death. Mutant huntingtin disrupts the transcriptional activation of BDNF expression, thereby reducing BDNF delivery from cortex to striatum. Striatal neurons depend on BDNF to maintain their health (21, 22). Huntingtin has been known to associate with vesicles (34). Mutant huntingtin impairs endosomal recycling (39), thereby reducing uptake of transferrin receptor and EAAC1, probably among other recycled receptors (39, 40). Loss of cysteine (EAAC1 recycling defect) decreases glutathione and increases reactive oxygen species (40). Mutant huntingtin is associated with impaired axonal trafficking (37) and loss of BDNF delivery from the cortical to striatal neurons (36). Mitochondria defects (107) are well described, but it is unclear whether these are early events. A role in HD pathogenesis of protein aggregation in nuclear inclusions or cytoplasmic aggregates (48) is not established. Cell death can occur without generation of mutant huntingtin aggregation (108), and aggregates might be protective (109). Interference with HDAC efficiency has led to the idea that HDAC inhibition can counter a harmful effect of mutant huntingtin (110). Autophagy clears mutant huntingtin associated with organelles; an increase in autophagy might have therapeutic value (111). A recent review details these and other postulated molecular mechanisms in HD (15).