Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease

Prolyl oligopeptidase inhibition reduces PolyQ aggregation and improves cell viability in cellular model of Huntington’s disease

“…Recently, great interests have been devoted to the possibility to reduce mHtt burden by lowering the expression levels of mHtt using DNA‐ or RNA‐targeted therapies. However, these approaches are in their infancy and may bear risks related to complete loss of Htt that may have toxic effects …”

One decade ago, one decade ahead in huntington's disease

“…Owing to concerns that “silencing” might be taken as implying reduction of huntingtin production to zero, the preferred term now is “huntingtin lowering.” Some of these approaches—those delivered by transfecting viruses—are also gene therapies because they produce permanent alterations to the genome of the recipient. We do not want to completely silence huntingtin, and even if we did, it would be impossible to do so using any method currently being developed for patient use …”

“…Looking farther ahead, it is conceivable that the coming decade will see gene‐editing techniques, currently exemplified by CRISPR‐Cas9, being employed to deactivate or even correct the causative mutation in human carriers. So far, such tools have been deployed as a therapeutic strategy in HD animal models and of course are increasingly used to accelerate the process of creating novel genetic variants of model systems for experimental use …”

Regulated control of gene therapies with a drug induced switch

“…The editing enzymes are foreign proteins and may induce immune responses, and prolonged gene expression would increase opportunities for off-target editing 15,16 . We tested the utility of the X on system to regulate editing, using huntingtin (HTT), a target for gene silencing approaches for Huntington's disease (HD) 17 , as an example.…”