Huntingtin lowering therapies targeting RNA in Huntington’s Disease

Abstract

Huntington’s disease is characterized by a progressive deterioration of motor, behavioural and cognitive functioning. The disease is a dominantly autosomal inheritable neurodegenerative disease caused by a genetic mutation in the DNA encoding for the huntingtin protein. An extended CAG repeat in the huntingtin gene causes a gain of toxic properties of the huntingtin protein. Various cellular mechanisms do not function adequately, thereby progressively worsening the performance of multiple cellular pathways. Various animal studies have shown an therapeutic effectiveness of lowering mutant huntingtin levels, resulting in reduced downstream pathogenic effects. Reducing synthesis of mutant huntingtin can be achieved by targeting huntingtin RNA at a post-transcriptional level. Being close to the proximal cause of Huntington’s disease, together with the current ongoing human trials, makes RNA targeting currently the most relevant method for therapies applicable in the near future. Huntington’s disease patients express the mutant huntingtin as well as the wild-type huntingtin protein. Huntingtin lowering therapies can be designed in two specific ways. Firstly, the allele-selective approach, specifically targeting the mutant huntingtin. The second is in an non-allele specific manner, targeting both the mutant huntingtin and the wild-type huntingtin. The non-allele specific manner raises theoretical risks concerning normal cellular functioning after reduction of wild-type huntingtin levels, but has less limitations for effective targeting of mutant huntingtin RNA. Several reports suggest that lowering both mutant huntingtin and wild-type huntingtin is tolerable up to a certain range, resulting in an overall beneficial effect for Huntington’s disease patients. The methods that are efficient in modulating the translation at a post-transcriptional level, either allele selective or non-selective, include antisense oligonucleotides, RNA interference and small molecule modulators. The sequence specific targeting of antisense oligonucleotides allow for specific targeting of mutant huntingtin at pre-RNA level. Repeated intrathecal injection are required for a maintained therapeutic effect. Advantages of antisense oligonucleotides consist of relatively low invasive administration, ability for discontinuation of treatment and broader target range at the pre-RNA level. Disadvantages include need for multiple administrations and inability to spread to deeper brain structures. RNA interference targets RNA at a more downstream location compared to antisense oligonucleotide, reducing the range of possible targets in the processed RNA. RNA interference therapies are most commonly delivered using a viral vector after direct administration into deeper brain structures. Viral vector delivery enables a one time administration of the therapy, but posses a risk due to the inability to discontinue the treatment. The local delivery to the highly effected deeper brain regions could posses a major advantage. The oral availability and widespread action of small molecules make them an attractive approach, however a greater risks of possible off target effect is present. The advanced development and seemingly positive risk-benefit profile indicate that therapies targeting RNA for huntingtin lowering have great potential to be therapeutically beneficial for patients in the near future.