Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities

Abstract

Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.

Figure 1. Diagram of Huntington’s disease pathogenesis and possible therapeutic targets

Gray boxes with red border indicate potential therapies. ASO=antisense oligonucleotide. BDNF=brain-derived neurotrophic factor. ER=endoplasmic reticulum. LUBAC=linear ubiquitin chain assembly complex. mHTT=mutant Huntingtin. NMDA=N-methyl-D-aspartate. RNAi=RNA interference. TrkB=tyrosine receptor kinase B. ZFP=Zinc-finger protein. Adapted from Bates et al (2015) with permission

Figure 2. Production of huntingtin protein (HTT) and HTT-lowering therapeutic approaches

Red sections of the DNA, RNA and protein represent the pathogenic CAG tract and the polyglutamine product. Yellow boxes indicate therapeutic approaches. Dotted arrows indicate proposed mechanisms for the production of alternative toxic species. Different ASO colours indicate different mechanisms of action (black, RNAse H mediated degradation; blue, translational arrest). ASO=antisense oligonucleotide. mHTT=mutant huntingtin protein. PROTACS=proteolysis-targeting chimera. RAN=repeat-associated non-ATG. RNase H=Ribonuclease H. RISC=RNA-induced silencing complex. wtHTT=wild-type huntingtin protein. ZFP=zinc-finger protein. Adapted from Wild and Tabrizi (2017) with permission

Figure 3. Mechanism of action of a huntingtin lowering splicing modulator small molecule

Splicing of the human HTT gene at the exon 49-50 region in the absence (upper panel) or presence (lower panel) of branaplam, a small molecule splicing modulator. Branaplam recognizes a preferred sequence motif in the intron between exon 49 and 50, defining it as an exon. Inclusion of this pseudoexon introduces in-frame stop codons in the mature HTT transcript leading to downregulation of HTT mRNA and protein.

Figure 4. The role of DNA repair in repeat expansion, and its new therapeutic targets.

Left: MutSβ initiates mismatch repair at a CAG loopout, introducing repeat expansion (turquoise). Right: FAN1 protects against repeat expansion through a mechanism that depends on its nuclease activity and binding to MLH1. MSH3 inhibition (top left), e.g., by knockdown or ATPase inhibition, is expected to slow repeat expansion and be well tolerated. Red lines = CAG repeat DNA containing a loopout. Red boxes = repair proteins promoting repeat expansion. Green boxes = protect against expansion. Black ribbon = genes whose loss of function in is associated with cancer in humans.