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Worldwide people are being diagnosed with the severe, but relatively rare, neurodegenerative disease called Huntington’s disease, at a prevalence of approximately 2.7 individuals per 100,0001. Huntington’s disease is a hereditary disease with debilitating symptoms, that typically manifests in early adulthood, and progresses with age. All individuals diagnosed with Huntington’s disease have inherited at least one copy of the mutant huntingtin (HTT) gene. The disease negatively impacts motor, psychiatric and cognitive function, until the individual is unable to perform simple tasks2.
To date, there are no disease-modifying interventions available to prevent the severe disease progression. Current FDA approved treatments for Huntington’s disease simply act to alleviate one aspect of the clinical profile, and are therefore limited to a symptomatic treatment of the disease. The vesicular monoamine transport (VMAT) inhibitors, Tetrabenazine and Deutetrabenazine, are the active ingredients of FDA approved treatments for the most common motor symptom, chorea, a form of dyskinesia characterized by involuntary jerky movements. Mood stabilizers including antidepressants, such as Fluoxetine and atypical antipsychotics, such as Risperidone, are also commonly prescribed to Huntington’s disease patients.
Although the HTT gene is ubiquitously expressed, the clinical profile of Huntington’s disease reflects the selective vulnerability of mutant HTT (mHTT) in a brain pathway known as the basal ganglia circuit. A class of striatal GABAergic neurons, termed medium spiny neurons (MSNs), are a major component of the circuit. MSNs are one of the earliest cells to succumb to the mHTT-induced cellular stress and undergo apoptosis, closely followed by cortical glutamatergic projection neurons3. Striatal and cortical atrophy is a major hallmark of Huntington’s disease, along with mHTT RNA and protein aggregates, which form RNA foci and inclusion bodies respectively in the cell2.
The mHTT gene differs from the healthy allele in that there is an unstable repeat expansion of a three nucleotide sequence, CAG, within exon 1 the mutant form; this nucleotide sequence is known as a microsatellite. If the microsatellite repeat expansion reaches above the tolerated threshold of 35 CAG repeats, the gene now encodes for a mutant transcript and protein2. On transcription of the mHTT gene, the resulting messenger RNA (mRNA) and protein can each form an abnormal tertiary structure due to their poly-CAG and poly-glutamine tract, respectively. The aberrant HTT mRNA and protein cause cellular stress by dysregulating transcription and translation, inducing mitochondrial impairment and disrupting nuclear-cytoplasmic transport4,5,6. Furthermore, the loss of normal HTT function further aggravates the cellular pathology, as evidenced by individuals homozygous for the mutant allele developing a more severe disease progression7. Ultimately, over time the cellular stress becomes too great, and the cell undergoes apoptosis.
The clinical profile of patients with Huntington’s disease is highly variable, even among individuals with the same number of CAG repeats. This inter-individual heterogeneity, independent of mHTT, led to the search for risk genes beyond HTT8. Through large cohort genome-wide association studies (GWAS), specific single-nucleotide polymorphisms (SNP) in DNA repair genes were identified as significant influencers on both the age of onset and severity/speed of disease progression8.9. The robustness of this discovery has further been supported by research in patient-derived induced pluripotent stem cell (iPSC) and rodent models 10,11,12.
Somatic instability is a phenomenon in which the expanded region of CAG repeats in the mHTT gene expands still further with time, as a result of faulty DNA repair. During DNA replication and transcription, regions of repetitive DNA sequences, in this case CAG repeats, can fold onto themselves to form short DNA hairpin/loop structures called “slipped DNA”. The mismatch repair proteins recognize the mismatched slipped DNA sequence, but during the repair reaction, the loops become incorporated into the gene sequence. Every time this erroneous mismatch repair occurs in cells, the CAG repeat region grows further13. As the process occurs in somatic cells, the term somatic instability was coined. The activity of specific DNA repair proteins are known to influence the rate of somatic instability. The higher the rate of somatic instability the faster the disease progression in model systems11. Furthermore, somatic instability rates are cell type-dependent, with MSN neurons showing one of the highest rates of somatic instability. This in part explains the selective vulnerability of MSN in Huntington’s disease.
Slowing or stopping somatic instability could significantly mitigate disease progression, and provide a much sought after disease-modifying therapy. The DNA damage repair proteins are therefore of interest as novel druggable targets in Huntington’s disease14. Worthy of note is the protective action of the nuclease FAN1 against the erroneous repairs generated by the MSH3/MSH2 complex, MutSβ, recently reported by Goold et al.11. Research is under way within the pharma industry to develop small molecules to modulate these mismatch repair proteins, but at the time of writing none are yet available. In addition, histone deacetylases (HDAC) inhibitors have been reported to reduce somatic instability in research models, with the first HDAC6 inhibitor developed in this context, CKD 504 from South Korean Pharma company Chong Kun Dang, reaching phase I clinical trials in 2018. Moreover, initial reports from in vitro Huntington’s disease models would support further investigation into the use of topoisomerase 1 and tyrosyl-DNA phosphodiesterase inhibitors to slow CAG repeat expansion rates. Topoisomerase inhibitors have already reached the clinic in combination therapies in oncology, but their efficacy and tolerance in Huntington’s disease require further research12.
Figure 1: Schematic summarizing CAG repeat expansion and instability in the mHTT gene and a potential therapeutic approach by targeting the DNA repair machinery. Adapted from Nakamori and Mochizuki (2021) Targeting expanded repeats by small molecules in repeat expansion disorders. Mov. Disord. 36 298.
There are around 50 known inherited diseases caused by trinucleotide repeat expansions and Huntington’s disease is one of at least nine CAG repeat disorders15. Although these diseases range from those impacting muscular integrity (myotonic dystrophy), motor control (amyotrophic lateral sclerosis) and cognition (Fragile X Syndrome), somatic instability is a shared feature of all. Research tools in this area could significantly impact the field, and bring us closer to a common disease-modifying therapy.