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Review
. 2021;10(1):203-220.
doi: 10.3233/JHD-200421.

Drugging DNA Damage Repair Pathways for Trinucleotide Repeat Expansion Diseases

Caroline L Benn  1 , Karl R Gibson  2 , David S Reynolds  1
Affiliations
Review

Drugging DNA Damage Repair Pathways for Trinucleotide Repeat Expansion Diseases

Caroline L Benn et al. J Huntingtons Dis. 2021.

Abstract

DNA damage repair (DDR) mechanisms have been implicated in a number of neurodegenerative diseases (both genetically determined and sporadic). Consistent with this, recent genome-wide association studies in Huntington's disease (HD) and other trinucleotide repeat expansion diseases have highlighted genes involved in DDR mechanisms as modifiers for age of onset, rate of progression and somatic instability. At least some clinical genetic modifiers have been shown to have a role in modulating trinucleotide repeat expansion biology and could therefore provide new disease-modifying therapeutic targets. In this review, we focus on key considerations with respect to drug discovery and development using DDR mechanisms as a target for trinucleotide repeat expansion diseases. Six areas are covered with specific reference to DDR and HD: 1) Target identification and validation; 2) Candidate selection including therapeutic modality and delivery; 3) Target drug exposure with particular focus on blood-brain barrier penetration, engagement and expression of pharmacology; 4) Safety; 5) Preclinical models as predictors of therapeutic efficacy; 6) Clinical outcome measures including biomarkers.

Keywords: ATM; CAG repeat; Huntingtin (HTT); PARP; mismatch repair (MMR); polyglutamine (polyQ); somatic instability.

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Conflict of interest statement

CLB and DSR are employees of LoQus23 Therapeutics Ltd. KRG is an employee of Sandexis Medicinal Chemistry and employed as a chemistry consultant by LoQus23 Therapeutics.

Figures

Fig. 1
Fig. 1
Mechanisms of DNA damage and repair contributing to somatic and intergenerational expansion of the HTT CAG repeat is a critical aspect of HD pathophysiology. A) CAG repeats (grey boxes, 1 box = 4 CAG repeats; 20 CAG repeats shown) in normal HTT alleles are translated into a correctly folded protein (illustration from [117]) and are stable in cellular populations, represented below in schematic of striatal neurons (polyglutamine repeat lengths, assuming canonical allele configuration, are indicated in green circles). As the repeat sizes increase, there is increased propensity for somatic and/or intergenerational instability, with a notable bias toward expansion in a time- and tissue- dependent fashion; as represented by the second repeat schematic depicting intermediate alleles (grey and yellow boxes, 1 box = 4 CAG repeats; 32 CAG repeat shown). Disease associated repeat alleles (grey, yellow and red boxes, 1 box = 4 CAG repeats; 44 CAG repeats are shown) are translated into a protein that is incorrectly folded and accordingly has altered functionality. Importantly, the increased disease-associated repeats are more unstable at the DNA level which in turn increases the instability further, triggering additional pathophysiological sequelae including mis-splicing and premature truncation of the protein as a toxic N-terminal fragment (illustration from [118]). The overall mutational burden drastically increases over time; expansion in an individual cell is a stochastic event such that cells within a population may have vastly differing repeat lengths. This is illustrated in the schematic with impaired striatal neurons (polyglutamine repeat length numbers are in yellow/orange/red circles) ultimately progressing to toxicity and cell deaths (absence of cells within the population). Experimental data points to DDR pathways such as MMR as being critical for driving the repeat expansions. B) Summary of MMR pathway is illustrated as a sequence of steps where MutSβ is required for initial recognition of the mismatched DNA substrate (perhaps due to polymerase errors). MutSβ (MSH2 in red and MSH3 in orange) in turn mediates recruitment of additional factors including MutL heterodimers (blue) and other proteins including EXO1 (navy) and PCNA (green) to mediate the repair process. The detail of how this goes awry is unclear, but one mechanism could include MutL-mediated incision on the opposite strand of the additional CAG nucleotides [121] and subsequent gap-filling synthesis and ligation. Only a few proteins are shown for simplicity including LIG1 (pink), RPA (brown) and a polymerase (purple). Similarly, a gap of one trinucleotide repeat unit is shown here for simplicity. It is likely that this process occurs multiple times with single trinucleotide repeat unit “bubbles” which ultimately contributes to expansion of the repeats. Key: D in white circles = ADP; T in yellow circles = ATP.
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