DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder

Figures

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  Fig. 1. Main genetic, clinical, neuroimaging and neuropathological features of DRPLA. a Illustration of location of the trinucleotide repeat within the gene—In DRPLA, the CAG trinucleotide repeat expansion occurs in coding exon 5 of the atrophin-1 (ATN1) gene, which is located on chromosome 12p13.31. Normal alleles in the ATN1 gene have 6–35 CAG repeats. ≥ 20 repeats are considered normal mutable alleles that expand on transmission and result in symptoms in the next generation, and ≥ 48 repeats demonstrate fully penetrant clinical phenotype. The unstable CAG repeat sequence causes a polyglutamine (polyQ) expansion in the atrophin-1 protein [13, 25, 44, 55, 60, 68, 94]. b Clinical features—The primary clinical features of DRPLA are ataxia and cognitive impairment, however, the age of onset affects the clinical presentation, with different symptoms observed between adult-onset and juvenile-onset DRPLA (Wardle et al. [98]; [34, 48, 55]. c Neuroimaging findings—[47, 106]. d Neuropathological findings—[36, 84, 106, 107]

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  Fig. 2. Estimated number of reported cases of DRPLA based on a literature search. a World map with dots corresponding to the number of reported cases of DRPLA, as per studies shown in (b). b Table of DRPLA families/cases found outside of Japan as reported in literature. DRPLA literature search for studies written in English published between January 1945 and July 2020 was performed on PubMed and Scopus databases, using the following key words: DRPLA; dentatorubral–pallidoluysian atrophy; Naito-Oyanagi disease; Haw-River syndrome; or ataxia. Cases for Thailand and Germany based on personal communication

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  Fig. 3. Normal process of protein synthesis and common mechanisms of ASOs on target RNA. Normal process of protein synthesis (left): DNA is transcribed to pre-messenger RNA (pre-mRNA), which contains coding (exon) and non-coding (intron) regions between 5′ and 3′ untranslated regions (UTR). Pre-mRNA undergoes post-transcriptional modifications into mature mRNA, including 5′ capping, removal of introns (splicing), and polyadenylation (poly-A tail). The mature mRNA undergoes ribosome-dependent protein synthesis. Mechanisms of ASOs on target RNA (right): Splicing modulation—ASO binds to pre-mRNA intron/exon junctions and modulate splicing to include or skip the target exon, resulting in the synthesis of a modified protein. Translation inhibition—ASO binds to the mRNA and sterically blocks and prevents the binding of ribosomes to the mRNA, inhibiting translation and resulting in reduced protein synthesis. RNase H-mediated degradation of mRNA—ASO binds to the mRNA to form an RNA–DNA hybrid, allowing the recruitment of RNase H nuclease, inducing degradation of the target mRNA, resulting in reduced protein synthesis [22, 70, 73, 78, 102]. Diagram created on biorender.com

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  Fig. 4. Progress in the development of ASO therapies for repeat expansions associated with neurological disorders. Table shows stages in the research towards developing ASO therapies for neurological repeat expansion disorders. Information. Chr: chromosome; HD; Huntington’s disease; ALS: amyotrophic lateral sclerosis; SCA: spinocerebellar ataxia; DM1: myotonic dystrophy; SBMA: spinobulbar muscular atrophy

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  Fig. 5. Facilitating DRPLA therapeutic development through understanding of natural history and discovery of biomarkers. Natural history studies follow the course of a disease from prior to inception, through the presymptomatic and clinical stages, to the point it ends (the patient is either cured, chronically disabled or dead, without external intervention) [20]. International, collaborative clinical studies are paramount to the DRPLA drug discovery process by identifying milestones of the disease progression and facilitating the discovery of longitudinal or cross-sectional biomarkers to objectively track disease-related biological changes. The discovery of biomarkers is, in turn, essential for clinical trials. The figure showcases the process by which a clinical and biobank resource for DRPLA can be uncovered, through collaborative efforts. Several methods are used for biomarker discovery; in particular, ‘omics’ technologies contribute towards the rapid discovery and validation of biomarkers. Genomics allows the identification of gene mutations or polymorphisms; transcriptomics can identify changes in RNA; epigenetics can identify modified epigenetic mechanisms; metabolomics and…