Assessing average somatic CAG repeat instability at the protein level

Aviolat, Hubert; Pinto, Ricardo Mouro; Godschall, Elizabeth; Murtha, Ryan; Richey, Hannah E.; Sapp, Ellen; Vodička, Petr; Wheeler, Vanessa C.; Kegel-Gleason, Kimberly B.; DiFiglia, Marian

doi:10.1038/s41598-019-55202-x

Cited by 21 publications

(18 citation statements)

References 66 publications

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“…Another potentially important biomarker for DRPLA disease progression and severity, which may also act as a potential therapeutic target, is repeat expansion somatic instability. This has been observed in HD mouse models and human brain tissue; it is worth exploring as a prominent biomarker for DRPLA and other repeat expansion disorders [ 3 , 24 , 85 ]. In addition to being clinically beneficial in regard to improving diagnostic accuracy and monitoring disease progression, biological biomarkers for DRPLA would also be influential in research.…”

Section: Global Burdenmentioning

confidence: 99%

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

Chaudhry

Anthanasiou-Fragkouli

Houlden

2020

J Neurol

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Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion. There are currently no disease-modifying treatments available. The broad development of therapies for DRPLA, as well as other similar rare diseases, has hit a roadblock due to the rarity of the condition and the wide global distribution of patients and families, consequently inhibiting biomarker development and therapeutic research. Considering the shifting focus towards diverse populations, widespread genetic testing, rapid advancements in the development of clinical and wet biomarkers for Huntington’s disease (HD), and the ongoing clinical trials for antisense oligonucleotide (ASO) therapies, the prospect of developing effective treatments in rare disorders has completely changed. The awareness of the HD ASO program has prompted global collaboration for rare disorders in natural history studies and the development of biomarkers, with the eventual goal of undergoing treatment trials. Here, we discuss DRPLA, which shares similarities with HD, and how in this and other repeat expansion disorders, neurogenetics groups like ours at UCL are gearing up for forthcoming natural history studies to accelerate future ASO treatment trials to hopefully emulate the progress seen in HD.

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Section: Global Burdenmentioning

confidence: 99%

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

Chaudhry

Anthanasiou-Fragkouli

Houlden

2020

J Neurol

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“…Given that the 2B7-MW1 signal increases with increasing polyQ length, a higher signal could correspond to more HTT, or to longer polyQ tracts, which mutant HTT proteins in CSF might contain. An attempt to resolve this problem used two MSD assays by which the equivalent of 2B7-MW1 was normalized to an assay that detected full-length HTT ( Aviolat et al , 2019 ). This detailed study provided a means of calculating the average polyQ length in a sample, but it is likely that full-length HTT assays would be subject to polyQ-length interference, which may then affect the interpretation of these results for very long polyQ tracts.…”

Section: Discussionmentioning

confidence: 99%

Development of novel bioassays to detect soluble and aggregated Huntingtin proteins on three technology platforms

Landles

Milton

Alexandre

et al. 2021

Brain Communications

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Huntington’s disease is caused by a CAG/polyglutamine repeat expansion. Mutated CAG repeats undergo somatic instability, resulting in tracts of several hundred CAGs in the brain; and genetic modifiers of Huntington’s disease have indicated that somatic instability is a major driver of age of onset and disease progression. As the CAG repeat expands, the likelihood that exon 1 does not splice to exon 2 increases, resulting in two transcripts that encode full-length HTT, as well as the highly pathogenic and aggregation-prone exon 1 HTT protein. Strategies that target the huntingtin gene or transcripts are a major focus of therapeutic development. It is essential that the levels of all isoforms of HTT can be tracked, to better understand molecular pathogenesis, and to assess the impact of HTT lowering approaches in preclinical studies and clinical trials. HTT bioassays for soluble and aggregated forms of HTT are in widespread use on the homogeneous time-resolved fluorescence and Meso Scale Discovery platforms, but these do not distinguish between exon 1 HTT and full-length HTT. In addition, they are frequently used to quantify HTT levels in the context of highly expanded polyglutamine tracts, for which appropriate protein standards do not currently exist. Here, we set out to develop novel HTT bioassays to ensure that all soluble HTT isoforms could be distinguished. We utilised the zQ175 Huntington’s disease mouse model that has approximately 190 CAGs, a CAG repeat size for which protein standards are not available. Initially, 30 combinations of six antibodies were tested on three technology platforms: homogeneous time-resolved fluorescence, amplified luminescent proximity homogeneous assay and Meso Scale Discovery, and a triage strategy was employed to select the best assays. We found that, without a polyQ-length matched standard, the vast majority of soluble mutant HTT assays cannot be used for quantitative purposes, as the highly expanded polyQ tract decreased assay performance. The combination of our novel assays, with those already in existence, provides a tool-kit to track: total soluble mutant HTT, soluble exon 1 HTT, soluble mutant HTT (excluding the exon 1 HTT protein) and total soluble full-length HTT (mutant and wild-type). Several novel aggregation assays were also developed that track with disease progression. These selected assays can be used to compare levels of HTT isoforms in a wide variety of mouse models of Huntington’s disease and to determine how these change in response to genetic or therapeutic manipulations.

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“…The clinical trial with buspirone to treat apathy had a negative result (16). Currently, dextromethorphan/quinidine and SRX46, a vasopressin 1A receptor antagonist, are being assessed for irritability (12), while psychiatric symptoms are treated based on expert consensus 1 . Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) are recommended for both depression and anxiety, while irritability is managed by sedative antidepressants, antipsychotics, or mood stabilizers.…”

Section: Treatment Approaches Of Hdmentioning

confidence: 99%

“…Cariprazine (CAR) is a third-generation antipsychotic approved for the treatment of schizophrenia as well as for the depressive and manic and mixed episodes associated with bipolar I disorder in adult patients 3 . Furthermore, two studies had positive results for the adjunctive treatment of major depression disorder (MDD) 1 . Cariprazine is a dopamine D3 receptor preferring partial agonist at the D2/D3 receptors as well as at the serotonin 5-HT1A receptors, and acts as an antagonist at the 5-HT2B receptors (18).…”

Section: Cariprazinementioning

confidence: 99%

Improving Mood and Cognitive Symptoms in Huntington's Disease With Cariprazine Treatment

Molnár

Fedor

et al. 2022

Front. Psychiatry

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In Huntington's disease (HD), the main clinical symptoms include depression, apathy, cognitive deficits, motor deficiencies and involuntary movements. Cognitive, mood and behavioral changes may precede motor symptoms by up to 15 years. The treatment of these diverse symptoms is challenging. Tetrabenazine and deutetrabenazine are the only medications specifically approved for Huntington's chorea, but they do not affect the non-motor symptoms. For these, antidepressants, antipsychotics, and benzodiazepines have demonstrated benefit in some cases and can be used off-label. These drugs, due to sedative side effects, may negatively influence cognition. Sixteen patients having HD received a 12-week off-label cariprazine (CAR) treatment (1.5–3 mg/day). Cognitive performance and behavioral changes were measured by the Addenbrooke Cognitive Examination (ACE) test, the Cognitive and Behavioral part of the Unified Huntington's Disease Rating Scale (UHDRS), and the Beck Depression Inventory (BDI). Mixed model for repeated measures was fitted to the data, with terms of visit, baseline (BL) and their interaction. Cariprazine treatment resulted in the following changes from BL to week 12, respectively: the mean score of BDI decreased from 17.7 ± 10.7 to 10.0 ± 10.7 (p <0.0097), while the Behavioral Assessment score of the UHDRS decreased from 54.9 ± 11.3 to 32.5 ± 15.4 (p < 0.0001); ACE score increased from 75.1 ± 11.0 to 89.0 ± 9.3 (p < 0.0001); Cognitive Verbal Fluency score from 6.2 ± 2.5 to 7.7 ± 2.7 (p < 0.0103); Symbol Digit Test from 9.2 ± 6.9 to 12.3 ± 8.9 (p < 0.0009). Mild akathisia was the most frequent side effect, presenting in 2 out of 16 patients (12.5%). We conclude that CAR had a positive effect on depressive mood, apathy and cognitive functions in patients with early stage of HD. Based on the neurobiological basis of these symptoms, CAR can improve the dopamine imbalance of the prefrontal cortex. This draws attention to the transdiagnostic approach which supports the further understanding of the similar symptomatology of different neuropsychiatric disorders and helps to identify new indications of pharmaceutical compounds.

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Assessing average somatic CAG repeat instability at the protein level

Cited by 21 publications

References 66 publications

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

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

Development of novel bioassays to detect soluble and aggregated Huntingtin proteins on three technology platforms

Improving Mood and Cognitive Symptoms in Huntington's Disease With Cariprazine Treatment

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