Spinocerebellar ataxia clinical trials: opportunities and challenges

Brooker, Sarah M.; Edamakanti, Chandrakanth Reddy; Akasha, Sara M.; Kuo, Sheng Han; Opal, Puneet

doi:10.1002/acn3.51370

Cited by 40 publications

(45 citation statements)

References 146 publications

(350 reference statements)

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“…The observed plasma NfL levels in individuals with Wolfram syndrome overlap with similar-aged, untreated children with pediatric MS ( Reinert et al, 2020 ) and appear similar to those in people with asymptomatic spinocerebellar ataxia type 3 [median (IQR) NfL = 12.2 (10.2–13.9) pg/mL] ( Peng et al, 2020 ). The latter disease, like Wolfram syndrome, is caused by a genetic mutation with variable expressivity, rate of progression, age of onset, and phenotype, and is accompanied by cerebellar and brainstem atrophy ( Brooker et al, 2021 ). The plasma NfL levels observed here in Wolfram syndrome also overlap with those obtained from older (mean age = 57.4 years) individuals with type 1 diabetes [mean (SD) plasma NfL = 13.3 (6.7) pg/mL].…”

Section: Discussionmentioning

confidence: 99%

Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome

et al. 2022

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Wolfram syndrome is a rare disease caused by pathogenic variants in the WFS1 gene with progressive neurodegeneration. As an easily accessible biomarker of progression of neurodegeneration has not yet been found, accurate tracking of the neurodegenerative process over time requires assessment by costly and time-consuming clinical measures and brain magnetic resonance imaging (MRI). A blood-based measure of neurodegeneration, neurofilament light chain (NfL), is relatively inexpensive and can be repeatedly measured at remote sites, standardized, and measured in individuals with MRI contraindications. To determine whether NfL levels may be of use in disease monitoring and reflect disease activity in Wolfram syndrome, plasma NfL levels were compared between children and young adults with Wolfram syndrome (n = 38) and controls composed of their siblings and parents (n = 35) and related to clinical severity and selected brain region volumes within the Wolfram group. NfL levels were higher in the Wolfram group [median (interquartile range) NfL = 11.3 (7.8–13.9) pg/mL] relative to controls [5.6 (4.5–7.4) pg/mL]. Within the Wolfram group, higher NfL levels related to worse visual acuity, color vision and smell identification, smaller brainstem and thalamic volumes, and faster annual rate of decrease in thalamic volume over time. Our findings suggest that plasma NfL levels can be a powerful tool to non-invasively assess underlying neurodegenerative processes in children, adolescents and young adults with Wolfram syndrome.

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Section: Discussionmentioning

confidence: 99%

Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome

et al. 2022

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“…Clinician-performed ataxia rating scales are currently used for assessments in A-T and other ataxias, including the Brief Ataxia Rating Scale (BARS) [ 7 ] and the Scale for the Assessment and Rating of Ataxia (SARA) [ 8 ]. Subjectivity and imprecision in these scales necessitate large and long trials, which increase costs, place significant burden on patients, and are a barrier for successful drug development [ 9 , 10 ]. These scales have additional limitations in pediatric populations; in particular, they are not suitable for children under the age of 4 and demonstrate age dependence in healthy individuals up until 10–12 years of age [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Real-life Wrist Movement Patterns Capture Motor Impairment in Individuals with Ataxia-Telangiectasia

et al. 2022

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Sensitive motor outcome measures are needed to efficiently evaluate novel therapies for neurodegenerative diseases. Devices that can passively collect movement data in the home setting can provide continuous and ecologically valid measures of motor function. We tested the hypothesis that movement patterns extracted from continuous wrist accelerometer data capture motor impairment and disease progression in ataxia-telangiectasia. One week of continuous wrist accelerometer data were collected from 31 individuals with ataxia-telangiectasia and 27 controls aged 2–20 years old. Longitudinal wrist sensor data were collected in 14 ataxia-telangiectasia participants and 13 controls. A novel algorithm was developed to extract wrist submovements from the velocity time series. Wrist sensor features were compared with caregiver-reported motor function on the Caregiver Priorities and Child Health Index of Life with Disabilities survey and ataxia severity on the neurologist-performed Brief Ataxia Rating Scale. Submovements became smaller, slower, and less variable in ataxia-telangiectasia compared to controls. High-frequency oscillations in submovements were increased, and more variable and low-frequency oscillations were decreased and less variable in ataxia-telangiectasia. Wrist movement features correlated strongly with ataxia severity and caregiver-reported function, demonstrated high reliability, and showed significant progression over a 1-year interval. These results show that passive wrist sensor data produces interpretable and reliable measures that are sensitive to disease change, supporting their potential as ecologically valid motor biomarkers. The ability to obtain these measures from a low-cost sensor that is ubiquitous in smartwatches could help facilitate neurological care and participation in research regardless of geography and socioeconomic status. Supplementary Information The online version contains supplementary material available at 10.1007/s12311-022-01385-5.

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“…Only a few symptomatic therapies for improving a patient's quality of life are available. 16 For example, amantadine can improve dystonia and bradykinesia in SCA3. 17 Periodic leg movements are responsive to dopaminergic treatment in SCA2 and SCA3, whereas muscle cramps are improved in both disorders with B-complex vitamins and magnesium, respectively.…”

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confidence: 99%

“…Moreover, drugs that target other downstream pathogenic mechanisms, such as calcium signaling stabilizers, antioxidant drugs, antiglutamatergic agents, and histone deacetylase inhibitors, are being studied. 5,16 Undoubtedly, the most promising treatments against PolyQ ataxias are those that target the central pathological mechanisms at early stages of neurodegeneration. In this scenario, gene therapy approaches seem to be hopeful alternatives.…”

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confidence: 99%

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Gene Therapy for Polyglutamine Spinocerebellar Ataxias: Advances, Challenges, and Perspectives

et al. 2021

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A BS TRACT: Polyglutamine spinocerebellar ataxias (SCAs) comprise a heterogeneous group of six autosomal dominant ataxias caused by cytosine-adenineguanine repeat expansions in the coding region of single genes. Currently, there is no curative or disease-slowing treatment for these disorders, but their monogenic inheritance has informed rationales for development of gene therapy strategies. In fact, RNA interference strategies have shown promising findings in cellular and/or animal models of SCA1, SCA3, SCA6, and SCA7. In addition, antisense oligonucleotide therapy has provided encouraging proofs of concept in models of SCA1, SCA2, SCA3, and SCA7, but they have not yet progressed to clinical trials. On the contrary, the gene editing strategies, such as the clustered regularly interspaced short palindromic repeat (CRISPR/Cas9), have been introduced to a limited extent in these disorders. In this article, we review the available literature about gene therapy in polyglutamine SCAs and discuss the main technological and ethical challenges toward the prospect of their use in future clinical trials. Although antisense oligonucleotide therapies are further along the path to clinical phases, the recent failure of three clinical trials in Huntington's disease may delay their utilization for polyglutamine SCAs, but they offer lessons that could optimize the likelihood of success in potential future clinical studies.

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Spinocerebellar ataxia clinical trials: opportunities and challenges

Cited by 40 publications

References 146 publications

Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome

Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome

Real-life Wrist Movement Patterns Capture Motor Impairment in Individuals with Ataxia-Telangiectasia

Gene Therapy for Polyglutamine Spinocerebellar Ataxias: Advances, Challenges, and Perspectives

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