Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 1, 2024

Abstract Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up 75% of such patients remain without diagnosis. In an era emerging disease‐modifying gene‐stratified therapies, the identification causative alleles has become increasingly important. Over past few years, implementation advanced bioinformatics tools long‐read sequencing allowed number novel repeat expansion disorders, as recently described spinocerebellar ataxia 27B (SCA27B) caused by (GAA)•(TTC) intron 1 fibroblast growth factor 14 ( FGF14 ) gene. SCA27B is rapidly gaining recognition one most common forms adult‐onset hereditary ataxia, with several studies showing that it accounts for substantial (9–61%) previously undiagnosed cases from different cohorts. First natural history multiple reports have already outlined progression core phenotype this disease, which consists late‐onset slowly progressive pan‐cerebellar syndrome frequently associated cerebellar oculomotor signs, downbeat nystagmus, episodic symptoms. Furthermore, preliminary shown promising symptomatic benefits 4‐aminopyridine, marketed drug. This review describes current knowledge molecular basis, epidemiology, features prospective treatment strategies SCA27B.

Language: Английский

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Functional brain networks in the evaluation of patients with neurodegenerative disorders

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 19(2), P. 73 - 90

Published: Dec. 20, 2022

Language: Английский

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The inherited cerebellar ataxias: an update

Journal of Neurology, Journal Year: 2022, Volume and Issue: 270(1), P. 208 - 222

Published: Sept. 24, 2022

Language: Английский

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Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective

Movement Disorders, Journal Year: 2022, Volume and Issue: 37(6), P. 1125 - 1130

Published: April 27, 2022

Ataxias, in particular if of genetic origin, have long been considered untreatable. They are now becoming models for the development targeted molecular therapies due to their defined etiology. The current decade will thus translate advance genomics ataxias, which has allowed unraveling almost 50 autosomal dominant spinocerebellar ataxias (SCAs) and more than 100 recessive ataxia (ARCA) genes, into therapy approaches based on underlying gene mutations derived mechanisms.1-3 most advanced them cross threshold clinical trials, raising hopes availability effective treatments specific within next years. To facilitate a worldwide research platform, Ataxia Global Initiative (AGI), was recently established. Although small molecules had mainstay drug since beginning modern medicine, biomedical developed an arsenal macromolecules that complement small-molecule approach may be particularly suitable treatment diseases. These options further expanded by gene-based therapies.4 Currently, antisense oligonucleotides (ASOs) inducing cleavage RNA encoding presumably toxic disease proteins main focus ataxias. Such ASOs already underwent successful early-phase trials Huntington's superoxide dismutase 1 amyotrophic lateral sclerosis (SOD1 ALS).5, 6 However, subsequent phase 3 did not prove efficacy, but positive effect fluid biomarkers SOD1 ALS (https://investors.biogen.com/news-releases/news-release-details/biogen-announces-topline-results-tofersen-phase-3-study-and-its). In animal SCAs caused CAG repeat expansions, such proved effective, 1/2 polyglutamine imminent (ClinicalTrials.gov: NCT05160558).7, 8 modulate splicing promise even wider applications, including individualized single patients.9 interventions currently being telangiectasia optic atrophy 1, often associated with ataxia.9, 10 Another line is adeno-associated virus-based deliver interfering RNAs or microRNAs targeting genes coding proteins.11 Efficient delivery still presents major bottleneck application viral vectors. Distribution brain after intrathecal injection appears sufficient several ASO types, repeated injections burden patients.12 Gene vectors advantage single-dose application. many questions regarding vector design, immunogenicity, route application, distribution awaiting final anwers.13 manifold promising new way, number challenges stand way trials. include: (1) limited access existing data, (2) inappropriate sensitivity questionable patient relevance outcome assessments, (3) lack validated biomarkers, (4) absence trial infrastructure. address these timely manner we established AGI 2021 (https://ataxia-global-initiative.net/). platform formed individual members, academic industry-based researchers, investigators, clinicians, representatives organizations. 185 members from 29 countries. addition, partnering industry companies organizations (Fig. 1). achieve its goals, organizational structure consisting multistakeholder working groups trial-readiness services, Trial Site Registry Advisory Committee Therapy.14 provides information personnel, facilities, populations at participating sites around globe readily available, standardized fashion. Therapy allows preclinical plans evaluated international board preclinical, clinical, regulatory, industrial experts, as well representatives, aim de-risk 2). started collaboration Critical Path Institute resulting launch Therapeutics Ataxias (CPTA), data sharing driving toward regulatory acceptance biomarker outcomes (https://c-path.org/programs/cpta/). resources via website (https://ataxia-global-initiative.net), monthly newsletter (received 700 people), scientific conferences symposia specifically focused readiness. foster expertise young Young Investigator implement training curriculum regular webinar various methods measures, open participation all people interested research. provide about laypeople, can play important role, there representation both Steering membership AGI. partnership SCASource (https://scasource.net/), online multilingual disseminates news lay language.15 Reliable natural history key design. longitudinal cohort available (SCA1, SCA2, SCA3, SCA6) frequent ARCAs (Friedreich ataxia, ARSACS, SPG7, RFC1 disease),16-19 they missing large majority other ARCAs. Extensive efforts undertaken partners map ideal position serve exchanging data. this, developing procedures preparing templates help overcome related legal administrative hurdles. One ongoing initiative bring together coordinated CPTA. novel, in-depth rigorous studies needed robust trial-like first (Biomarkers Genetic Modifierers Pre Postsymptomatic SCA3/MJD, BIGPRO, Clinical Research Consortium Study Ataxia, CRC-SCA, European Spinocerebellar type 3/Machado Joseph Disease Initiative, ESMI, Integrated Multimodal Progression Chart Spastic PROSPAX, Readiness SCA1 READISCA, others), dedicated public funding needed, ideally positioned coordinate multicenter endeavors global scale. Both planning execution challenged between- within-center variability assessment. This includes literally domains, example, digital, imaging, this challenge, cross-center harmonized standard operating each domain, biomarker, magnetic resonance (MR) digital-motor complemented tools, Scale Assessment Rating (SARA) tool (https://ataxia-global-initiative.net/resources/sara-training-tool/), recorded webinars. Given relatively slow progression survival times exceeding 20 years onset,20 parameters need sufficiently sensitive change. SARA serves widely applied primary substantial intraindividual variability, reaching 20% entire scale range testing 14 days.21 Thus, sample size calculations come unanimous conclusion that, least year duration, hundreds participants would detect disease-slowing investigational drug.16, 22 There debate whether modified versions, Modified Functional used (https://clinicaltrials.gov/ct2/show/NCT03701399), higher sensitivity. A thorough analysis properties SARA, potential modification scale, careful validation possible versions some tasks Nevertheless, obvious follow strategies improve assessment go beyond scales hospital. capture body-worn sensors.23-25 Further improvement achieved shifting real life, either video (SARAhome) sensors, shown dramatically reduce calculated sizes.21, 25, 26 Standard show just neurological proxies functions, indeed reflect meaningful benefit patients' lives. challenge might alleviated correlating change patient-reported reflecting daily life impact closely, Friedreich Activity Daily Living scale,27 PROM-Ataxia,28 under partners, leveraging infrastructure close interaction organization, National Foundation UK. start project evaluation Patient Reported Outcome Measure (PROM-Ataxia) goal make languages, assess longitudinally setting, directly compare them. An alternative innovative novel establish patient-ranked order function respective functions ALS.29 For urgent efficacy patients before moving registration outcomes. blood concentrations neurofilament light chain, marker axonal injury,30, 31 gait-related sensor data,25 MR imaging regional volumes,32, 33 diffusion tensor imaging-derived measures,34 neurochemical abnormalities detected spectroscopy,35 candidates. future, preventive preataxic mutation carriers also realistic option. converted manifest could outcome, ATLAS (Adults With Confirmed Superoxide Dismutase Mutation) (https://clinicaltrials.gov/ct2/show/NCT04856982). approach, however, requires population enriched proximity conversion disease. stratifying results, because mentioned earlier showed increasing onset. same premanifest presence appropriate well-characterized, genetically stratified prerequisite readiness consortia running valuable done assist globally. end, reliable local infrastructures centers precise numbers trial-ready patients. Results recent neurodegenerative diseases, NURTURE study infants spinal muscular atrophy, suggest superior initiated early stages compared those later.36 fact highlights develop efficiently identify recruit subjects stages. seems programs systematically family-based recruitment relatives symptomatic index patients.37-39 must combined adequate support counseling. It difficult practice, Due inheritance, usually medical attendance only when symptoms mild moderate stage visit referral sites. observations highlight screening so far undiagnosed who belong group potentially treatable ARCAs, systematic genetic, phenotype, machine learning–, biomarker-based approaches. Successful exemplary domains developed, Niemann-Pick Type C ataxia,40 work supported Joint Programme Rare Diseases part PROSPAX consortium EJP RD COFUND-EJP 825575 (via Deutsche Forschungsgemeinschaft (German Foundation; M.S. B.B.) Grant 779257 "Solve-RD" Horizon 2020 innovation program (to H.G.). T.K., A.D., H.G., Reference Network Neurological (ERN-RD, 739510). Open enabled organized Projekt DEAL. T.K. received Bundesministerium für Bildung und Forschung (BMBF) Institutes Health (NIH). He consultancy honoraria Biogen, UCB, Vico Therapeutics. T.A. grants NIH (NS104326, NS124065, NS115002), Foundation, Myotonic Dystrophy Biohaven Pharmaceuticals. B.B. does report financial disclosures. R.C. paid employee Biogen. A.D. B.F. J.G. S.H. Foundation. L.B.J. Fundação de Apoio à Pesquisa do Rio Grande Sul (FAPERGS), Brazil Conselho Nacional Desenvolvimento Científico e Tecnológico (CNPq), Brazil. She Movement Disorders Society. H.J. supports Key Development Program China (Grant 2021YFA0805200) Natural Science 82171254). O.O. J.L.P. B.-W.S. D.S. H.G. Ionis Pharmaceuticals, Janssen Orphayzme unrelated manuscript. Thomas Klockgether, Holm Graessner, Matthis Synofzik conceived wrote Tetsuo Ashizawa, Bernard Brais, Rosalind Chuang, Alexandra Durr, Brent Fogel, Julie Greenfield, Sue Hagen, Laura Bannach Jardim, Hong Jiang, Osamu Onodera, José Luiz Pedroso, Bin-Weng Soong, David Szmulewicz were involved conception manuscript editing version. Members consortium, leads office, follows: Sirio Cocozza (Department Advanced Biomedical Sciences, University Naples "Federico II", Naples, Italy); Jennifer Faber Center Neurodegenerative [DZNE], Bonn, Germany; Department Neurology, Hospital Germany); Fogel (Departments Human Genetics Geffen School Medicine, California Los Angeles, CA, USA; Ian Harding Neuroscience, Central School, Monash University, Melbourne, Australia; Imaging, Australia); Pierre-Gilles Henry (Center Magnetic Resonance Research, Minnesota, MN, USA); Heike Jacobi Heidelberg, Francesca Maltecca (Neurogenomics Unit, Division IRCCS Ospedale San Raffaele, Milan, Mengel (Hertie Brain Tübingen, Andrea Nemeth (Nuffield Neurosciences, Oxford, United Kingdom; Oxford Centre Genomic Hospitals NHS Trust, Kingdom); Puneet Opal Northwestern Feinberg Chicago, IL, Gulin Oz Hélène Puccio (Institut Neuromyogène, Inserm, Lyon, France); Filippo Santorelli (Molecular Fondazione Stella Maris, Pisa, Andreas Traschütz (Division Translational Genomics Diseases, Neurology Hertie-Institute Adam Vogel (Centre Neuroscience Speech, Victoria, Stephan Zuchner (Dr. John T. Macdonald P. Hussman Genomics, Miami, Miller FL, Annemarie Post (Institute Medical Applied Birte Zurek Germany). viewpoint paper

Language: Английский

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Standards of NGS Data Sharing and Analysis in Ataxias: Recommendations by the NGS Working Group of the Ataxia Global Initiative

The Cerebellum, Journal Year: 2023, Volume and Issue: 23(2), P. 391 - 400

Published: March 4, 2023

Abstract The Ataxia Global Initiative (AGI) is a worldwide multi-stakeholder research platform to systematically enhance trial-readiness in degenerative ataxias. next-generation sequencing (NGS) working group of the AGI aims improve methods, platforms, and international standards for ataxia NGS analysis data sharing, ultimately allowing increase number genetically patients amenable natural history treatment trials. Despite extensive implementation clinical settings, diagnostic gap remains sizeable, as approximately 50% with hereditary remain undiagnosed. One current shortcoming fragmentation datasets on different platforms databases around world. collaboration associated platforms—CAGC, GENESIS, RD-Connect GPAP—provides clinicians scientists access user-friendly adaptable interfaces analyze genome-scale patient data. These also foster within community. efforts tools have led diagnosis > 500 discovery 30 novel genes. Here, presents their consensus recommendations sharing initiatives field, focusing harmonized variant standardized metadata collection, combined collaborative tool across platforms.

Language: Английский

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Transcriptomic analysis of repeat expansion-ataxias uncovers distinct non-neuronal cell type-specific signatures of disease across the human brain

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Abstract Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by the clinical syndrome progressive loss coordination from neurodegeneration cerebellum. A commonality across most prevalent is underlying disease mechanism secondary to expansions short tandem DNA repeats. There currently an incomplete understanding pathogenic mechanisms these repeat expansion disorders, core feature which revolves around RNA-dysregulation. In this study, we used both bulk and single nuclear RNA-sequencing study post-mortem brain tissue human donors with range repeat-expansion reveal further mechanistic insights. We compared paired cerebellar frontal cortex data 23 ataxia patients 22 sex-, age-matched controls two banks (spinocerebellar (SCA)1, SCA2, SCA6, SCA7, SCA17, Friedreich’s (FRDA), 7 cases unknown molecular diagnoses). analysed for transcript usage, differential cell-type-specific expression transcriptomically profile diseases. also generated cerebellum SCA1, SCA6 FRDA decipher changes in cell type proportions state. Using approach, found that: (i) despite commonalities genetics ataxia, there were components their transcriptional signatures distinct; (ii) extensive evident not only but cases; (iii) activation immune inflammatory pathways, as well involvement non-neuronal types was all lesser or greater extent. This provides novel resource understand ataxia. Furthermore, taken together, results highlight pathways role early potentially important therapeutic targets. These findings provide map transcriptomic pathogenesis.

Language: Английский

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Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: June 4, 2024

Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, deletions varying lengths. Dynamic expansion the most common form mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on type mutation, pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All which disrupt range cellular processes, such as impaired quality control pathways, ion channel dysfunction, mitochondrial transcriptional dysregulation, DNA damage, loss nuclear integrity, ultimately, impairment neuronal function integrity causes diseases. Many disease-modifying therapies, editing technology, interference, antisense oligonucleotides, stem cell pharmacological therapies are currently under trials. However, development curative approaches for diseases remains global challenge, beset by technical, ethical, other challenges. Therefore, study spinocerebellar great importance sustained molecular therapies.

Language: Английский

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Nanocarriers for Delivery of Oligonucleotides to the CNS

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(2), P. 760 - 760

Published: Jan. 11, 2022

Nanoparticles with oligonucleotides bound to the outside or incorporated into matrix can be used for gene editing modulate expression in CNS. These nanocarriers are usually optimised transfection of neurons glia. They also facilitate transcytosis across brain endothelium circumvent blood-brain barrier. This review examines different formulations and their oligonucleotide cargoes, relation ability enter disease. The size nanocarrier is critical determining rate clearance from plasma as well intracellular routes endothelial transcytosis. surface charge important how it interacts target cell. structure affects its stability degradation, while chemical formulation primarily controls location cargo release. Due major anatomical differences between humans animal models disease, successful therapy has required intrathecal injection. In models, some progress been made intraventricular intravenous injection on nanocarriers. However, getting significant amounts barrier will likely require targeting solute carriers vesicular transport systems.

Language: Английский

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Systematic assessment of plasma biomarkers in spinocerebellar ataxia

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 181, P. 106112 - 106112

Published: March 30, 2023

Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), phosphorylated-tau (p-tau), and β-amyloid (Aβ) have emerged as promising markers in several neurodegenerative disorders, but whether they can be used biomarkers spinocerebellar ataxias (SCA) is yet to determined. This study aimed identify sensitive plasma for SCA investigate their effectiveness tracking ataxia severity, cognition, non-motor symptoms, brain atrophy.This observational recruited consecutive participants from Huashan Hospital the CABLE November 2019. Patients with were genetically diagnosed, grouped according compared healthy older individuals patients multiple system atrophy type C (MSA-C). NfL, GFAP, p-tau, Aβ levels measured by Simoa all participants. Analysis of covariance, Spearman correlation, multivariable regression explore candidate SCA.A total 190 (60 SCA, 56 MSA-C, 74 controls) enrolled. NfL level increased early pre-ataxic stage (32.23 ± 3.07 vs. 11.41 6.62 pg/mL controls), was positively associated severity (r = 0.45, P 0.005) CAG repeat length 0.51, 0.001), varied among different subtypes (39.57 13.50 SCA3, which higher than 28.17 8.02 SCA2, 17.08 6.78 SCA8, 24.44 18.97 rare SCAs; < 0.05), brainstem atrophy. alone (area under curve [AUC] 0.867) or combined p-tau181 (AUC 0.929), showed excellent performance discriminating controls. GFAP distinguished MSA-C moderate accuracy > 0.700) correlated cognitive cortical Changes observed They both while also such anxiety depression.Plasma may serve a biomarker its elevated stage. The indicates differences underlying neuropathology MSA-C. Moreover, amyloid useful detecting memory dysfunction other symptoms SCA.

Language: Английский

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Neurofilaments in neurologic disorders and beyond

Journal of the Neurological Sciences, Journal Year: 2022, Volume and Issue: 441, P. 120380 - 120380

Published: Aug. 13, 2022

Language: Английский

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