RESUMO
We evaluated the efficacy and safety of 1-year treatment with nilotinib (Tasigna®) in patients with autosomal dominant spinocerebellar ataxia (ADSCA) and the factors associated with responsiveness. From an institutional cohort, patients with ADSCA who completed a 1-year treatment with nilotinib (150-300 mg/day) were included. Ataxia severity was assessed using the Scale for the Rating and Assessment of Ataxia (SARA), scores at baseline and 1, 3, 6, and 12 months. A subject was categorized 'responsive' when the SARA score reduction at 12 M was > 0. Pretreatment serum proteomic analysis included subjects with the highest (n = 5) and lowest (n = 5) SARA score change at 12 months and five non-ataxia controls. Thirty-two subjects (18 [56.2%] females, median age 42 [30-49.5] years) were included. Although SARA score at 12 M did not significantly improve in overall population, 20 (62.5%) subjects were categorized as responsive. Serum proteomic analysis identified 4 differentially expressed proteins, leucine-rich alpha-2-glycoprotein (LRG1), vitamin-D binding protein (DBP), and C4b-binding protein (C4BP) beta and alpha chain, which are involved in the autophagy process. This preliminary data suggests that nilotinib might improve ataxia severity in some patients with ADSCA. Serum protein markers might be a clue to predict the response to nilotinib.Trial Registration Information: Effect of Nilotinib in Cerebellar Ataxia Patients (NCT03932669, date of submission 01/05/2019).
Assuntos
Pirimidinas , Ataxias Espinocerebelares , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica/métodos , Pirimidinas/uso terapêutico , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Resultado do TratamentoRESUMO
Spinocerebellar ataxia (SCA) is a rare neurological illness inherited dominantly that causes severe impairment and premature mortality. While each rare disease may affect individuals infrequently, collectively they pose a significant healthcare challenge. It is mainly carried out due to the expansion of RNA triplet (CAG) repeats, although missense or point mutations can also be induced. Unfortunately, there is no cure; only symptomatic treatments are available. To date, SCA has about 48 subtypes, the most common of these being SCA 1, 2, 3, 6, 7, 12, and 17 having CAG repeats. Using molecular docking and molecular dynamics (MD) simulation, this study seeks to investigate effective natural herbal neuroprotective compounds against CAG repeats, which are therapeutically significant in treating SCA. Initially, virtual screening followed by molecular docking was used to estimate the binding affinity of neuroprotective natural compounds toward CAG repeats. The compound with the highest binding affinity, somniferine, was then chosen for MD simulation. The structural stability, interaction mechanism, and conformational dynamics of CAG repeats and somniferine were investigated via MD simulation. The MD study revealed that during the simulation period, the interaction between CAG repeats and somniferine stabilizes and results in fewer conformational variations. This in silico study suggests that Somniferine can be used as a therapeutic medication against RNA CAG repeats in SCA.
Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Humanos , Descoberta de Drogas/métodos , RNA/química , RNA/metabolismo , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/metabolismo , Expansão das Repetições de Trinucleotídeos , Repetições de Trinucleotídeos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/químicaRESUMO
Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder of the cerebellum and brainstem. Memantine has been proposed as a potential treatment for SCA1. It blocks N-methyl-D-aspartate (NMDA) receptors on neurons, reduces excitotoxicity and decreases neurodegeneration in Alzheimer models. However, in cerebellar neurodegenerative diseases, the potential value of memantine is still unclear. We investigated the effects of memantine on motor performance and synaptic transmission in the cerebellum in a mouse model where mutant ataxin 1 is specifically targeted to glia. Lentiviral vectors (LVV) were used to express mutant ataxin 1 selectively in Bergmann glia (BG). In mice transduced with the mutant ataxin 1, chronic treatment with memantine improved motor activity during initial tests, presumably due to preserved BG and Purkinje cell (PC) morphology and numbers. However, mice were unable to improve their rota rod scores during next days of training. Memantine also compromised improvement in the rota rod scores in control mice upon repetitive training. These effects may be due to the effects of memantine on plasticity (LTD suppression) and NMDA receptor modulation. Some effects of chronically administered memantine persisted even after its wash-out from brain slices. Chronic memantine reduced morphological signs of neurodegeneration in the cerebellum of SCA1 model mice. This resulted in an apparent initial reduction of ataxic phenotype, but memantine also affected cerebellar plasticity and ultimately compromised motor learning. We speculate that that clinical application of memantine in SCA1 might be hampered by its ability to suppress NMDA-dependent plasticity in cerebellar cortex.
Assuntos
Modelos Animais de Doenças , Memantina , Fenótipo , Ataxias Espinocerebelares , Animais , Memantina/farmacologia , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/patologia , Camundongos , Ataxina-1/metabolismo , Ataxina-1/genética , Atividade Motora/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Cerebelo/metabolismo , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/patologia , Células de Purkinje/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neuroglia/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacosRESUMO
Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up to 75% of such patients remain without a genetic diagnosis. In an era of emerging disease-modifying gene-stratified therapies, the identification of causative alleles has become increasingly important. Over the past few years, the implementation of advanced bioinformatics tools and long-read sequencing has allowed the identification of a number of novel repeat expansion disorders, such as the recently described spinocerebellar ataxia 27B (SCA27B) caused by a (GAA)â¢(TTC) repeat expansion in intron 1 of the fibroblast growth factor 14 (FGF14) gene. SCA27B is rapidly gaining recognition as one of the most common forms of adult-onset hereditary ataxia, with several studies showing that it accounts for a substantial number (9-61%) of previously undiagnosed cases from different cohorts. First natural history studies and multiple reports have already outlined the progression and core phenotype of this novel disease, which consists of a late-onset slowly progressive pan-cerebellar syndrome that is frequently associated with cerebellar oculomotor signs, such as downbeat nystagmus, and episodic symptoms. Furthermore, preliminary studies in patients with SCA27B have shown promising symptomatic benefits of 4-aminopyridine, an already marketed drug. This review describes the current knowledge of the genetic and molecular basis, epidemiology, clinical features and prospective treatment strategies in SCA27B.
Assuntos
Ataxias Espinocerebelares , Adulto , Humanos , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Ataxia/complicações , FenótipoRESUMO
Spinocerebellar ataxias (SCAs) are a large and diverse group of autosomal-dominant neurodegenerative diseases. No drugs have been approved for these relentlessly progressive and fatal SCAs. Our previous studies indicate that oxidative stress, neuroinflammation, and neuronal apoptosis are elevated in the SCA17 mice, which are the main therapeutic targets of hyperbaric oxygen treatment (HBOT). HBOT is considered to be an alternative and less invasive therapy for SCAs. In this study, we evaluated the HBOT (2.2 ATA for 14 days) effect and the persistence for the management of SCA17 mice and their wild-type littermates. We found HBOT attenuated the motor coordination and cognitive impairment of SCA17 mice and which persisted for about 1 month after the treatment. The results of several biochemistry and liver/kidney hematoxylin and eosin staining show the HBOT condition has no obvious toxicity in the mice. Immunostaining analyses show that the neuroprotective effect of HBOT could be through the promotion of BDNF production and the amelioration of neuroinflammation. Surprisingly, HBOT executes different effects on the male and female SCA17 mice, including the reduction of neuroinflammation and activation of CaMKII and ERK. This study suggests HBOT is a potential alternative therapeutic treatment for SCA17. Accumulated findings have revealed the similarity in disease pathomechanisms and possible therapeutic strategies in polyQ diseases; therefore, HBOT could be an optional treatment as well as the other polyQ diseases.
Assuntos
Disfunção Cognitiva , Oxigenoterapia Hiperbárica , Peptídeos , Ataxias Espinocerebelares , Camundongos , Masculino , Feminino , Animais , Oxigenoterapia Hiperbárica/métodos , Doenças Neuroinflamatórias , Disfunção Cognitiva/terapia , Ataxias Espinocerebelares/terapia , Ataxias Espinocerebelares/tratamento farmacológicoRESUMO
Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant inherited disease characterized by progressive ataxia and retinal degeneration. SCA7 belongs to a group of neurodegenerative diseases caused by an expanded CAG repeat in the disease-causing gene, resulting in aberrant polyglutamine (polyQ) protein synthesis. PolyQ ataxin-7 is prone to aggregate in intracellular inclusions, perturbing cellular processes leading to neuronal death in specific regions of the central nervous system (CNS). Currently, there is no treatment for SCA7; however, a promising approach successfully applied to other polyQ diseases involves the clearance of polyQ protein aggregates through pharmacological activation of autophagy. Nonetheless, the blood-brain barrier (BBB) poses a challenge for delivering drugs to the CNS, limiting treatment effectiveness. This study aimed to develop a polymeric nanocarrier system to deliver therapeutic agents across the BBB into the CNS. We prepared poly(lactic-co-glycolic acid) nanoparticles (NPs) modified with Poloxamer188 and loaded with rapamycin to enable NPs to activate autophagy. We demonstrated that these rapamycin-loaded NPs were successfully taken up by neuronal and glial cells, demonstrating high biocompatibility without adverse effects. Remarkably, rapamycin-loaded NPs effectively cleared mutant ataxin-7 aggregates in a SCA7 glial cell model, highlighting their potential as a therapeutic approach to fight SCA7 and other polyQ diseases.
Assuntos
Ataxias Espinocerebelares , Humanos , Ataxina-7/genética , Ataxina-7/metabolismo , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Neurônios/metabolismo , Neuroglia/metabolismo , SirolimoRESUMO
We report a case of a man with spinocerebellar ataxia (SCA) on high-dose amantadine who was admitted for acute on chronic dysphagia secondary to progression of SCA. Four days after oral medications were held due to patient's dysphagia, he developed fever, tachycardia and mild rigidity in extremities and became obtunded. Despite antibiotics treatment, the vitals and mental status changes persisted for 8 days. When amantadine was resumed, the patient's vital signs and encephalopathy improved within 2 days. This is among the first reports of amantadine withdrawal syndrome (AWS) in a patient without Parkinson's disease. Our case reinforces the importance of careful medication review at admission and consideration of pharmacologic side effects with not only medication initiation but also discontinuation.
Assuntos
Transtornos de Deglutição , Doença de Parkinson , Ataxias Espinocerebelares , Síndrome de Abstinência a Substâncias , Masculino , Humanos , Transtornos de Deglutição/complicações , Amantadina/efeitos adversos , Doença de Parkinson/complicações , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/tratamento farmacológico , Síndrome de Abstinência a Substâncias/complicaçõesRESUMO
Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder caused by a pathological expansion of CAG repeats in ATXN2 gene. SCA2 is accompanied by cerebellar degeneration and progressive motor decline. Cerebellar Purkinje cells (PCs) seem to be primarily affected in this disorder. The majority of the ataxia research is focused on the motor decline observed in ataxic patients and animal models of the disease. However, recent evidence from patients and ataxic mice suggests that SCA2 can also share the symptoms of the cerebellar cognitive affective syndrome. We previously reported that SCA2-58Q PC-specific transgenic mice exhibit anxiolytic behavior, decline in spatial memory, and a depressive-like state. Here we studied the effect of the activation of the small conductance calcium-activated potassium channels (SK channels) by chlorzoxazone (CHZ) combined with the folic acid (FA) on the PC firing and also motor, cognitive and affective symptoms in SCA2-58Q mice. We realized that CHZ-FA combination improved motor and cognitive decline as well as ameliorated mood alterations in SCA2-58Q mice without affecting the firing rate of their cerebellar PCs. Our results support the idea of the combination therapy for both ataxia and non-motor symptoms in ataxic mice without affecting the firing frequency of PCs.
Assuntos
Disfunção Cognitiva , Ataxias Espinocerebelares , Camundongos , Animais , Clorzoxazona , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Camundongos Transgênicos , Disfunção Cognitiva/tratamento farmacológico , CogniçãoRESUMO
Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder, with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1154Q/2Q and healthy SCA12Q/2Q mice were administered either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation, and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models, combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1.
Assuntos
Disfunção Cognitiva , Ataxias Espinocerebelares , Camundongos , Animais , Edaravone/farmacologia , Edaravone/uso terapêutico , Teorema de Bayes , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/metabolismo , Mitocôndrias , Disfunção Cognitiva/metabolismo , Cerebelo/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos , Células de PurkinjeRESUMO
Spinocerebellar ataxia 6 (SCA6) often presents with pure cerebellar ataxia. It is rarely accompanied by extrapyramidal symptoms, such as dystonia and parkinsonism. Here, we describe a case of SCA6 with dopa-responsive dystonia for the first time. A 75-year-old woman was admitted to the hospital with slowly progressive cerebellar ataxia and dystonia in the left upper limb for the past six years. Genetic testing confirmed the diagnosis of SCA6. Her dystonia improved with oral levodopa, and she was able to raise her left hand. Oral levodopa administration may provide early-phase therapeutic benefits for SCA6-associated dystonia.
Assuntos
Ataxia Cerebelar , Distonia , Ataxias Espinocerebelares , Feminino , Humanos , Idoso , Distonia/etiologia , Distonia/genética , Levodopa/uso terapêutico , Ataxia Cerebelar/complicações , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genéticaRESUMO
ß-III-Spectrin is a key cytoskeletal protein that localizes to the soma and dendrites of cerebellar Purkinje cells and is required for dendritic arborization and signaling. A spinocerebellar ataxia type 5 L253P mutation in the cytoskeletal protein ß-III-spectrin causes high-affinity actin binding. Previously we reported a cell-based fluorescence assay for identification of small-molecule actin-binding modulators of the L253P mutant ß-III-spectrin. Here we describe a complementary, in vitro, fluorescence resonance energy transfer (FRET) assay that uses purified L253P ß-III-spectrin actin-binding domain (ABD) and F-actin. To validate the assay for high-throughput compatibility, we first confirmed that our 50% FRET signal was responsive to swinholide A, an actin-severing compound, and that this yielded excellent assay quality with a Z' value > 0.77. Second, we screened a 2684-compound library of US Food and Drug Administration-approved drugs. Importantly, the screening identified numerous compounds that decreased FRET between fluorescently labeled L253P ABD and F-actin. The activity and target of multiple Hit compounds were confirmed in orthologous cosedimentation actin-binding assays. Through future medicinal chemistry, the Hit compounds can potentially be developed into a spinocerebellar ataxia type 5-specific therapeutic. Furthermore, our validated FRET-based in vitro high-throughput screening platform is poised for screening large compound libraries for ß-III-spectrin ABD modulators.
Assuntos
Actinas , Espectrina , Ataxias Espinocerebelares , Humanos , Actinas/genética , Actinas/metabolismo , Descoberta de Drogas , Neurônios/metabolismo , Espectrina/metabolismo , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismoRESUMO
Spinocerebellar ataxias are neurodegenerative diseases, the hallmark symptom of which is the development of ataxia due to cerebellar dysfunction. Purkinje cells, the principal neurons of the cerebellar cortex, are the main cells affected in these disorders, but the sequence of pathological events leading to their dysfunction is poorly understood. Understanding the origins of Purkinje cells dysfunction before it manifests is imperative to interpret the functional and behavioural consequences of cerebellar-related disorders, providing an optimal timeline for therapeutic interventions. Here, we report the cascade of events leading to Purkinje cells dysfunction before the onset of ataxia in a mouse model of spinocerebellar ataxia 1 (SCA1). Spatiotemporal characterization of the ATXN1[82Q] SCA1 mouse model revealed high levels of the mutant ATXN1[82Q] weeks before the onset of ataxia. The expression of the toxic protein first caused a reduction of Purkinje cells intrinsic excitability, which was followed by atrophy of Purkinje cells dendrite arborization and aberrant glutamatergic signalling, finally leading to disruption of Purkinje cells innervation of climbing fibres and loss of intrinsic plasticity of Purkinje cells. Functionally, we found that deficits in eyeblink conditioning, a form of cerebellum-dependent motor learning, precede the onset of ataxia, matching the timeline of climbing fibre degeneration and reduced intrinsic plasticity. Together, our results suggest that abnormal synaptic signalling and intrinsic plasticity during the pre-ataxia stage of spinocerebellar ataxias underlie an aberrant cerebellar circuitry that anticipates the full extent of the disease severity. Furthermore, our work indicates the potential for eyeblink conditioning to be used as a sensitive tool to detect early cerebellar dysfunction as a sign of future disease.
Assuntos
Ataxia Cerebelar , Ataxias Espinocerebelares , Camundongos , Animais , Camundongos Transgênicos , Ataxias Espinocerebelares/tratamento farmacológico , Ataxia , Cerebelo , Células de Purkinje/patologia , Modelos Animais de Doenças , Ataxina-1/genética , Ataxina-1/metabolismoRESUMO
Type 1 spinocerebellar ataxia (SCA1) is a progressive neurodegenerative disorder with no effective treatment to date. Using mice modeling SCA1, it has been demonstrated that a drug that amplifies mGlu1 receptor activation (mGlu1 receptor PAM, Ro0711401) improves motor coordination without the development of tolerance when cerebellar dysfunction manifests (i.e., in 30-week-old heterozygous ataxin-1 [154Q/2Q] transgenic mice). SCA1 is also associated with cognitive dysfunction, which may precede cerebellar motor signs. Here, we report that otherwise healthy, 8-week-old SCA1 mice showed a defect in spatial learning and memory associated with reduced protein levels of mGlu1α receptors, the GluN2B subunit of NMDA receptors, and cannabinoid CB1 receptors in the hippocampus. Systemic treatment with Ro0711401 (10 mg/kg, s.c.) partially corrected the learning deficit in the Morris water maze and restored memory retention in the SCA1 mice model. This treatment also enhanced hippocampal levels of the endocannabinoid, anandamide, without changing the levels of 2-arachidonylglycerol. These findings suggest that mGlu1 receptor PAMs may be beneficial in the treatment of motor and nonmotor signs associated with SCA1 and encourage further studies in animal models of SCA1 and other types of SCAs.
Assuntos
Disfunção Cognitiva , Ataxias Espinocerebelares , Camundongos , Animais , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/metabolismo , Ataxinas , Camundongos Transgênicos , Modelos Animais de DoençasRESUMO
Mutations in the ataxin-2 gene (ATXN2) cause the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). A therapeutic strategy using antisense oligonucleotides targeting ATXN2 has entered clinical trial in humans. Additional ways to decrease ataxin-2 levels could lead to cheaper or less invasive therapies and elucidate how ataxin-2 is normally regulated. Here, we perform a genome-wide fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in human cells and identify genes encoding components of the lysosomal vacuolar ATPase (v-ATPase) as modifiers of endogenous ataxin-2 protein levels. Multiple FDA-approved small molecule v-ATPase inhibitors lower ataxin-2 protein levels in mouse and human neurons, and oral administration of at least one of these drugs-etidronate-is sufficient to decrease ataxin-2 in the brains of mice. Together, we propose v-ATPase as a drug target for ALS and SCA2 and demonstrate the value of FACS-based screens in identifying genetic-and potentially druggable-modifiers of human disease proteins.
Assuntos
Esclerose Lateral Amiotrófica , Ataxias Espinocerebelares , ATPases Vacuolares Próton-Translocadoras , Animais , Humanos , Camundongos , Ataxina-2/genética , Ataxina-2/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Preparações Farmacêuticas , Ácido Etidrônico , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Oligonucleotídeos Antissenso/genéticaRESUMO
CAG repeat expansions in the ATXN2 (ataxin-2) gene can cause the autosomal dominant disorder spinocerebellar ataxia type 2 (SCA2) as well as increase the risk of ALS. Abnormal molecular, motor, and neurophysiological phenotypes in SCA2 mouse models are normalized by lowering ATXN2 transcription, and reduction of nonmutant Atxn2 expression has been shown to increase the life span of mice overexpressing the TDP-43 (transactive response DNA-binding protein 43 kDa) ALS protein, demonstrating the potential benefits of targeting ATXN2 transcription in humans. Here, we describe a quantitative high-throughput screen to identify compounds that lower ATXN2 transcription. We screened 428,759 compounds in a multiplexed assay using an ATXN2-luciferase reporter in human embryonic kidney 293 (HEK-293) cells and identified a diverse set of compounds capable of lowering ATXN2 transcription. We observed dose-dependent reductions of endogenous ATXN2 in HEK-293 cells treated with procillaridin A, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), and heat shock protein 990 (HSP990), known inhibitors of HSP90 and Na+/K+-ATPases. Furthermore, HEK-293 cells expressing polyglutamine-expanded ATXN2-Q58 treated with 17-DMAG had minimally detectable ATXN2, as well as normalized markers of autophagy and endoplasmic reticulum stress, including STAU1 (Staufen 1), molecular target of rapamycin, p62, LC3-II (microtubule-associated protein 1A/1B-light chain 3II), CHOP (C/EBP homologous protein), and phospho-eIF2α (eukaryotic initiation factor 2α). Finally, bacterial artificial chromosome ATXN2-Q22 mice treated with 17-DMAG or HSP990 exhibited highly reduced ATXN2 protein abundance in the cerebellum. Taken together, our study demonstrates inhibition of HSP90 or Na+/K+-ATPases as potentially effective therapeutic strategies for treating SCA2 and ALS.
Assuntos
Esclerose Lateral Amiotrófica , Ataxias Espinocerebelares , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Ataxina-2/genética , Cerebelo/metabolismo , Proteínas do Citoesqueleto/metabolismo , Células HEK293 , Humanos , Proteínas de Ligação a RNA/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genéticaRESUMO
BACKGROUND: Several pieces of evidence have shown the neurotrophic effect of erythropoietin (EPO) and its introduction in the therapeutic practice of neurological diseases. However, its usefulness in the treatment of spinocerebellar ataxia type 2 (SCA2) has not been proven despite the fact that it is endogenously reduced in these patients. OBJECTIVE: The study aims to investigate the safety, tolerability, and clinical effects of a nasally administered recombinant EPO in SCA2 patients. METHODS: Thirty-four patients were enrolled in this double-blind, randomized, placebo-controlled, phase I-II clinical trial of the nasally administered human-recombinant EPO (NeuroEPO) for 6 months. The primary outcome was the change in the spinocerebellar ataxia functional index (SCAFI), while other motor, neuropsychological, and oculomotor measures were assessed. RESULTS: The 6-month changes in SCAFI score were slightly higher in the patients allocated to NeuroEPO treatment than placebo in spite of the important placebo effect observed for this parameter. However, saccade latency was significantly decreased in the NeuroEPO group but not in placebo. The frequency and severity of adverse events were similar between both groups, without evidences of hematopoietic activity of the drug. CONCLUSIONS: This study demonstrated the safety and tolerability of NeuroEPO in SCA2 patients after 6 months of treatments and suggested a small clinical effect of this drug on motor and cognitive abnormalities, but confirmatory studies are warranted. © 2022 International Parkinson and Movement Disorder Society.
Assuntos
Eritropoetina , Ataxias Espinocerebelares , Método Duplo-Cego , Epoetina alfa , Eritropoetina/uso terapêutico , Estudos de Viabilidade , Humanos , Proteínas Recombinantes/uso terapêutico , Ataxias Espinocerebelares/tratamento farmacológicoRESUMO
BACKGROUND: Riluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants' causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases. Participants were patients with spinocerebellar ataxia type 2 with an age at disease onset of up to 50 years and a scale for the assessment and rating of ataxia (SARA) score of at least 5 and up to 26. Patients were randomly assigned centrally (1:1) to receive either riluzole 50 mg orally or placebo twice per day for 12 months. Two visits, at baseline and at 12 months, included clinical measures and 3T brain MRI. The primary endpoint was the proportion of patients whose SARA score improved by at least 1 point. Analyses were done in the intention-to-treat population (all participants who were randomly assigned) and were done with only the observed data (complete case analysis). This trial is registered at ClinicalTrials.gov (NCT03347344) and has been completed. FINDINGS: Between Jan 18, 2018, and June 14, 2019, we enrolled 45 patients. 22 patients were randomly assigned to receive riluzole and 23 to receive placebo. Median age was 42 years (IQR 36-57) in the riluzole group and 49 years (40-56) in the placebo group and 23 (51%) participants were women. All participants presented with moderate-stage disease, characterised by a median SARA score of 13·5 (IQR 9·5-16·5). The primary endpoint, SARA score improvement of at least 1 point after 12 months, was observed in seven patients (32%) in the treated group versus nine patients (39%) in the placebo group, with a mean difference of -10·3% (95% CI -37·4% to 19·2%; p=0·75). SARA score showed a median increase (ie, worsening) of 0·5 points (IQR -1·5 to 1·5) in the riluzole group versus 0·3 points (-1·0 to 2·5) in the placebo group (p=0·70). No serious adverse event was reported in the riluzole-treated group whereas four patients in placebo group had a serious adverse event (hepatic enzyme increase, fracture of external malleolus, rectorrhagia, and depression). The number of patients with adverse events was similar in both groups (riluzole 16 [73%] patients vs placebo 19 [83%] patients; p=0·49). INTERPRETATION: We were able to recruit 45 patients moderately affected by spinocerebellar ataxia type 2 for this trial. Riluzole did not improve clinical or radiological outcomes in these patients. However, our findings provide data on progression of spinocerebellar ataxia type 2 that might prove to be valuable for the design of other clinical trials. FUNDING: French Ministry of Health.
Assuntos
Riluzol , Ataxias Espinocerebelares , Adulto , Encéfalo , Método Duplo-Cego , Feminino , Humanos , Riluzol/efeitos adversos , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Resultado do TratamentoRESUMO
Spinocerebellar ataxia type 2 (SCA2) is an incurable hereditary disorder accompanied by cerebellar degeneration following ataxic symptoms. The causative gene for SCA2 is ATXN2. The ataxin-2 protein is involved in RNA metabolism; the polyQ expansion may interrupt ataxin-2 interaction with its molecular targets, thus representing a loss-of-function mutation. However, mutant ataxin-2 protein also displays the features of gain-of-function mutation since it forms the aggregates in SCA2 cells and also enhances the IP3-induced calcium release in affected neurons. The cerebellar Purkinje cells (PCs) are primarily affected in SCA2. Their tonic pacemaker activity is crucial for the proper cerebellar functioning. Disturbances in PC pacemaking are observed in many ataxic disorders. The abnormal intrinsic pacemaking was reported in mouse models of episodic ataxia type 2 (EA2), SCA1, SCA2, SCA3, SCA6, Huntington's disease (HD), and in some other murine models of the disorders associated with the cerebellar degeneration. In our studies using SCA2-58Q transgenic mice via cerebellar slice recording and in vivo recording from urethane-anesthetized mice and awake head-fixed mice, we have demonstrated the impaired firing frequency and irregularity of PCs in these mice. PC pacemaker activity is regulated by SK channels. The pharmacological activation of SK channels has demonstrated some promising results in the electrophysiological experiments on EA2, SCA1, SCA2, SCA3, SCA6, HD mice, and also on mutant CACNA1A mice. In our studies, we have reported that the SK activators CyPPA and NS309 converted bursting activity into tonic, while oral treatment with CyPPA and NS13001 significantly improved motor performance and PC morphology in SCA2 mice. The i.p. injections of chlorzoxazone (CHZ) during in vivo recording sessions converted bursting cells into tonic in anesthetized SCA2 mice. And, finally, long-term injections of CHZ recovered the precision of PC pacemaking activity in awake SCA2 mice and alleviated their motor decline. Thus, the SK activation can be used as a potential way to treat SCA2 and other diseases accompanied by cerebellar degeneration.