Emerging Therapies for Hereditary Ataxia

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 12029

Special Issue Editors


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Guest Editor
Department of Anatomy, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
Interests: neuroanatomy of cerebellar ataxia; modulators of oxidative stress; functional food

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Guest Editor
School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Interests: neurogenetics; neurodegeneration; neurodevelopment
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Guest Editor
1. Division of Neuroscience, Department of Psychology, University La Sapienza, Rome, Italy
2. European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy
Interests: neurodegenerative diseases; neurodevelopment; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We invite the submission of original research and review articles for a Special Issue titled “Emerging Therapies for Hereditary Ataxia”. Hereditary ataxia (HA) represents a group of genetically heterogeneous neurodegenerative diseases. It can be classified by the pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked ataxia. Mitochondrial dysfunction and oxidative damage have been increasingly implicated in the pathogenesis of HA. With no cure and a reduced lifespan, HA causes motor incoordination and progressive functional disabilities in young and middle-aged populations. The lack of effective therapeutic options remains a major gap in the field. Therapy aimed at boosting antioxidant defenses is efficient in the treatment of HA. The combined use of a mitochondrial antioxidant and an iron-binding chelator is rapidly emerging as a powerful therapeutic strategy for a wide range of HAs. Stem cell transplantation may represent a new avenue for clinical research in HA. Additionally, complementary and alternative medicines could play a key role in regulating cellular metabolic processes including inflammatory signaling, mitochondrial function and lipid metabolism, therefore facilitating the process of drug development and discovery for HA. We welcome cellular models of pathology and in vivo studies that provide valuable information for all stages of biomedical research, as well as research involving human subjects in compliance with the Declaration of Helsinki.

Potential topics include, but are not limited to:

  • Disease-modifying management of hereditary ataxia;
  • Stem cell transplantation for hereditary ataxia;
  • Dysregulation of iron metabolism and mitochondrial dysfunction;
  • Role of oxidative stress in hereditary ataxia;
  • Future perspectives for complementary and alternative medicines.

Dr. Kah-Hui Wong
Dr. Patrícia Maciel
Dr. Piergiorgio La Rosa
Guest Editors

Manuscript Submission Information

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Keywords

  • hereditary ataxia
  • movement disorder
  • emerging neurotherapeutics
  • complementary and alternative medicines
  • secondary metabolites
  • neuroprotection
  • mitigation of oxidative stress
  • mitochondria-targeted antioxidants

Published Papers (7 papers)

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Research

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23 pages, 15268 KiB  
Article
Development of a Polymeric Pharmacological Nanocarrier System as a Potential Therapy for Spinocerebellar Ataxia Type 7
by Fabiola V. Borbolla-Jiménez, Ian A. García-Aguirre, María Luisa Del Prado-Audelo, Oscar Hernández-Hernández, Bulmaro Cisneros, Gerardo Leyva-Gómez and Jonathan J. Magaña
Cells 2023, 12(23), 2735; https://doi.org/10.3390/cells12232735 - 30 Nov 2023
Viewed by 1080
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Emerging Therapies for Hereditary Ataxia)
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13 pages, 2503 KiB  
Article
Increased Actin Binding Is a Shared Molecular Consequence of Numerous SCA5 Mutations in β-III-Spectrin
by Alexandra E. Atang, Amanda R. Keller, Sarah A. Denha and Adam W. Avery
Cells 2023, 12(16), 2100; https://doi.org/10.3390/cells12162100 - 19 Aug 2023
Viewed by 739
Abstract
Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the SPTBN2 gene encoding the cytoskeletal protein β-III-spectrin. Previously, we demonstrated that a L253P missense mutation, localizing to the β-III-spectrin actin-binding domain (ABD), causes increased actin-binding affinity. Here we investigate [...] Read more.
Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the SPTBN2 gene encoding the cytoskeletal protein β-III-spectrin. Previously, we demonstrated that a L253P missense mutation, localizing to the β-III-spectrin actin-binding domain (ABD), causes increased actin-binding affinity. Here we investigate the molecular consequences of nine additional ABD-localized, SCA5 missense mutations: V58M, K61E, T62I, K65E, F160C, D255G, T271I, Y272H, and H278R. We show that all of the mutations, similar to L253P, are positioned at or near the interface of the two calponin homology subdomains (CH1 and CH2) comprising the ABD. Using biochemical and biophysical approaches, we demonstrate that the mutant ABD proteins can attain a well-folded state. However, thermal denaturation studies show that all nine mutations are destabilizing, suggesting a structural disruption at the CH1-CH2 interface. Importantly, all nine mutations cause increased actin binding. The mutant actin-binding affinities vary greatly, and none of the nine mutations increase actin-binding affinity as much as L253P. ABD mutations causing high-affinity actin binding, with the notable exception of L253P, appear to be associated with an early age of symptom onset. Altogether, the data indicate that increased actin-binding affinity is a shared molecular consequence of numerous SCA5 mutations, which has important therapeutic implications. Full article
(This article belongs to the Special Issue Emerging Therapies for Hereditary Ataxia)
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Review

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35 pages, 1289 KiB  
Review
Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?
by Federica Pilotto, Andrea Del Bondio and Hélène Puccio
Cells 2024, 13(4), 319; https://doi.org/10.3390/cells13040319 - 09 Feb 2024
Viewed by 981
Abstract
Cerebellar ataxias are a wide heterogeneous group of movement disorders. Within this broad umbrella of diseases, there are both genetics and sporadic forms. The clinical presentation of these conditions can exhibit a diverse range of symptoms across different age groups, spanning from pure [...] Read more.
Cerebellar ataxias are a wide heterogeneous group of movement disorders. Within this broad umbrella of diseases, there are both genetics and sporadic forms. The clinical presentation of these conditions can exhibit a diverse range of symptoms across different age groups, spanning from pure cerebellar manifestations to sensory ataxia and multisystemic diseases. Over the last few decades, advancements in our understanding of genetics and molecular pathophysiology related to both dominant and recessive ataxias have propelled the field forward, paving the way for innovative therapeutic strategies aimed at preventing and arresting the progression of these diseases. Nevertheless, the rarity of certain forms of ataxia continues to pose challenges, leading to limited insights into the etiology of the disease and the identification of target pathways. Additionally, the lack of suitable models hampers efforts to comprehensively understand the molecular foundations of disease’s pathophysiology and test novel therapeutic interventions. In the following review, we describe the epidemiology, symptomatology, and pathological progression of hereditary ataxia, including both the prevalent and less common forms of these diseases. Furthermore, we illustrate the diverse molecular pathways and therapeutic approaches currently undergoing investigation in both pre-clinical studies and clinical trials. Finally, we address the existing and anticipated challenges within this field, encompassing both basic research and clinical endeavors. Full article
(This article belongs to the Special Issue Emerging Therapies for Hereditary Ataxia)
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44 pages, 552 KiB  
Review
Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options
by Tatiana Bremova-Ertl, Jan Hofmann, Janine Stucki, Anja Vossenkaul and Matthias Gautschi
Cells 2023, 12(18), 2314; https://doi.org/10.3390/cells12182314 - 19 Sep 2023
Viewed by 1483
Abstract
A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic [...] Read more.
A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic ataxias summarized by disease, highlighting novel clinical trials and emerging therapies with a particular emphasis on first-in-human gene therapies. We present disease-specific treatments if they exist and review the current evidence for symptomatic treatments of these highly heterogeneous diseases (where cerebellar ataxia is part of their phenotype) that aim to improve the disease burden and enhance quality of life. In general, a multimodal and holistic approach to the treatment of cerebellar ataxia, irrespective of etiology, is necessary to offer the best medical care. Physical therapy and speech and occupational therapy are obligatory. Genetic counseling is essential for making informed decisions about family planning. Full article
(This article belongs to the Special Issue Emerging Therapies for Hereditary Ataxia)
25 pages, 1347 KiB  
Review
The Therapeutic Potential of Non-Invasive and Invasive Cerebellar Stimulation Techniques in Hereditary Ataxias
by Alberto Benussi, Giorgi Batsikadze, Carina França, Rubens G. Cury and Roderick P. P. W. M. Maas
Cells 2023, 12(8), 1193; https://doi.org/10.3390/cells12081193 - 20 Apr 2023
Cited by 5 | Viewed by 2982
Abstract
The degenerative ataxias comprise a heterogeneous group of inherited and acquired disorders that are characterized by a progressive cerebellar syndrome, frequently in combination with one or more extracerebellar signs. Specific disease-modifying interventions are currently not available for many of these rare conditions, which [...] Read more.
The degenerative ataxias comprise a heterogeneous group of inherited and acquired disorders that are characterized by a progressive cerebellar syndrome, frequently in combination with one or more extracerebellar signs. Specific disease-modifying interventions are currently not available for many of these rare conditions, which underscores the necessity of finding effective symptomatic therapies. During the past five to ten years, an increasing number of randomized controlled trials have been conducted examining the potential of different non-invasive brain stimulation techniques to induce symptomatic improvement. In addition, a few smaller studies have explored deep brain stimulation (DBS) of the dentate nucleus as an invasive means to directly modulate cerebellar output, thereby aiming to alleviate ataxia severity. In this paper, we comprehensively review the clinical and neurophysiological effects of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and dentate nucleus DBS in patients with hereditary ataxias, as well as the presumed underlying mechanisms at the cellular and network level and perspectives for future research. Full article
(This article belongs to the Special Issue Emerging Therapies for Hereditary Ataxia)
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18 pages, 1287 KiB  
Review
Myelinating Glia: Potential Therapeutic Targets in Polyglutamine Spinocerebellar Ataxias
by Alexandra F. Putka, Juan P. Mato and Hayley S. McLoughlin
Cells 2023, 12(4), 601; https://doi.org/10.3390/cells12040601 - 13 Feb 2023
Cited by 1 | Viewed by 2096
Abstract
Human studies, in combination with animal and cellular models, support glial cells as both major contributors to neurodegenerative diseases and promising therapeutic targets. Among glial cells, oligodendrocytes and Schwann cells are the myelinating glial cells of the central and peripheral nervous system, respectively. [...] Read more.
Human studies, in combination with animal and cellular models, support glial cells as both major contributors to neurodegenerative diseases and promising therapeutic targets. Among glial cells, oligodendrocytes and Schwann cells are the myelinating glial cells of the central and peripheral nervous system, respectively. In this review, we discuss the contributions of these central and peripheral myelinating glia to the pathomechanisms of polyglutamine (polyQ) spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17. First, we highlight the function of oligodendrocytes in healthy conditions and how they are disrupted in polyQ SCA patients and diseased model systems. We then cover the role of Schwann cells in peripheral nerve function and repair as well as their possible role in peripheral neuropathy in polyQ SCAs. Finally, we discuss potential polyQ SCA therapeutic interventions in myelinating glial. Full article
(This article belongs to the Special Issue Emerging Therapies for Hereditary Ataxia)
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Other

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14 pages, 696 KiB  
Systematic Review
Gene Suppression Therapies in Hereditary Cerebellar Ataxias: A Systematic Review of Animal Studies
by Carolina Santos, Sofia Malheiro, Manuel Correia and Joana Damásio
Cells 2023, 12(7), 1037; https://doi.org/10.3390/cells12071037 - 29 Mar 2023
Viewed by 1680
Abstract
Introduction: Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) [...] Read more.
Introduction: Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) as a new hope for disease-modifying strategies. In this article, we aim to perform a review of in vivo studies investigating the efficacy and safety profile of GSTs in HCAs. Methods: A structured PubMed® search on GSTs in HCAs from January 1993 up to October 2020 was performed. Inclusion and exclusion criteria were defined, and the selection process was conducted accordingly. The screening process was independently carried out by two authors and was initially based on title and abstract, followed by full-text reading. The risk-of-bias assessment was performed with SYRCLE’s tool. A data extraction sheet was created to collect relevant information from each selected article. Results: The initial search yielded 262 papers, of which 239 were excluded. An additional article was obtained following reference scrutiny, resulting in a total of 24 articles for final analysis. Most studies were not clear on the tools used to assess bias. In SCA1, SCA2, MJD/SCA3 and SCA7, RNA interference (iRNA) and antisense oligonucleotide (ASO) therapies proved to be well tolerated and effective in suppressing mutant proteins, improving neuropathological features and the motor phenotype. In SCA6, the phenotype was improved, but no investigation of adverse effects was performed. In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed. Conclusion: The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype in vivo. Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2. Full article
(This article belongs to the Special Issue Emerging Therapies for Hereditary Ataxia)
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