Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

Chen, Yu-Shuan; Hong, Zhen-Xiang; Lin, Shinn‐Zong; Harn, Horng‐Jyh

doi:10.3390/ijms21093063

Cited by 28 publications

(28 citation statements)

References 122 publications

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“…For example, the tyrosine kinase inhibitor nilotinib, which is used to treat chronic myelogenous leukemia, is under active clinical investigation for the SCAs. 36 , 37 , 38 …”

Section: Introductionmentioning

confidence: 99%

Spinocerebellar ataxia clinical trials: opportunities and challenges

Brooker

Edamakanti

Akasha

et al. 2021

Ann Clin Transl Neurol

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The spinocerebellar ataxias (SCAs) are a group of dominantly inherited diseases that share the defining feature of progressive cerebellar ataxia. The disease process, however, is not confined to the cerebellum; other areas of the brain, in particular, the brainstem, are also affected, resulting in a high burden of morbidity and mortality. Currently, there are no disease-modifying treatments for the SCAs, but preclinical research has led to the development of therapeutic agents ripe for testing in patients. Unfortunately, due to the rarity of these diseases and their slow and variable progression, there are substantial hurdles to overcome in conducting clinical trials. While the epidemiological features of the SCAs are immutable, the feasibility of conducting clinical trials is being addressed through a combination of strategies. These include improvements in clinical outcome measures, the identification of imaging and fluid biomarkers, and innovations in clinical trial design. In this review, we highlight current challenges in initiating clinical trials for the SCAs and also discuss pathways for researchers and clinicians to mitigate these challenges and harness opportunities for clinical trial development.

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“…For example, the tyrosine kinase inhibitor nilotinib, which is used to treat chronic myelogenous leukemia, is under active clinical investigation for the SCAs. 36 , 37 , 38 …”

Section: Introductionmentioning

confidence: 99%

Spinocerebellar ataxia clinical trials: opportunities and challenges

Brooker

Edamakanti

Akasha

et al. 2021

Ann Clin Transl Neurol

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show abstract

“…In conclusion, this novel study investigated various extracerebellar signs of early-stage SCAs in the Korean population, some of which were characteristic of specific SCA subtypes. Recent studies have introduced molecular biomarkers 41 42 and potential therapeutic targets in SCAs, 43 and so characterizing early-stage findings will not only facilitate early diagnosis but may also provide patients with more treatment options.…”

Section: Discussionmentioning

confidence: 99%

Extracerebellar Signs and Symptoms in 117 Korean Patients with Early-Stage Spinocerebellar Ataxia

et al. 2021

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Background and Purpose Spinocerebellar ataxias (SCAs) are the most common form of hereditary ataxias. Extracerebellar signs have been well described and are helpful in differentiating the SCA subtypes. However, there are few reports on the early-stage extracerebellar signs in various SCA subtypes. This study explored the clinical and magnetic resonance imaging (MRI) characteristics of early-stage SCAs in the Korean population. Methods We retrospectively reviewed the medical records of genetically confirmed SCA patients with a disease duration of <5 years. Data on baseline characteristics, extracerebellar signs, and initial MRI findings were organized based on SCA subtypes. Results This study included 117 SCA patients with a median age at onset of 40.6 years. The family history was positive in 71.8% of the patients, and the median disease duration and the score on the Scale for the Assessment and Rating of Ataxia at the initial visit were 2.6 years and 5.0, respectively. SCA3 was the most prevalent subtype, and oculomotor abnormalities were the most frequent extracerebellar signs in early-stage SCAs. Saccadic slowing was characteristic of SCA2 and SCA7, and gaze-evoked nystagmus was prominent in SCA6. Parkinsonism was relatively frequent in SCA8 and SCA3. Decreased visual acuity was specific for SCA7. Dementia was not an early manifestation of SCAs. Brain MRI revealed a pattern of pontocerebellar atrophy in SCA2 and SCA7, while SCA6 demonstrated only cerebellar cortical atrophy. Conclusions SCA patients exhibited diverse extracerebellar signs even in the early stage. Specific extracerebellar signs were characteristic of specific subtypes, which could facilitate differential diagnoses of early-stage SCAs.

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“…Trophic factors from ASCs can also be used in the treatment of SCA3 due to protective function of neurons by reducing the production of reactive oxygen species [131]. Furthermore, it has been proven that miR-21 from ASCs stimulates neuronal differentiation [132] as well as miR-24 [133].…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Adipose-Derived Stem Cells Secretome and Its Potential Application in “Stem Cell-Free Therapy”

2021

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Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides cytokines, proteins, and growth factors, the therapeutic effect of secretome is hidden in non-coding RNAs such as miR-21, miR-24, and miR-26 carried via exosomes secreted by adequate cells. The whole secretome, including ASC-derived exosomes (ASC-exos) has been proven in many studies to have immunomodulatory, proangiogenic, neurotrophic, and epithelization activity and can potentially be used for neurodegenerative, cardiovascular, respiratory, inflammatory, and autoimmune diseases as well as wound healing treatment. Due to limitations in the use of stem cells in cell-based therapy, its secretome with emphasis on exosomes seems to be a reasonable and safer alternative with increased effectiveness and fewer side effects. Moreover, the great advantage of cell-free therapy is the possibility of biobanking the ASCs secretome. In this review, we focus on the current state of knowledge on the use of the ASCs secretome in stem cell-free therapy.

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Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

Cited by 28 publications

References 122 publications

Spinocerebellar ataxia clinical trials: opportunities and challenges

Spinocerebellar ataxia clinical trials: opportunities and challenges

Extracerebellar Signs and Symptoms in 117 Korean Patients with Early-Stage Spinocerebellar Ataxia

Adipose-Derived Stem Cells Secretome and Its Potential Application in “Stem Cell-Free Therapy”

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