Stem cell models of polyglutamine diseases and their use in cell-based therapies

Siska, Evangelia K.; Koliakos, George; Petrakis, Spyros

doi:10.3389/fnins.2015.00247

Cited by 9 publications

(10 citation statements)

References 54 publications

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“…The replacement of dead and/or damaged neurons by new neural cells with the proper ability to integrate, function, and also contributing to neurogenesis and the production of trophic factors may provide additional neuroprotection and promote the reestablishment of neuronal homeostasis. The attractiveness of these strategies lies partially in the fact that they might be effective even after disease manifestation, but many technical hurdles are still in the way of their translation to the clinic …”

Section: Therapeutic Strategies For Polyq Diseasesmentioning

confidence: 99%

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Duarte‐Silva

Maciel

2016

Medicinal Research Reviews

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Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.

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Section: Therapeutic Strategies For Polyq Diseasesmentioning

confidence: 99%

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Duarte‐Silva

Maciel

2016

Medicinal Research Reviews

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“…Disease-specific human pluripotent stem cell (hPSC) lines, including patient-derived induced pluripotent stem cell (iPSC) lines and human embryonic stem cell (hESC) lines derived from donated disease embryos, are proving to be increasingly important model systems for the study of neurodegenerative diseases 6,7 . Disease-specific hPSC lines enable the study of disease processes in human disease-vulnerable differentiated cellular populations that express endogenous levels of pathogenic genes.…”

Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line

et al. 2019

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Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here we report the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred to as SCA3-hESC, this line is heterozygous for the mutant polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. We observed relevant molecular hallmarks of the human disease at all differentiation stages from stem cells to cortical neurons, including robust ATXN3 aggregation and altered expression of key components of the protein quality control machinery. In addition, SCA3-hESCs exhibit nuclear accumulation of mutant ATXN3 and form p62-positive aggresomes. Finally, antisense oligonucleotide-mediated reduction of ATXN3 markedly suppressed aggresome formation. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of candidate therapies for SCA3.

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“…One of the novel therapeutic approaches for treating polyQ diseases focuses on the development of cell replacement therapies. 195 Such therapies are anticipated in either replacing damaged neurons or stimulating the endogenous neurogenesis pathways of the brain. Stem cells represent a favorable tool for regenerative medicine in human disorders cure.…”

Section: Landscape Of Polyq Disease Researchmentioning

confidence: 99%

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

Tenchov,

Sasso,

Zhou

2024

Preprint

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Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins with abnormally expanded polyglutamine tract. A total of nine polyQ disorders have been identified, including Huntington's disease, six spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). The diseases of this class are each considered rare, yet polyQ diseases constitute the largest group of monogenic neurodegenerative disorders. While each subtype of polyQ diseases has its own causative gene, certain pathologic molecular attributes have been implicated in virtually all of the polyQ diseases, including protein aggregation, proteolytic cleavage, neuronal dysfunction, transcription dysregulation, autophagy impairment, and mitochondrial dysfunction. Although animal models of polyQ disease are available helping to understand their pathogenesis and access disease-modifying therapies, there is neither a cure nor prevention for these diseases, with only symptomatic treatments available. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in the class of polyQ diseases. We examine the publication landscape in the area in effort to provide insights into current knowledge advances and developments. We review the most discussed concepts and assess the strategies to combat these diseases. Finally, we inspect clinical applications of products against polyQ diseases with their development pipelines. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding the class of polyQ diseases, to outline challenges, and evaluate growth opportunities to further efforts in combating the diseases.

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Stem cell models of polyglutamine diseases and their use in cell-based therapies

Cited by 9 publications

References 54 publications

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

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