Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications

Cendelín, Jan; Cvetanović, Marija; Gandelman, Mandi; Hirai, Hirokazu; Orr, Harry T.; Pulst, Stefan M.; Strupp, Michael; Tichánek, Filip; Tůma, Jan; Manto, Mario

doi:10.1007/s12311-021-01311-1

Cited by 21 publications

(16 citation statements)

References 326 publications

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“…As ataxias espinocerebelares (SCAs) são um grupo de doenças autossômicas que afeta vários sistemas neuronais, como o cerebelo, a medula, o tronco cerebral e alguns nervos, causando degeneração e levando a um prejuízo na qualidade e expectativa de vida do paciente (CENDELIN et al, 2022). Dentro das SCAs existem as doenças de poliglutaminas (poliQ) em que ocorrem a repetições de nucleotídeos, sendo consideradas as principais doenças nesse quesito.…”

Section: Espinocerebelarunclassified

“…Para alguns estudos são exigidos modelos mais simples em que se destacam os componentes da doença especificamente, sendo a maioria dos animais utilizados, camundongos, por permitir a pesquisa em vários níveis da doença. Na pesquisa de ataxias espinocerebelares, ocorre a produção de camundongos usando vetores virais, os vírus associados ao adeno (AAVs) (CENDELIN et al, 2022). Os AAVs são muito utilizados na transferência de genes in vivo, por fornecerem uma entrega mais específica, para determinado órgão ou população celular (CHAN et al, 2017).…”

Section: Espinocerebelarunclassified

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Terapia gênica no avanço do tratamento da ataxia espinocerebelar

Souza¹,

Silva²,

Marques³

et al. 2022

BJDV

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Objetivo-. Este trabalho teve como objetivo apresentar os avanços da terapia gênica na ataxia cerebelar, com ênfase na área espinocerebelar. Métodos - Foram coletadas informações de artigos originais, publicados em revistas, nos idiomas, inglês, português e espanhol, as bases de busca foram a Biblioteca Virtual em Saúde (BVS), Scientific Electronic Library Online (SciELO), Google Acadêmico e no site do National Center for Biotechnology Information (NCBI), com prioridade de artigos dos últimos dez anos. Resultados- Foi demonstrado que o modelo de tratamento de ataxias espinocerebelares por meio de vírus associados a adeno (AAV) junto a um RNA é uma técnica com potencial, capaz de retardar e reverter os sintomas da doença, porém ainda não se tem comprovação de segurança, devido ao pouco conhecimento sobre o assunto(excluir pois não podemos desmerecer a técnica). Conclusão – Como abordado nesse trabalho, A terapia gênica tem se mostrado a forma mais adequada de tratamento de ataxias espinocerebelares que causam poliglutaminas, por este fato se faz necessário mais pesquisas a respeito.

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Section: Espinocerebelarunclassified

Terapia gênica no avanço do tratamento da ataxia espinocerebelar

Souza¹,

Silva²,

Marques³

et al. 2022

BJDV

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“…Therefore, to follow the 3Rs principle, novel models need to be developed and used to further characterize the pathophysiology of NDDs, leading to a path were these models could also be used for the development of therapeutics. In addition, the limitations of animal models are due to the differences and variabilities between different species [10][11][12][13][14]. Besides, the use of human tissue to study NDDs is restricted by the inability to obtain either brain or spinal cord tissue from NDD patients throughout the disease [2,15,16].…”

Section: Introductionmentioning

confidence: 99%

An insight into the iPSCs-derived two-dimensional culture and three-dimensional organoid models for neurodegenerative disorders

et al. 2022

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The use of induced pluripotent stem cells (iPSCs) is a promising approach when used as models to study neurodegenerative disorders (NDDs) in vitro . iPSCs have been used in in vitro two-dimensional cultures; however, these two-dimensional cultures do not mimic the physiological three-dimensional cellular environment. The use of iPSCs-derived three-dimensional organoids has risen as a powerful alternative to using animal models to study NDDs. These iPSCs-derived three-dimensional organoids can resemble the complexity of the tissue of interest, making it an approachable, cost-effective technique, to study NDDs in an ethical manner. Furthermore, the use of iPSCs-derived organoids will be an important tool to develop new therapeutics and pharmaceutics to treat NDDs. Herein, we will highlight how iPSCs-derived two-dimensional cultures and three-dimensional organoids have been used to study NDDs, as well as the advantages and disadvantages of both techniques.

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“…Animal models specific to individual forms of ataxias may ultimately prove important in generating new therapeutic strategies. While there are a number of animal models of ataxia, particularly for the spinocerebellar ataxias [1][2][3][4][5][6][7][8][9][10] , there are no models of most forms of ataxia. While many ataxia rodent models have been generated by genetic engineering, a small number of natural occurring ataxic mutant mice have been investigated [11][12][13][14][15][16][17][18][19] , contributing to understanding cerebellar function and neurodegeneration, as well as to therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat

Figueroa

Anderson

Paul

et al. 2022

Preprint

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Background: The shaker rat carries a naturally occurring mutation leading to progressive ataxia characterized by Purkinje cell (PC) loss. We previously reported on fine-mapping the shaker locus to the long arm of the rat X chromosome. In this work, we sought to identify the mutated gene underlying the shaker phenotype and confirm its identity by functional complementation. Methods: We fine-mapped the candidate region and analyzed cerebellar transcriptomes to identify deleterious variants. We generated an adeno-associated virus (AAV) targeting solute carrier family 9, member A6 (Slc9a6) expression to PCs using a mouse L7-6 (L7) promoter, as well as a control green fluorescent protein (GFP)-expressing virus. We administered AAVs prior to the onset of PC degeneration through intracerebroventricular injection and evaluated the molecular, cellular, and motor phenotypes. Results: We identified a XM_217630.9 (Slc9a6):c.[191_195delinsA] variant in the Slc9a6 gene that segregated with disease. This mutation is predicted to generate a truncated sodium-hydrogen exchanger 6 (NHE6) protein, p.(Ala64Glufs*23). Administration of AAV9-PHP.eB expressing rat Slc9a6 prior to symptom onset reduced the shaker motor, molecular, and cellular phenotypes. Interpretation: Slc9a6 is mutated in shaker and also in human Christianson syndrome, an epileptic encephalopathy. AAV-based gene therapy may be a viable therapeutic strategy for Christianson syndrome, and the shaker rat model may aid in therapeutic development.

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Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications

Cited by 21 publications

References 326 publications

Terapia gênica no avanço do tratamento da ataxia espinocerebelar

Terapia gênica no avanço do tratamento da ataxia espinocerebelar

An insight into the iPSCs-derived two-dimensional culture and three-dimensional organoid models for neurodegenerative disorders

Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat

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