Efficient SMN Rescue following Subcutaneous Tricyclo-DNA Antisense Oligonucleotide Treatment

Robin, Valérie; Griffith, Graziella; Carter, John-Paul L.; Leumann, Christian J.; Garcı́a, Luis; Goyenvalle, Aurélie

doi:10.1016/j.omtn.2017.02.009

Cited by 30 publications

(29 citation statements)

References 48 publications

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“…O gene SMN-2, devido a substituição de C por T no exon 7, é capaz de produzir somente 10% de proteína SMN biologicamente ativa 3,4,7 . Os outros 90% correspondem a uma proteína instável, sendo rapidamente degradada e portanto, incapaz de manter a função dos neurônios motores 2,3 . O segmento do genoma onde se localiza o gene da doença, 5q11.2-q13.3, é instável, o que facilita a ocorrência de mutações diferentes no mesmo lócus 19,20 .…”

Section: Resultsunclassified

“…Atrofia Muscular Espinhal (AME) tipo I, ou doença de Werdnig-Hoffmann é uma doença neuromuscular de origem genética, autossômica recessiva, que resulta em atrofia muscular progressiva e fraqueza 1,2 . É causada por baixos níveis da proteína de sobrevivência do neurônio motor (SMN) devido à mutações na decodificação do gene SMN-1 3 , localizado no cromossomo 5q13 4,5 .…”

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“…É causada por baixos níveis da proteína de sobrevivência do neurônio motor (SMN) devido à mutações na decodificação do gene SMN-1 3 , localizado no cromossomo 5q13 4,5 . As alterações mais comumente encontradas são deleções homozigóticas, que são responsáveis pela principal característica fisiopatológica da doença: a degeneração dos neurônios motores inferiores, localizados no corno anterior da medula espinhal 2,6 . O gene SMN-2 é uma cópia quase idêntica do SMN-1, exceto pela substituição de C (citosina) por T (timina) na posição 6 do exon 7 2,6 .…”

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“…As alterações mais comumente encontradas são deleções homozigóticas, que são responsáveis pela principal característica fisiopatológica da doença: a degeneração dos neurônios motores inferiores, localizados no corno anterior da medula espinhal 2,6 . O gene SMN-2 é uma cópia quase idêntica do SMN-1, exceto pela substituição de C (citosina) por T (timina) na posição 6 do exon 7 2,6 . Essa diferença faz com que o gene SMN-2 produza somente uma pequena quantidade de proteína SMN biologicamente ativa, que é o suficiente para a sobrevivência da maioria das células somáticas, com exceção dos neurônios motores 3,7 .…”

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Atrofia muscular espinhal tipo I: aspectos clínicos e fisiopatológicos

Chrun

Costa

Miranda

et al. 2017

Rev. Med. (São Paulo)

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Discussão: A doença de Werdnig-Hoffmann, atrofia muscular espinhal tipo I, é uma doença hereditária caracterizada pela atrofia e fraqueza muscular progressiva, resultando em elevada e precoce mortalidade. As atrofias musculares espinhais são doenças neuromusculares caracterizadas pela degeneração dos motoneurônios inferiores e são transmitidas seguindo o padrão mendeliano autossômico recessivo. Suas manifestações clínicas são: hipotonia, atrofia, debilidade muscular e diminuição ou ausência dos reflexos osteotendinosos. O tratamento inclui medidas de suporte e medicação específica, o Nusinersen (Spinraza®), administrado por via intratecal, e pode retardar ou até impedir a evolução da doença, caso seja iniciado precocemente. Conclusão: A doença tem características semelhantes na maioria dos casos e evolui de forma grave. Entretanto, o tratamento emergencial e intensivo, incluindo a medicação específica e atuação de equipe multidisciplinar, pode redefinir e prolongar a sobrevida dos pacientes.Descritores: Atrofia muscular espinal/fisiopatologia; Atrofias musculares espinais da infância/fisiopatologia;Doenças neuromusculares; Doenças da medula espinal/fisiopatologia. ABSTRACT:Objective: To produce a literature review about etiology, diagnosis, treatment and future perspectives around spinal muscular atrophy type I (Werdnig-Hoffmann disease). Methods: Using databases like Medline, Lilacs and Scielo; the most important articles about this issue were chosen, using the keywords: spinal muscular atrophy; spinal muscular atrophy of childhood; neuromuscular diseases; spinal cord diseases; Werdnig-Hoffmann disease. Results: 68 articles were collected. After analysis process, 43 studies which focus on the clinical and/or pathophysiological aspects, were selected. Discussion: Werdnig-Hoffmann disease, the spinal muscular atrophy type I, is a hereditary disorder that causes progressive hypotony and muscular weakness. This process evolves with the loss of essential functions, resulting in high and early mortality. The spinal muscular atrophies are neuromuscular diseases characterized by degeneration of lower motor neurons. They are transmitted following the pattern mendelian autosomal recessive. The clinic signs are: hypotony, atrophy, muscular weakness and decrease or absence of osteotendinous reflexes. Treatment includes supportive care and specific medication, Nusinersen (Spinraza®), administered by intrathecal injection, and can delay or even stop disease progression if started early. Conclusions: The sickness has similar features on most cases and worsens sorely. However, the intensive and immediate treatment, with the specific medication and the multidisciplinary team -can promote a better quality of life to patients.

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Atrofia muscular espinhal tipo I: aspectos clínicos e fisiopatológicos

Chrun

Costa

Miranda

et al. 2017

Rev. Med. (São Paulo)

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“…SMN2 , a nearly identical copy of SMN1 , fails to compensate for the loss of SMN1 due to predominant skipping of exon 7 during SMN2 pre-mRNA splicing (35). Our earlier discovery of an intronic splicing silencer N1 (ISS-N1) produced the leading therapeutic target for an ASO-mediated restoration of SMN2 exon 7 inclusion (13,36–41). ISS-N1 is a complex regulatory element that harbors two hnRNP A1/A2 motifs, is engaged in long-distance interactions, and sequesters a putative cryptic 5′ splice site (15,16,36–42).…”

Section: Introductionmentioning

confidence: 99%

Pre-mRNA Splicing Modulation by Antisense Oligonucleotides

Singh

Luo

Singh

2018

Methods in Molecular Biology

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Pre-mRNA splicing, a dynamic process of intron removal and exon joining, is governed by a combinatorial control exerted by overlapping cis-elements that are unique to each exon and its flanking intronic sequences. Splicing cis-elements are usually 4-to-8-nucleotide-long linear motifs that provide binding sites for specific proteins. Pre-mRNA splicing is also influenced by secondary and higher order RNA structures that affect accessibility of splicing cis-elements. Antisense oligonucleotides (ASOs) that block splicing cis-elements and/or affect RNA structure have been shown to modulate splicing in vivo. Therefore, ASO-based strategies have emerged as a powerful tool for therapeutic manipulation of splicing in pathological conditions. Here we describe an ASO-based approach to increase the production of the full-length SMN2 mRNA in spinal muscular atrophy patient cells.

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Partial Restoration of Brain Dystrophin and Behavioral Deficits by Exon Skipping in the Muscular Dystrophy X‐Linked (mdx) Mouse

Zarrouki

Relizani

Bizot

et al. 2022

Annals of Neurology

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Objectives Duchenne muscular dystrophy is associated with various degrees of cognitive impairment and behavioral disturbances. Emotional and memory deficits also constitute reliable outcome measures to assess efficacy of treatments in the mdx mouse lacking the muscle and neuronal full‐length dystrophins. The present study aimed to evaluate whether these deficits could be alleviated by the restoration of brain dystrophin. Methods We performed intracerebroventricular administration of a new potent tricyclo‐DNA antisense oligonucleotide (tcDNA‐ASO) containing a full phosphodiester backbone conjugated to a palmitic acid moiety (tcDNA‐ASO), designed to skip the mutated exon 23 of mdx mice. Results We first show that the tcDNA‐ASO rescues expression of brain dystrophin to 10–30% of wild‐type levels and significantly reduces the abnormal unconditioned fear responses in mdx mice in a dose‐dependent manner, 5 weeks post‐injection. Exon skipping efficiency, ASO biodistribution, protein restoration and effect on the fear response were optimal with a dose of 400 μg at 6–7 weeks post‐injection, with synaptic‐like expression in brain tissues such as the hippocampus and amygdala. Furthermore, this dose of tcDNA‐ASO restored long‐term memory retention of mdx mice in an object recognition task, but only had minor effects on fear conditioning. Interpretation These results suggest for the first time that postnatal re‐expression of brain dystrophin could reverse or at least alleviate some cognitive deficits associated with Duchenne muscular dystrophy. ANN NEUROL 2022;92:213–229

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Efficient SMN Rescue following Subcutaneous Tricyclo-DNA Antisense Oligonucleotide Treatment

Cited by 30 publications

References 48 publications

Atrofia muscular espinhal tipo I: aspectos clínicos e fisiopatológicos

Atrofia muscular espinhal tipo I: aspectos clínicos e fisiopatológicos

Pre-mRNA Splicing Modulation by Antisense Oligonucleotides

Partial Restoration of Brain Dystrophin and Behavioral Deficits by Exon Skipping in the Muscular Dystrophy X‐Linked (mdx) Mouse

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