Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.
Science
; 345(6197): 688-93, 2014 Aug 08.
Article
en En
| MEDLINE
| ID: mdl-25104390
ABSTRACT
Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirimidinonas
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Atrofia Muscular Espinal
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Empalme Alternativo
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Cumarinas
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Isocumarinas
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Bibliotecas de Moléculas Pequeñas
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Proteína 2 para la Supervivencia de la Neurona Motora
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Longevidad
Límite:
Animals
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Humans
Idioma:
En
Revista:
Science
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos