Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome.
Genes Brain Behav
; 21(1): e12739, 2022 01.
Article
em En
| MEDLINE
| ID: mdl-33942492
ABSTRACT
Rett syndrome is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in MECP2, encoding transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Although no disease-modifying therapies exist at this time, some proposed therapeutic strategies aim to supplement the mutant allele with a wild-type allele producing typical levels of functional MeCP2, such as gene therapy. Because MECP2 is a dosage-sensitive gene, with both loss and gain of function causing disease, these approaches must achieve a narrow therapeutic window to be both safe and effective. While MeCP2 supplementation rescues RTT-like phenotypes in mouse models, the tolerable threshold of MeCP2 is not clear, particularly for partial loss-of-function mutations. We assessed the safety of genetically supplementing full-length human MeCP2 in the context of the R294X allele, a common partial loss-of-function mutation retaining DNA-binding capacity. We assessed the potential for adverse effects from MeCP2 supplementation of a partial loss-of-function mutant and the potential for dominant negative interactions between mutant and full-length MeCP2. In male hemizygous R294X mice, MeCP2 supplementation rescued RTT-like behavioral phenotypes and did not elicit behavioral evidence of excess MeCP2. In female heterozygous R294X mice, RTT-specific phenotypes were similarly rescued. However, MeCP2 supplementation led to evidence of excess MeCP2 activity in a motor coordination assay, suggesting that the underlying motor circuitry is particularly sensitive to MeCP2 dosage in females. These results show that genetic supplementation of full-length MeCP2 is safe in males and largely so females. However, careful consideration of risk for adverse motor effects may be warranted for girls and women with RTT.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
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Síndrome de Rett
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Genes Brain Behav
Assunto da revista:
CIENCIAS DO COMPORTAMENTO
/
GENETICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos