RESUMO
Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).
Assuntos
Proteínas de Membrana Transportadoras/genética , Mutagênese Insercional , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Oligonucleotídeos Antissenso/uso terapêutico , Medicina de Precisão , Doenças Raras/tratamento farmacológico , Biópsia , Criança , Desenvolvimento Infantil , Descoberta de Drogas , Drogas em Investigação/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Testes Neuropsicológicos , RNA Mensageiro , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Pele/patologia , Sequenciamento Completo do GenomaRESUMO
OBJECTIVES: The progression of infant gross motor development during an acute hospitalization is unknown. Understanding gross motor skill acquisition in hospitalized infants with complex medical conditions is necessary to develop and evaluate interventions that may lessen delays. Establishing a baseline of gross motor abilities and skill development for these infants will guide future research. The primary purposes of this observational study were to: (1) describe gross motor skills of infants with complex medical conditions (n = 143) during an acute hospitalization and (2) evaluate the rate of change in gross motor skill development in a heterogenous group of hospitalized infants with prolonged length of stay (n = 45). METHODS: Gross motor skills in hospitalized infants aged birth to 18 months receiving physical therapy were evaluated monthly using the Alberta Infant Motor Scale. Regression analysis was completed to assess rate of change in gross motor skills. RESULTS: Of the 143 participants, 91 (64%) demonstrated significant motor delay at initial evaluation. Infants with prolonged hospitalization (mean 26.9 ± 17.5 weeks) gained new gross motor skills at a significant rate of 1.4 points per month in Alberta Infant Motor Scale raw scores; however, most (76%) continued with gross motor delays. CONCLUSIONS: Infants with complex medical conditions admitted for prolonged hospitalization frequently have delayed gross motor development at baseline and have slower than typical acquisition of gross motor skills during hospitalization, gaining 1.4 new skills per month compared with peers acquiring 5 to 8 new skills monthly. Further research is needed to determine effectiveness of interventions designed to mitigate gross motor delay in hospitalized infants.