Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

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Abstract

Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.

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Glucose metabolism and pancreatic defects in spinal muscular atrophy.

Rashmi Kothary, Kirstin Scott, John-Paul Michalski … (2012)

Spinal muscular atrophy (SMA) is the number 1 genetic killer of young children. It is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although SMA is primarily a motor neuron disease, metabolism abnormalities such as metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia, and hyperglycemia have been reported in SMA patients. We thus initiated an in-depth analysis of glucose metabolism in SMA. Glucose metabolism and pancreas development were investigated in the Smn(2B/-) intermediate SMA mouse model and type I SMA patients. Here, we demonstrate in an SMA mouse model a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon-producing α cells at the expense of insulin-producing β cells. These SMA mice display fasting hyperglycemia, hyperglucagonemia, and glucose resistance. We demonstrate similar abnormalities in pancreatic islets from deceased children with the severe infantile form of SMA in association with supportive evidence of glucose intolerance in at least a subset of such children. Our results indicate that defects in glucose metabolism may play an important contributory role in SMA pathogenesis. Copyright © 2012 American Neurological Association.

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Assessment of gross motor development in the WHO Multicentre Growth Reference Study.

T. Wang, Laura A. Onyango, Badriya Al-Rahbi … (2004)

The objective of the Motor Development Study was to describe the acquisition of selected gross motor milestones among affluent children growing up in different cultural settings. This study was conducted in Ghana, India, Norway, Oman, and the United States as part of the longitudinal component of the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS). Infants were followed from the age of four months until they could walk independently. Six milestones that are fundamental to acquiring self-sufficient erect locomotion and are simple to evaluate were assessed: sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone. The information was collected by both the children's caregivers and trained MGRS fieldworkers. The caregivers assessed and recorded the dates when the milestones were achieved for the first time according to established criteria. Using standardized procedures, the fieldworkers independently assessed the motor performance of the children and checked parental recording at home visits. To ensure standardized data collection, the sites conducted regular standardization sessions. Data collection and data quality control took place simultaneously. Data verification and cleaning were performed until all queries had been satisfactorily resolved.

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Developmental milestones in type I spinal muscular atrophy

Roberto De Sanctis, Giorgia Coratti, Amy Pasternak … (2016)

Highlights • This paper reports patterns of natural progression in type I SMA. • The HINE is used to capture motor developmental milestones in SMA. • Motor developmental milestones are rarely acquired in type I SMA infants.