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Mol Ther. 2016 May;24(5):855-66. doi: 10.1038/mt.2016.33. Epub 2016 Feb 10.

Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.

Author information

1
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, USA.
2
Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.
3
Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.
4
Department of Biological Sciences, College of Art and Sciences, University of Missouri, Columbia, Missouri, USA.
5
Genetics Area Program, Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.
6
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri, USA.

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disease occurring during childhood. The gene responsible for disease development is a ubiquitously expressed protein, IGHMBP2. Mutations in IGHMBP2 result in the loss of α-motor neurons leading to muscle atrophy in the distal limbs accompanied by respiratory complications. Although genetically and clinically distinct, proximal SMA is also caused by the loss of a ubiquitously expressed gene (SMN). Significant preclinical success has been achieved in proximal SMA using viral-based gene replacement strategies. We leveraged the technologies employed in SMA to demonstrate gene replacement efficacy in an SMARD1 animal model. Intracerebroventricular (ICV) injection of single-stranded AAV9 expressing the full-length cDNA of IGHMBP2 in a low dose led to a significant level of rescue in treated SMARD1 animals. Consistent with drastically increased survival, weight gain, and strength, the rescued animals demonstrated a significant improvement in muscle, NMJ, motor neurons, and axonal pathology. In addition, increased levels of IGHMBP2 in lumbar motor neurons verified the efficacy of the virus to transduce the target tissues. Our results indicate that AAV9-based gene replacement is a viable strategy for SMARD1, although dosing effects and potential negative impacts of high dose and ICV injection should be thoroughly investigated.

PMID:
26860981
PMCID:
PMC4881770
DOI:
10.1038/mt.2016.33
[Indexed for MEDLINE]
Free PMC Article

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