Amelioration of Muscle and Nerve Pathology in LAMA2 Muscular Dystrophy by AAV9-Mini-Agrin

Molecular Therapy. Methods & Clinical Development
Chunping QiaoXiao Xiao

Abstract

LAMA2-related muscular dystrophy (LAMA2 MD) is the most common and fatal form of early-onset congenital muscular dystrophies. Due to the large size of the laminin α2 cDNA and heterotrimeric structure of the protein, it is challenging to develop a gene-replacement therapy. Our group has developed a novel adeno-associated viral (AAV) vector carrying the mini-agrin, which is a non-homologous functional substitute for the mutated laminin α2. A significant therapeutic effect in skeletal muscle was observed in our previous study using AAV serotype 1 (AAV1). In this investigation, we examined AAV9 vector, which has more widespread transduction than AAV1, to determine if the therapeutic effects could be further improved. As expected, AAV9-mini-agrin treatment offered enhanced therapeutic effects over the previously used AAV1-mini-agrin in extending mouse lifespan and improvement of muscle pathology. Additionally, overexpression of mini-agrin in peripheral nerves of dy w /dy w mice partially amended nerve pathology as evidenced by improved motor function and sensorimotor processing, partial restoration of myelination, partial restoration of basement membrane via EM examination, as well as decreased regeneration of Schwann cells. In con...Continue Reading

Citations

May 28, 2020·Frontiers in Molecular Neuroscience·Kinga I Gawlik, Madeleine Durbeej
Jul 3, 2020·Frontiers in Bioengineering and Biotechnology·Maria Giulia BigottiAndrea Brancaccio
Jan 31, 2020·Frontiers in Molecular Biosciences·Salvatore R GuarinoFederico Forneris
Jan 11, 2020·Frontiers in Molecular Neuroscience·Peter D Yurchenco, Karen K McKee
May 12, 2020·Frontiers in Molecular Neuroscience·Stefano Carlo Previtali, Alberto Andrea Zambon
Apr 20, 2021·Molecular Therapy. Methods & Clinical Development·Davin Packer, Paul T Martin
Jul 15, 2021·Nature Reviews. Molecular Cell Biology·James J DowlingMelissa J Spencer
Aug 8, 2021·International Journal of Molecular Sciences·Shama R IyerRichard M Lovering

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Methods Mentioned

BETA
biopsy
gene replacement therapy
transmission electron microscopy
light microscopy
transgenic
transfection
dot-blot
Assay
electron microscopy

Clinical Trials Mentioned

NCT01805024

Software Mentioned

Graph Pad Prism

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