Specific Retrograde Transduction of Spinal Motor Neurons Using Lentiviral Vectors Targeted to Presynaptic NMJ Receptors

To understand how receptors are involved in neuronal trafficking and to be able to utilize them for specific targeting via the peripheral route would be of great benefit. Here, we describe the generation of novel lentiviral vectors with tropism to motor neurons that were made by coexpressing onto th...

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Bibliographic Details
Published in:	Molecular therapy Vol. 22; no. 7; pp. 1285 - 1298
Main Authors:	Eleftheriadou, I, Trabalza, A, Ellison, SM, Gharun, K, Mazarakis, ND
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-07-2014 Elsevier Limited Nature Publishing Group
Subjects:	Adenovirus Adenoviruses Amyotrophic lateral sclerosis Animals Antibodies Cell Line Cell Line, Tumor Coxsackievirus Cytomegalovirus Gene therapy Genetic engineering Genetic Vectors - genetics Genomes Glycoproteins Humans Legs Lentivirus - genetics Mice Motor Neurons - metabolism Nervous system Neurodegeneration Neuromuscular Junction Neurons Original PC12 Cells Plasmids Proteins Rabies Rats Receptors, Presynaptic - genetics Spinal cord Transduction, Genetic - methods Vectors (Biology) United Kingdom > UK
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Summary:	To understand how receptors are involved in neuronal trafficking and to be able to utilize them for specific targeting via the peripheral route would be of great benefit. Here, we describe the generation of novel lentiviral vectors with tropism to motor neurons that were made by coexpressing onto the lentiviral surface a fusogenic glycoprotein (mutated sindbis G) and an antibody against a cell-surface receptor (Thy1.1, p75NTR, or coxsackievirus and adenovirus receptor) on the presynaptic terminal of the neuromuscular junction. These vectors exhibit binding specificity and efficient transduction of receptor positive cell lines and primary motor neurons in vitro. Targeting of each of these receptors conferred to these vectors the capability of being transported retrogradely from the axonal tip, leading to transduction of motor neurons in vitro in compartmented microfluidic cultures. In vivo delivery of coxsackievirus and adenovirus receptor-targeted vectors in leg muscles of mice resulted in predicted patterns of motor neuron labeling in lumbar spinal cord. This opens up the clinical potential of these vectors for minimally invasive administration of central nervous system-targeted therapeutics in motor neuron diseases.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The first two authors contributed equally to this work.
ISSN:	1525-0016 1525-0024
DOI:	10.1038/mt.2014.49