Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex

J. H. Jara, M. J. Stanford, Y. Zhu, M. Tu, W. W. Hauswirth, M. C. Bohn, S. H. Devries, P. H. Özdinler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Direct gene delivery to the neurons of interest, without affecting other neuron populations in the cerebral cortex, represent a challenge owing to the heterogeneity and cellular complexity of the brain. Genetic modulation of corticospinal motor neurons (CSMN) is required for developing effective and long-term treatment strategies for motor neuron diseases, in which voluntary movement is impaired. Adeno-associated viruses (AAV) have been widely used for neuronal transduction studies owing to long-term and stable gene expression as well as low immunoreactivity in humans. Here we report that AAV2-2 transduces CSMN with high efficiency upon direct cortex injection and that transduction efficiencies are similar during presymptomatic and symptomatic stages in hSOD1 G93A transgenic amyotrophic lateral sclerosis (ALS) mice. Our findings reveal that choice of promoter improves selectivity as AAV2-2 chicken β-actin promoter injection results in about 70% CSMN transduction, the highest percentage reported to date. CSMN transduction in both wild-type and transgenic ALS mice allows detailed analysis of single axon fibers within the corticospinal tract in both cervical and lumbar spinal cord and reveals circuitry defects, which mainly occur between CSMN and spinal motor neurons in hSOD1 G93A transgenic ALS mice. Our findings set the stage for CSMN gene therapy in ALS and related motor neuron diseases.

Original languageEnglish (US)
Pages (from-to)272-282
Number of pages11
JournalGene therapy
Volume23
Issue number3
DOIs
StatePublished - Mar 1 2016

Funding

This work was supported by grants from Les Turner ALS and Wenske Foundations (to PHO), NUCATS (to PHO and MCB), 1R01NS085161-01 (to PHO), ALSA Safenowitz fellowship (to JHJ) and Northwestern Weinberg Grant (to MJS). WD Weber and J Xie helped with histochemistry. Stephanie R Villa contributed to the generation of preliminary findings. We also thank the Microscopy and Imaging Facility at Stanley Manne Children's Research Institute and B Goossens for help with confocal microscopy. This work was supported by grants from Les Turner ALS and Wenske Foundations (to PHO), NUCATS (to PHO and MCB), 1R01NS085161-01 (to PHO), ALSA Safenowitz fellowship (to JHJ) and Northwestern Weinberg Grant (to MJS). WD Weber and J Xie helped with histochemistry. Stephanie R Villa contributed to the generation of preliminary findings. We also thank the Microscopy and Imaging Facility at Stanley Manne Children''s Research Institute and B Goossens for help with confocal microscopy.

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Molecular Biology

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