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Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion

Nature Medicine volume 9, pages 1076–1080 (2003)Cite this article

Abstract

Seizure disorders present an attractive gene therapy target, particularly because viral vectors such as adeno-associated virus (AAV) and lentivirus can stably transduce neurons1,2,3. When we targeted the N-methyl-D-aspartic acid (NMDA) excitatory amino acid receptor with an AAV-delivered antisense oligonucleotide, however, the promoter determined whether focal seizure sensitivity was significantly attenuated or facilitated4. One potential means to circumvent this liability would be to express an inhibitory neuroactive peptide and constitutively secrete the peptide from the transduced cell. The neuropeptide galanin can modulate seizure activity in vivo5,6, and the laminar protein fibronectin is usually secreted through a constitutive pathway7,8. Initially, inclusion of the fibronectin secretory signal sequence (FIB)9 in an AAV vector caused significant gene product secretion in vitro. More importantly, the combination of this secretory signal with the coding sequence for the active galanin peptide significantly attenuated in vivo focal seizure sensitivity, even with different promoters, and prevented kainic acid–induced hilar cell death. Thus, neuroactive peptide expression and local secretion provides a new gene therapy platform for the treatment of neurological disorders.

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Figure 1: GFP expression patterns in HELA cells and in the hippocampus.
Figure 2: Effects of AAV vector microinjections on focal seizure sensitivity in rat inferior collicular cortex.
Figure 3: Effects of unilateral AAV-FIB-GAL or AAV-GAL infusion on hippocampal hilar neurons 2 weeks before peripheral administration of kainic acid.
Figure 4: FIB-GAL mRNA and kainic acid-induced electrographic seizure activity after hippocampal AAV-FIB-GAL infusion.

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Acknowledgements

The authors thank the UNC Virus Vector Core for production of the recombinant AAV viruses and H.E. Criswell for his invaluable electrophysiological advice. This work was supported by National Institute of Neurological Disorders and Stroke grant NS 35633 to T.J.M.

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Authors and Affiliations

  1. Gene Therapy Center, 7119 Thurston-Bowles Building, CB 7352, University of North Carolina School of Medicine, Chapel Hill, 27599, North Carolina, USA

    Rebecca P Haberman, R Jude Samulski & Thomas J McCown

  2. Department of Psychiatry, 7119 Thurston-Bowles Building, CB 7352, University of North Carolina School of Medicine, Chapel Hill, 27599, North Carolina, USA

    Thomas J McCown

  3. Department of Pharmacology, 7119 Thurston-Bowles Building, CB 7352, University of North Carolina School of Medicine, Chapel Hill, 27599, North Carolina, USA

    R Jude Samulski

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Correspondence to Thomas J McCown.

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Haberman, R., Samulski, R. & McCown, T. Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Nat Med 9, 1076–1080 (2003). https://doi.org/10.1038/nm901

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