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Intranasal Delivery of pGDNF DNA Nanoparticles Provides Neuroprotection in the Rat 6-Hydroxydopamine Model of Parkinson’s Disease

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Abstract

Glial cell line-derived neurotrophic factor (GDNF) gene therapy could offer a disease-modifying treatment for Parkinson’s disease (PD). Here, we report that plasmid DNA nanoparticles (NPs) encoding human GDNF administered intranasally to rats induce transgene expression in the brain and protect dopamine neurons in a model of PD. To first test whether intranasal administration could transfect cells in the brain, rats were sacrificed 1 week after intranasal pGDNF NPs or the naked plasmid. GDNF ELISA revealed significant increases in GDNF expression throughout the brain for both treatments. To assess whether expression was sufficient to protect dopamine neurons, naked pGDNF and pGDNF DNA NPs were given intranasally 1 week before a unilateral 6-hydroxydopamine lesion in a rat model of PD. Three to four weeks after the lesion, amphetamine-induced rotational behavior was reduced, and dopaminergic fiber density and cell counts in the lesioned substantia nigra and nerve terminal density in the lesioned striatum were significantly preserved in rats given intranasal pGDNF. The NPs afforded a greater level of neuroprotection than the naked plasmid. These results provide proof-of-principle that intranasal administration of pGDNF DNA NPs can offer a non-invasive, non-viral gene therapy approach for early-stage PD.

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Acknowledgements

The authors gratefully acknowledge the expertise and technical assistance of Alexandra Christodoulou in performing the BIOQUANT analyses of microscopic images.

Funding

This research was supported in part by the Michael J. Fox Foundation for Parkinson’s Research and a Northeastern University Tier 1 grant (BLW).

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Author notes

  1. Amirah E-E. Aly and Brendan T. Harmon contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Northeastern University, Room 269, 140 The Fenway, 360 Huntington Avenue, Boston, MA, USA

    Amirah E.-E. Aly, Brendan T. Harmon & Barbara L. Waszczak

  2. Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada

    Amirah E.-E. Aly

  3. Copernicus Therapeutics, Inc., Cleveland, OH, USA

    Linas Padegimas, Ozge Sesenoglu-Laird & Mark J. Cooper

  4. Abeona Therapeutics, Inc., Cleveland, OH, USA

    Linas Padegimas

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  1. Amirah E.-E. Aly
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Correspondence to Barbara L. Waszczak.

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AEA, BTH, and BLW declare no conflict of interest. MJC and OSL are current employees of Copernicus Therapeutics, and LP is a past employee. MJC and OSL hold stock/stock options in the company.

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Aly, A.EE., Harmon, B.T., Padegimas, L. et al. Intranasal Delivery of pGDNF DNA Nanoparticles Provides Neuroprotection in the Rat 6-Hydroxydopamine Model of Parkinson’s Disease. Mol Neurobiol 56, 688–701 (2019). https://doi.org/10.1007/s12035-018-1109-6

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