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Gene therapy approaches in the non-human primate model of Parkinson’s disease

  • Neurology and Preclinical Neurological Studies - Review Article
  • Published:
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Abstract

The field of gene therapy has recently witnessed a number of major conceptual changes. Besides the traditional thinking that comprises the use of viral vectors for the delivery of a given therapeutic gene, a number of original approaches have been recently envisaged, focused on using vectors carrying genes to further modify basal ganglia circuits of interest. It is expected that these approaches will ultimately induce a therapeutic potential being sustained by gene-induced changes in brain circuits. Among others, at present, it is technically feasible to use viral vectors to (1) achieve a controlled release of neurotrophic factors, (2) conduct either a transient or permanent silencing of any given basal ganglia circuit of interest, (3) perform an in vivo cellular reprogramming by promoting the conversion of resident cells into dopaminergic-like neurons, and (4) improving levodopa efficacy over time by targeting aromatic l-amino acid decarboxylase. Furthermore, extensive research efforts based on viral vectors are currently ongoing in an attempt to better replicate the dopaminergic neurodegeneration phenomena inherent to the progressive intraneuronal aggregation of alpha-synuclein. Finally, a number of incoming strategies will soon emerge over the horizon, these being sustained by the underlying goal of promoting alpha-synuclein clearance, such as, for instance, gene therapy initiatives based on increasing the activity of glucocerebrosidase. To provide adequate proof-of-concept on safety and efficacy and to push forward true translational initiatives based on these different types of gene therapies before entering into clinical trials, the use of non-human primate models undoubtedly plays an instrumental role.

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Acknowledgements

Supported by the European Research Council (ERC Advanced Grant number 340527 ReproPARK), Pathfinder CoEN grant (Ref: Phase II Call), Spanish Ministry of Economy and Competitiveness (Grant number BFU2012-27907), CiberNed (2014/01) and Fundació La Marató TV3 (Grant number 20141331). Salary for Diego Pignataro is partially supported by a Grant from Jon Zarandona. The plasmids, maps, and sequences of hRheb-S16H are a generous gift from Drs. R.E. Burke and N. Kholodilov from the Department of Neurology, Columbia University.

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    Authors and Affiliations

    1. Department of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII Ave 55, Edificio CIMA, 31008, Pamplona, Navarra, Spain

      D. Pignataro, D. Sucunza, A. J. Rico, I. G. Dopeso-Reyes, E. Roda & José L. Lanciego

    2. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

      D. Pignataro, D. Sucunza, A. J. Rico, I. G. Dopeso-Reyes, E. Roda, A. I. Rodríguez-Perez, J. L. Labandeira-Garcia & José L. Lanciego

    3. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

      D. Pignataro, D. Sucunza, A. J. Rico, I. G. Dopeso-Reyes, E. Roda & José L. Lanciego

    4. Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain

      A. I. Rodríguez-Perez & J. L. Labandeira-Garcia

    5. Division of Neuroscience, Ospedale San Raffaele, 20132, Milan, Italy

      V. Broccoli

    6. CNR Institute of Neuroscience, 20129, Milan, Italy

      V. Broccoli

    7. Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan

      S. Kato & K. Kobayashi

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    1. D. Pignataro
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    Correspondence to José L. Lanciego.

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    D. Pignataro and D. Sucunza contributed equally to the conducted work.

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    702_2017_1681_MOESM1_ESM.tif

    Supplementary Figure 1: Intranigral delivery of hRheb(S16H)-AAV5. (A) The left substantia nigra pars compacta was injected with hRheb(S16H)-AAV5 (arrowheads), whereas a GFP-coding AAV5 was delivered in the contralateral side for control purposes (arrow). (A’-A’’) Insets taken at higher magnification from the AAV-injected areas, as seen with the immunohistochemical detection of TH. (B-B’’’) Illustrative examples of FLAG-positive stained neurons in lateral territories of the left substantia nigra. (C-C’’) Immunohistochemical detection of GFP. GFP-positive neurons were only found in the right substantia nigra. (D-D’’): FLAG-positive axons travelling through the left medial forebrain bundle. (TIFF 13005 kb)

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    Pignataro, D., Sucunza, D., Rico, A.J. et al. Gene therapy approaches in the non-human primate model of Parkinson’s disease. J Neural Transm 125, 575–589 (2018). https://doi.org/10.1007/s00702-017-1681-3

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