Widespread AAV1- and AAV2-mediated transgene expression in the nonhuman primate brain: implications for Huntington's disease

Piotr Hadaczek; Lisa Stanek; Agnieszka Ciesielska; Vivek Sudhakar; Lluis Samaranch; Philip Pivirotto; John Bringas; Catherine O'Riordan; Bryan Mastis; Waldy San Sebastian; John Forsayeth; Seng H Cheng; Krystof S Bankiewicz; Lamya S Shihabuddin

doi:10.1038/mtm.2016.37

Molecular Therapy: Methods & Clinical Development (Jan 2016)

Widespread AAV1- and AAV2-mediated transgene expression in the nonhuman primate brain: implications for Huntington's disease

Piotr Hadaczek,
Lisa Stanek,
Agnieszka Ciesielska,
Vivek Sudhakar,
Lluis Samaranch,
Philip Pivirotto,
John Bringas,
Catherine O'Riordan,
Bryan Mastis,
Waldy San Sebastian,
John Forsayeth,
Seng H Cheng,
Krystof S Bankiewicz,
Lamya S Shihabuddin

Affiliations

Piotr Hadaczek: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
Lisa Stanek: Rare Disease Unit, Neuroscience, Sanofi-Genzyme, Framingham, MA, USA
Agnieszka Ciesielska: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
Vivek Sudhakar: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
Lluis Samaranch: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
Philip Pivirotto: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
John Bringas: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
Catherine O'Riordan: Rare Disease Unit, Neuroscience, Sanofi-Genzyme, Framingham, MA, USA
Bryan Mastis: Rare Disease Unit, Neuroscience, Sanofi-Genzyme, Framingham, MA, USA
Waldy San Sebastian: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
John Forsayeth: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
Seng H Cheng: Rare Disease Unit, Neuroscience, Sanofi-Genzyme, Framingham, MA, USA
Krystof S Bankiewicz: Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
Lamya S Shihabuddin: Rare Disease Unit, Neuroscience, Sanofi-Genzyme, Framingham, MA, USA

DOI: https://doi.org/10.1038/mtm.2016.37
Journal volume & issue: Vol. 3, no. C

Abstract

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Huntington's disease (HD) is caused by a toxic gain-of-function associated with the expression of the mutant huntingtin (htt) protein. Therefore, the use of RNA interference to inhibit Htt expression could represent a disease-modifying therapy. The potential of two recombinant adeno-associated viral vectors (AAV), AAV1 and AAV2, to transduce the cortico-striatal tissues that are predominantly affected in HD was explored. Green fluorescent protein was used as a reporter in each vector to show that both serotypes were broadly distributed in medium spiny neurons in the striatum and cortico-striatal neurons after infusion into the putamen and caudate nucleus of nonhuman primates (NHP), with AAV1-directed expression being slightly more robust than AAV2-driven expression. This study suggests that both serotypes are capable of targeting neurons that degenerate in HD, and it sets the stage for the advanced preclinical evaluation of an RNAi-based therapy for this disease.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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