Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington's disease

Shilpa Ramaswamy; Jodi L. McBride; Ina Han; Elizabeth M. Berry-Kravis; Lili Zhou; Christopher D. Herzog; Mehdi Gasmi; Raymond T. Bartus; Jeffrey H. Kordower

doi:10.1016/j.nbd.2008.12.005

Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington's disease

Shilpa Ramaswamy, Jodi L. McBride, Ina Han, Elizabeth M. Berry-Kravis, Lili Zhou, Christopher D. Herzog, Mehdi Gasmi, Raymond T. Bartus, Jeffrey H. Kordower

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Abstract

Members of the GDNF family of ligands, including neurturin (NTN), have been implicated as potential therapeutic agents for Huntington's disease (HD). The present study examined the ability of CERE-120 (AAV2-NTN) to provide structural and functional protection in the N171-82Q transgenic HD mouse model. AAV2-NTN therapy attenuated rotorod deficits in this mutant relative to control treated transgenics (p < 0.01). AAV2-NTN treatment significantly reduced the number of transgenic mice that exhibited clasping behavior and partially restored their stride lengths (both p < 0.05). Stereological counts of NeuN-ir neurons revealed a significant neuroprotection in the striatum of AAV2-NTN treated relative to control treated transgenics (p < 0.001). Most fascinating, stereological counts of NeuN-labeled cells in layers V-VI of prefrontal cortex revealed that intrastriatal AAV2-NTN administration prevented the loss of frontal cortical NeuN-ir neurons seen in transgenic mice (p < 0.01). These data indicate that gene delivery of NTN may be a viable strategy for the treatment of this incurable disease.

Original language	English (US)
Pages (from-to)	40-50
Number of pages	11
Journal	Neurobiology of Disease
Volume	34
Issue number	1
DOIs	https://doi.org/10.1016/j.nbd.2008.12.005
State	Published - Apr 2009

Keywords

AAV2
CERE-120
Gene therapy
Huntington's disease
N171-82Q
Neurturin
Transgenic mouse model

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2008.12.005

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Ramaswamy, S., McBride, J. L., Han, I., Berry-Kravis, E. M., Zhou, L., Herzog, C. D., Gasmi, M., Bartus, R. T., & Kordower, J. H. (2009). Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington's disease. Neurobiology of Disease, 34(1), 40-50. https://doi.org/10.1016/j.nbd.2008.12.005

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title = "Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington's disease",

abstract = "Members of the GDNF family of ligands, including neurturin (NTN), have been implicated as potential therapeutic agents for Huntington's disease (HD). The present study examined the ability of CERE-120 (AAV2-NTN) to provide structural and functional protection in the N171-82Q transgenic HD mouse model. AAV2-NTN therapy attenuated rotorod deficits in this mutant relative to control treated transgenics (p < 0.01). AAV2-NTN treatment significantly reduced the number of transgenic mice that exhibited clasping behavior and partially restored their stride lengths (both p < 0.05). Stereological counts of NeuN-ir neurons revealed a significant neuroprotection in the striatum of AAV2-NTN treated relative to control treated transgenics (p < 0.001). Most fascinating, stereological counts of NeuN-labeled cells in layers V-VI of prefrontal cortex revealed that intrastriatal AAV2-NTN administration prevented the loss of frontal cortical NeuN-ir neurons seen in transgenic mice (p < 0.01). These data indicate that gene delivery of NTN may be a viable strategy for the treatment of this incurable disease.",

keywords = "AAV2, CERE-120, Gene therapy, Huntington's disease, N171-82Q, Neurturin, Transgenic mouse model",

author = "Shilpa Ramaswamy and McBride, {Jodi L.} and Ina Han and Berry-Kravis, {Elizabeth M.} and Lili Zhou and Herzog, {Christopher D.} and Mehdi Gasmi and Bartus, {Raymond T.} and Kordower, {Jeffrey H.}",

note = "Funding Information: The funding for this project was from the Hope for Huntington's Foundation and a generous donation from the Fiori Family. CDH, JHK, MG, and RTN have a financial interest in Ceregene Inc.",

year = "2009",

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doi = "10.1016/j.nbd.2008.12.005",

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AU - Ramaswamy, Shilpa

AU - McBride, Jodi L.

AU - Han, Ina

AU - Berry-Kravis, Elizabeth M.

AU - Zhou, Lili

AU - Herzog, Christopher D.

AU - Gasmi, Mehdi

AU - Bartus, Raymond T.

AU - Kordower, Jeffrey H.

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N2 - Members of the GDNF family of ligands, including neurturin (NTN), have been implicated as potential therapeutic agents for Huntington's disease (HD). The present study examined the ability of CERE-120 (AAV2-NTN) to provide structural and functional protection in the N171-82Q transgenic HD mouse model. AAV2-NTN therapy attenuated rotorod deficits in this mutant relative to control treated transgenics (p < 0.01). AAV2-NTN treatment significantly reduced the number of transgenic mice that exhibited clasping behavior and partially restored their stride lengths (both p < 0.05). Stereological counts of NeuN-ir neurons revealed a significant neuroprotection in the striatum of AAV2-NTN treated relative to control treated transgenics (p < 0.001). Most fascinating, stereological counts of NeuN-labeled cells in layers V-VI of prefrontal cortex revealed that intrastriatal AAV2-NTN administration prevented the loss of frontal cortical NeuN-ir neurons seen in transgenic mice (p < 0.01). These data indicate that gene delivery of NTN may be a viable strategy for the treatment of this incurable disease.

AB - Members of the GDNF family of ligands, including neurturin (NTN), have been implicated as potential therapeutic agents for Huntington's disease (HD). The present study examined the ability of CERE-120 (AAV2-NTN) to provide structural and functional protection in the N171-82Q transgenic HD mouse model. AAV2-NTN therapy attenuated rotorod deficits in this mutant relative to control treated transgenics (p < 0.01). AAV2-NTN treatment significantly reduced the number of transgenic mice that exhibited clasping behavior and partially restored their stride lengths (both p < 0.05). Stereological counts of NeuN-ir neurons revealed a significant neuroprotection in the striatum of AAV2-NTN treated relative to control treated transgenics (p < 0.001). Most fascinating, stereological counts of NeuN-labeled cells in layers V-VI of prefrontal cortex revealed that intrastriatal AAV2-NTN administration prevented the loss of frontal cortical NeuN-ir neurons seen in transgenic mice (p < 0.01). These data indicate that gene delivery of NTN may be a viable strategy for the treatment of this incurable disease.

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Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington's disease

Abstract

Keywords

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