Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington's disease.
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.
Ramaswamy
Shilpa
S
Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 300, Chicago, IL 60612, USA.
McBride
Jodi L
JL
Han
Ina
I
Berry-Kravis
Elizabeth M
EM
Zhou
Lili
L
Herzog
Christopher D
CD
Gasmi
Mehdi
M
Bartus
Raymond T
RT
Kordower
Jeffrey H
JH
D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology*; D003342:Corpus Striatum / Q000503:physiopathology*; D004268:DNA-Binding Proteins; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D051101:Neurturin / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D045442:Rotarod Performance Test
D004268:DNA-Binding Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D051101:Neurturin; D009687:Nuclear Proteins