Your browser doesn't support javascript.
loading
CRISPR/Cas9-mediated neuronal deletion of 5-lipoxygenase alleviates deficits in mouse models of epilepsy.
Guan, Qiwen; Wang, Zhaojun; Zhang, Kai; Liu, Zhaoqian; Zhou, Honghao; Cao, Danfeng; Mao, Xiaoyuan.
Afiliación
  • Guan Q; Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology and Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education
  • Wang Z; Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology and Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education
  • Zhang K; Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology and Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education
  • Liu Z; Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology and Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education
  • Zhou H; Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology and Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education
  • Cao D; Academician Workstation and Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical University, Changsha 410219, China.
  • Mao X; Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology and Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education
J Adv Res ; 63: 73-90, 2024 Sep.
Article en En | MEDLINE | ID: mdl-39048074
ABSTRACT

INTRODUCTION:

Our previous work reveals a critical role of activation of neuronal Alox5 in exacerbating brain injury post seizures. However, whether neuronal Alox5 impacts the pathological process of epilepsy remains unknown.

OBJECTIVES:

To prove the feasibility of neuron-specific deletion of Alox5 via CRISPR-Cas9 in the blockade of seizure onset and epileptic progression.

METHODS:

Here, we employed a Clustered regularly interspaced short-palindromic repeat-associated proteins 9 system (CRISPR/Cas9) system delivered by adeno-associated virus (AAV) to specifically delete neuronal Alox5 gene in the hippocampus to explore its therapeutic potential in various epilepsy mouse models and possible mechanisms.

RESULTS:

Neuronal depletion of Alox5 was successfully achieved in the brain. AAV delivery of single guide RNA of Alox5 in hippocampus resulted in reducing seizure severity, delaying epileptic progression and improving epilepsy-associated neuropsychiatric comorbidities especially anxiety, cognitive deficit and autistic-like behaviors in pilocarpine- and kainic acid-induced temporal lobe epilepsy (TLE) models. In addition, neuronal Alox5 deletion also reversed neuron loss, neurodegeneration, astrogliosis and mossy fiber sprouting in TLE model. Moreover, a battery of tests including analysis of routine blood test, hepatic function, renal function, routine urine test and inflammatory factors demonstrated no noticeable toxic effect, suggesting that Alox5 deletion possesses the satisfactory biosafety. Mechanistically, the anti-epileptic effect of Alox5 deletion might be associated with reduction of glutamate level to restore excitatory/inhibitory balance by reducing CAMKII-mediated phosphorylation of Syn ISer603.

CONCLUSION:

Our findings showed the translational potential of AAV-mediated delivery of CRISPR-Cas9 system including neuronal Alox5 gene for an alternative promising therapeutic approach to treat epilepsy.
Asunto(s)
Palabras clave

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Araquidonato 5-Lipooxigenasa / Modelos Animales de Enfermedad / Epilepsia / Sistemas CRISPR-Cas / Hipocampo / Neuronas Límite: Animals Idioma: En Revista: J Adv Res Año: 2024 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Araquidonato 5-Lipooxigenasa / Modelos Animales de Enfermedad / Epilepsia / Sistemas CRISPR-Cas / Hipocampo / Neuronas Límite: Animals Idioma: En Revista: J Adv Res Año: 2024 Tipo del documento: Article