Deacon R, Hurley M, Martínez Rebolledo C, Snape M, Altimiras F, Pino M, Leandro F, Glass L, Cogram P. Nrf2, A Novel Therapeutic Target in Fragile X Syndrome is Modulated by NNZ2566. 2017

Nrf2, A Novel Therapeutic Target in Fragile X Syndrome is Modulated by NNZ2566.

 

AUTORES Deacon R, Hurley M, Martínez Rebolledo C, Snape M, Altimiras F, Pino M, Leandro F, Glass L, Cogram P.
AÑO 2017
JOURNAL Brain and Behavior
VOLUMEN Feb 17
ABSTRACT Fragile X-associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders is fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism. Progress in basic neuroscience has led to identification of molecular targets for treatment in FXS; however, there is a gap in translation to targeted therapies in humans. The present study introduces a novel therapeutic target for FXS: nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor known to induce expression of over 100 cytoprotective genes. We also demonstrate that NNZ2566, a drug that has successfully completed a phase 2 clinical trial in FXS, is effective in modulating this target in FXS, partially reversing the FXS phenotype: NNZ2566 has a therapeutic role as Nrf2 activator. Effectively, treatment with NNZ2566 normalizes the translocation of Nrf2 to the nucleus, inducing expression of numerous oxidative stress related genes including NQO1, GST-α1 and EH and has a knockdown effect on E-cadherin. In summary, the Nrf2/ARE pathway appears to be a novel promising therapeutic target for FXS and NNZ2566 appears to be acting as an activator of the Nrf2/ARE pathway and suggests a potential benefit across multiple symptoms that could be associated with the pathobiological processes underlying FXS.
RESUMEN El presente estudio introduce una nueva vía molecular en el FXS, el factor 2 asociado con el factor nuclear eritroide 2 (Nrf2), un factor de transcripción regulador de la transcripción génica mediada por los elementos de respuesta antioxidante (ERA) implicado en el mantenimiento del equilibrio redox; así como los procesos de angiogenesis, autofagia y de neruoinflamación.