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