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Phosphodiesterase inhibitors as Friedreich's ataxia treatment

18th national competition for scientific and technical research

Rare diseases

Senior Researcher : Pilar González Cabo

Research Centre or Institution : Centro de Investigación Biomédica en Red (CIBER de Enfermedades Raras). Facultad de Medicina y Odontología. Universidad de Valencia


Friedreich's ataxia (FRDA) is a rare disease (OMIM # 229300, ORPHA95) that is classified as a hereditary peripheral neuropathy of the sensory type, with autosomal recessive inheritance, and that entails axonal loss that affects the thick fibers. It is caused by the deficiency of a protein, located in the mitochondria, called frataxin. This pathology does not yet have a treatment that alters the natural history of the neurological disease.

 In this project, a new treatment pathway for FRDA has been explored with the application of phosphodiesterase inhibitors, specifically the compounds rolipram and sidelnafil, developing a pre-clinical test in a FRDA mouse model (YG8sR). We observed that post-symptomatic treatment of the YG8sR mice, with both compounds, improved their motor dysfunction, attenuating the progression of the disease. These results suggest that phosphodiesterase inhibitors can be used as disease-modifying therapy, even when administered after the onset of symptoms.

We confirmed that both sildenafil and rolipram also improve the locomotor phenotype in Drosophila melanogaster model with systemic frataxin deficiency, or restricted to sensory or proprioceptive neurons. These pharmacological treatments do not lead to an increase in frataxin levels. To find out the biochemical mechanisms associated with the action of these compounds, 118 candidate genes related to G-protein-mediated cellular signaling pathways (GPCR) were studied, using the ubiquitous frataxin deficiency model. The genetic modifiers identified were validated in neuronal fly models of frataxin deficiency, reducing to 19 genes that modify the phenotype or affect the viability of flies in the different types of models. Our results indicate that the Rock-Limk pathway would mediate the effect of sildenafil, in addition to signaling as a new therapeutic target in FRDA the control of actin cytoskeleton dynamics.


Scientific Production
Magazine Articles 7
Communications at national conferences 3
Communications at international conferences 3


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