GSK-3 role as a potential therapeutic target for treatment of retinitis pigmentosa

A collaborative research project between the 3D Lab (Drs. Catalina Hernández-Sánchez and Enrique J. de la Rosa) and the Translational Medicinal and Biological Chemistry team (Prof. Ana Martínez and Dr. Carmen Gil), both at Centro de Investigaciones Biológicas, has provided a proof of concept for a potential therapy for retinitis pigmentosa which has been recently published in the Journal of Molecular Neurodegeneration.

Retinitis pigmentosa refers to a group of inherited retinal dystrophies caused by a large set of genetic mutations in numerous genes. Despite the genetic diversity, the causative mutations usually trigger photoreceptor cell degeneration and death, leading to visual function decline and, eventually, blindness. To date, no effective therapies have been transferred to clinic. Given the diverse genetic etiology of this neurodegenerative condition, targeting common cellular and molecular retinal alterations has emerged as a potential therapeutic strategy.

Glycogen synthase kinase 3 (GSK-3) plays a key role in modulating inflammatory response, a process occurring in the degenerating retina that involves microglial activation, reactive macrogliosis, and the production of pro-inflammatory cytokines. Employing a chemical genetic approach, the collaborative team had previously characterized the neuroprotective effects of 3 chemically diverse GSK-3 modulators in photoreceptor cells, results which were published in 2017 in J. Enzyme Inhib. Med. Chem.

In the present work, which has counted on the collaboration of groups of the UAH School of Medicine and the UCM School of Medicine, the researchers have validated in vivo the potential of GSK-3 as a therapeutic target for the treatment of retinitis pigmentosa. In vivo administration of VP3.15, the GSK-3 modulator selected in the previous work, reduced photoreceptor cell loss and preserved photoreceptor cell structure and visual function. This neuroprotective effect was accompanied by a decrease in the expression of neuroinflammatory markers.

The obtained results have a potential for knowledge transfer to drug development in the medium-term, but also increase the basic knowledge on the molecular bases of retinal neurodegenerative conditions.

References:
Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa. Alonso Sánchez-Cruz, Beatriz Villarejo-Zori, Miguel Marchena, Josefa Zaldivar-Díez, Valle Palomo, Carmen Gil, Ignacio Lizasoain, Pedro de la Villa, Ana Martínez, Enrique J. de la Rosa, and Catalina Hernández-Sánchez (2018) Mol Neurodegener. 13: 19. doi: 10.1186/s13024-018-0251-y

Small molecules targeting glycogen synthase kinase 3 as potential drug candidates for the treatment of retinitis pigmentosa. Miguel  Marchena, Beatriz Villarejo-Zori, Josefa Zaldivar-Díez, Valle Palomo, Carmen Gil, Catalina Hernández-Sánchez, Ana Martínez, and Enrique J. de la Rosa (2017) J Enzyme Inhib Med Chem. 32:522. doi: 10.1080/14756366.2016.1265522