ARI-YI Grant

Developing HDAC inhibitors to treat inherited photoreceptor degeneration

01.11.2013 bis 31.12.2017

Epigenetic processes are increasingly recognized as major factors in human diseases and we have previously demonstrated the relevance of epigenetics for photoreceptor degeneration in animal models for Retinitis Pigmentosa (RP) (Paquet-Durand et al., 2007; Sahaboglu et al., 2010; Sancho-Pelluz et al., 2010). Specifically, we showed that inhibition of histone deacetylase (HDAC) was particularly effective in protecting photoreceptors in the retinal degeneration-1 (rd1) mouse.
Interestingly, a single, short-term application of the HDAC inhibitor trichostatin A (TSA) on rd1 retina in vitro illustrated a long lasting protective effect, suggesting a stable reprogramming of the photoreceptor transcriptional machinery favoring cell survival. Apart from our own work, a number of recent studies from other labs suggest HDAC inhibition as a promising novel avenue for retinal protection.
In our study, we will initially assess the extent of HDAC activation in different animal models for inherited retinal degeneration (e.g. RP, Achromatopsia), to then test in the same animal models different HDAC inhibitors, first in vitro, then in vivo.

To this end, we propose to address the following objectives:
1) To test for HDAC activity in a number of different, human homologous animal models for inherited retinal degeneration (rd2, rd10, cpfl1, Rho P23H, Rho S334ter), to ascertain a general involvement of HDAC in photoreceptor degenerations triggered by different genetic defects.

2) To study several different HDAC inhibitors that are already clinically approved (SAHA, valproic acid) or are currently in clinical trials (Entinostat, Mocetinostat) for a variety of different other indications, in the context of inherited photoreceptor degeneration.

3) To test HDAC inhibitors that are not yet used in clinical trials but do exhibit isoform specificity (i.e. Apicidin, M344) in order to attribute protective effects to specific HDAC isoforms. The latter will be of importance for an improved targeting of HDAC inhibitors and thus the development of future HDAC inhibition based treatments.

4) To assess the long-term effects of HDAC inhibitors in varying in vitro and in vivo treatment paradigms to establish potential treatment regimes for further pre-clinical and clinical studies.