Inherited retinal dystrophies (IRD) are rare disorders of the retina that cause degeneration of photoreceptors. Even though a majority of IRD causative mutations primarily affect rod photoreceptors, the visual handicap severs over time. Primary rod degeneration is followed by secondary cone photoreceptor death, then leading to fast progressive visual field constriction, abnormal color vision, and finally complete blindness [1]. The causative mutations for IRD are tremendously complex covering a range of more than 200 genes [2]. However, developing individual tailor-made gene therapies is both time-consuming and expensive, creating a need for the development of complementary mutation-independent therapeutic strategies that are applicable regardless of the primary genetic defect. Retinal Müller glial cells (RMG) have been recognized as important intrinsic source of life-long support for photoreceptors and other retinal neurons [3]. 



The recent developments of innovative genome editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9 (CRISPR/Cas9) have boosted the field of gene therapy. Most importantly, the wildtype Cas9 nuclease was recently modified into a catalytically inactive form, deadCas9 (dCas9). Fusion with transcriptional activators transforms the dCas9 into a guidable modulator of target gene expression [4, 5]. Our aim is to develop an Adeno-Associated Virus (AAV) vector system to modify gene expression specifically in RMG. Thereby, multiplex induction of neurotrophic genes in RMG should supplement the loss of rod-derived neurotrophic factors. Furthermore, we investigate the immune-response and inflammatory potential of dCas9 expression in RMG.

1. Kennan, A., A. Aherne, and P. Humphries, Light in retinitis pigmentosa. Trends Genet, 2005. 21(2): p. 103-10.

2. Daiger, S.P., Sullivan, L.S., Bowne, S.J. RetNet - Retinal Information Network. 2019 May 21, 2019 [cited 2019 June 28]; Available from: https://sph.uth.edu/retnet/.

3. Bringmann, A., et al., Cellular signaling and factors involved in Muller cell gliosis: neuroprotective and detrimental effects. Prog Retin Eye Res, 2009. 28(6): p. 423-51.

4. Konermann, S., et al., Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature, 2015. 517(7536): p. 583-8.

5. Gilbert, L.A., et al., CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell, 2013. 154(2): p. 442-51.