Best disease (BD) is a progessive retinal disorder, which is usually symptomatic already in childhood and adolescence and progresses over the years, in some case until blindness. The disease is characterized by an accumulation of lipofuscin-like material and subretinal fluids causing the formation of serous retinal detachment and lesions. To date, no treatment exists. Dominant negative mutations in the Bestrophin 1 (BEST1) gene are causative for the disease thereby affecting the structure of the BEST1 chloride channel composed of five identical BEST1 subunits and ultimately lead to the loss of chloride conductivity of the channel in the retinal pigment epithelium (RPE) of the retina. To develop effective therapies, our Institute has established a highly innovative disease model by differentiating the retinal cell type of primary pathology from patient-derived induced pluripotent stem cell lines. Using this in vitro model we have built two pipelines including a high-throughput compound screening to search methodically for bioactive substances potentiating or correcting the mutated protein as well as genome editing technology to remove the mutated copy by leaving the non-mutated allele unaffected. The ongoing work is aimed to investigate the effectiveness of these two therapeutic approaches.
- Nachtigal AL, Milenkovic A, Brandl C, Schulz HL, Duerr LMJ, Lang GE, Reiff C, Herrmann P, Kellner U, Weber BHF. Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies. Int J Mol Sci. 2020 Feb 26;21(5):1597. doi: 10.3390/ijms21051597
- Milenkovic A, Schmied D, Tanimoto N, Seeliger MW, Sparrow JR, Weber BHF. The Y227N mutation affects bestrophin-1 protein stability and impairs sperm function in a mouse model of Best vitelliform macular dystrophy. Biol Open. 2019 Jul 2;8(7):bio041335. doi: 10.1242/bio.041335