Periodic Reporting for period 1 - RE-STORE (Pharmacological restoration of selective autophagy for the treatment of skeletal disorders)
Reporting period: 2021-01-01 to 2022-06-30
The ERC Starting grant BONEPHAGY allowed Dr. Settembre’s lab to identify and characterize an ER-to-lysosome procollagen trafficking route that is essential for collagen secretion. This process is mediated by autophagy of the endoplasmic reticulum (ER-phagy), via its receptor FAM134B. The Regulation of ER-phagy is particularly important in collagen producing cells, such as chondrocytes and osteoblasts during bone growth and it is defective in cells affected by lysosomal storage diseases (LSD).
The RE-STORE poc-grant main goal was the development of an integrated platform for the identification of selective inducers of the autophagy of endoplasmic reticulum (ER-phagy) that can restore ER-phagy and target the skeletal phenotype of lysosomal storage diseases and foster their drug development.
We have generated and validated ER-phagy reporter cell lines suitable for high content screening assay. We have tested three libraries of compounds and identified different ER-phagy inducing compounds. Next, In collaboration with the IRBM partner, we have generated a list of closely related analogs to be tested in the same phenotypic screening assay used during the hit’s generation campaign. In parallel we have optimised tools to study ER-phagy in vivo in mouse tissues and confirmed that ER-phagy is defective in tissues isolated from LSD mice, demonstrating that these tools can be useful to test hit compounds in vivo in disease relevant models. We monitored the findings in order to pursue an appropriate IPR protection strategy and analyse the market landscape to better evaluate our assets.
The RE-STORE poc-grant main goal was the development of an integrated platform for the identification of selective inducers of the autophagy of endoplasmic reticulum (ER-phagy) that can restore ER-phagy and target the skeletal phenotype of lysosomal storage diseases and foster their drug development.
We have generated and validated ER-phagy reporter cell lines suitable for high content screening assay. We have tested three libraries of compounds and identified different ER-phagy inducing compounds. Next, In collaboration with the IRBM partner, we have generated a list of closely related analogs to be tested in the same phenotypic screening assay used during the hit’s generation campaign. In parallel we have optimised tools to study ER-phagy in vivo in mouse tissues and confirmed that ER-phagy is defective in tissues isolated from LSD mice, demonstrating that these tools can be useful to test hit compounds in vivo in disease relevant models. We monitored the findings in order to pursue an appropriate IPR protection strategy and analyse the market landscape to better evaluate our assets.