An integrated drug discovery strategy for rare endolysosomal disorders
Cystinosis - a prototype for rare inborn errors of metabolism known as lysosomal storage disorders (LSD) - causes dysfunction of the kidney proximal tubule (PT) and currently lacks curative treatments.
In this project, we combine knowledge target−driven and systems biology−based drug repurposing strategies with phenotypic screens in disease–relevant model organisms and cellular systems to catalyze the development of “first−in−class” therapeutics for cystinosis and other rare inherited disorders related to endolysosome dysfunction. These studies will accelerate the translation of novel therapies for rare diseases towards clinic.
Publications
Rega LR, De Leo E, Nieri D, Luciani A. Defective Cystinosin, Aberrant Autophagy-Endolysosome Pathways, and Storage Disease: Towards Assembling the Puzzle. Cells. 2022 Jan 19;11(3):326. doi: 10.3390/cells11030326. PMID: 35159136; PMCID: PMC8834619.
Keller SA, Luciani A. Mitochondrial Distress in Methylmalonic Acidemia: Novel Pathogenic Insights and Therapeutic Perspectives. Cells. 2022 Oct 10;11(19):3179. doi: 10.3390/cells11193179. PMID: 36231140; PMCID: PMC9563610.
Keller SA, Chen Z, Gaponova A, Korzinkin M, Berquez M, Luciani A. Drug discovery and therapeutic perspectives for proximal tubulopathies. Kidney Int. 2023 Dec;104(6):1103-1112. doi: 10.1016/j.kint.2023.08.026. Epub 2023 Sep 30. PMID: 37783447.
Keller S, Luciani A, Devuyst O. The structure of megalin: shedding new light on receptor-mediated endocytosis. Kidney Int. 2024 Jan;105(1):11-14. doi: 10.1016/j.kint.2023.05.026. Epub 2023 Jun 26. PMID: 37380129.
Berquez M, Chen Z, Festa BP, Krohn P, Keller SA, Parolo S, Korzinkin M, Gaponova A, Laczko E, Domenici E, Devuyst O, Luciani A. Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization. Nat Commun. 2023 Jul 14;14(1):3994. doi: 10.1038/s41467-023-39261-3. PMID: 37452023; PMCID: PMC10349091.
Luciani A, Devuyst O. The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis. Autophagy. 2024 Jan;20(1):202-204. doi: 10.1080/15548627.2023.2250165. Epub 2023 Aug 24. PMID: 37621073; PMCID: PMC10761040.
Bellomo F, Pugliese S, Cairoli S, Krohn P, De Stefanis C, Raso R, Rega LR, Taranta A, De Leo E, Ciolfi A, Cicolani N, Petrini S, Luciani A, Goffredo BM, Porzio O, Devuyst O, Dionisi-Vici C, Emma F. Ketogenic Diet and Progression of Kidney Disease in Animal Models of Nephropathic Cystinosis. J Am Soc Nephrol. 2024 Nov 1;35(11):1493-1506. doi: 10.1681/ASN.0000000000000439. Epub 2024 Jul 12. PMID: 38995697; PMCID: PMC11543012.
Mallilankaraman KB, Kennedy BK, Sorrentino V, Luciani A. Editorial: Mitochondria at the nexus of metabolism, aging, and disease. Front Cell Dev Biol. 2024 Jan 11;11:1356278. doi: 10.3389/fcell.2023.1356278. PMID: 38274275; PMCID: PMC10808772.
Keller S, Luciani A, Devuyst O. The structure of megalin: shedding new light on receptor-mediated endocytosis. Kidney Int. 2024 Jan;105(1):11-14. doi: 10.1016/j.kint.2023.05.026. Epub 2023 Jun 26. PMID: 37380129.
Luciani A, Devuyst O. The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis. Autophagy. 2024 Jan;20(1):202-204. doi: 10.1080/15548627.2023.2250165. Epub 2023 Aug 24. PMID: 37621073; PMCID: PMC10761040.