A strategy of drug repurposing for rare disease population: Application to Zellweger spectrum disorders

Abstract

Drug repurposing is a strategy increasingly used to overcome the challenges of the pharmaceutical industry model. Apteeus has been pursuing an original strategy for 10 years to identify new opportunities of drug repurposing by running drug screening individually. The use of primary patient cells, differentiated or not, is a good way to model a pathology in vitro whenever the defect causing the symptoms is clearly expressed at the cellular level. This is the case for peroxisomal diseases. This strategy was efficiently applied to a Zellweger spectrum disorders (ZSD) program launched in 2021 and allowed us, in less than one year, to identify a promising therapy addressing ZSD. ZSD gather a group of diseases affecting peroxisomes biogenesis. This defect is caused by mutations in one of the 13 PEX genes encoding peroxins. Patients suffer from a broad diversity of symptoms depending to the disease severity. Through them, liver dysfunction is often responsible to an early death.Practically, we developed a screening assay and performed high-throughput screening of all the 2600 compounds of the TEE Library, our proprietary repurposable drug library. We found compounds able to restores the main disease hallmarks. Indeed, TEE1767 treatment increased peroxisome abundance, restored peroxisome assembly and improved lipid synthesis functions close to the levels observed for WT cells. We then extend the study to twenty more patients and confirmed the interest in going further with this drug.We now plan to transpose the in vitro results in patients by conducting a first proof of efficacy clinical trial. The trial will aim to assess the safety of TEE1767 in ZSD patients as well to show the first biochemical and clinical improvements. TEE1767 can be the first life-changing therapy for ZSD patients.