Personalized Drug Repurposing Screen Identifies Patient-Specific Therapeutic Candidates for Mucopolysaccharidosis...

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Mucopolysaccharidosis type IIIB (MPSIIIB) is a rare lysosomal storage disease due to alpha-N-acetylglucosaminidase (NAGLU) deficiency.
• Heparan sulfate accumulation and severe neurological decline characterize MPSIIIB.
• Genetic heterogeneity in MPSIIIB necessitates personalized therapeutic strategies.

Purpose of the Study:

• To establish a personalized drug repurposing platform for MPSIIIB.
• To screen compounds for correcting lysosomal defects in patient-derived fibroblasts.
• To investigate patient-specific drug efficacy based on genetic variations.

Main Methods:

• High-content imaging with lysotracker dye screened 2807 compounds.
• Patient fibroblasts with distinct NAGLU mutations were used.
• Hits were validated for efficacy and cytotoxicity, with cross-validation in a second patient's cells.

Main Results:

• A 2.6% hit rate yielded 72 compounds, with 10 confirmed.
• Four approved drugs showed efficacy in the index patient but not the second.
• Only one compound showed a trend toward activity in both cell lines, highlighting patient-specific effects.

Conclusions:

• A feasible framework for N-of-1 drug repurposing in rare diseases was demonstrated.
• Patient-specific efficacy underscores the limitations of a one-size-fits-all approach for MPSIIIB.
• Individualized drug screening offers a potential precision medicine strategy for rare diseases.