Clinical Development of Cell Therapies to Halt Lysosomal Storage Diseases: Results and Lessons Learned

: Although cross-correction was discovered more than 50 years ago, and held the promise of drastically improving disease management, still no cure exists for lysosomal storage diseases (LSDs). Cell therapies hold the potential to halt disease progression: either a subset of autologous cells can be ex vivo/ in vivo transfected with the functional gene or allogenic wild type stem cells can be transplanted. However, majority of cell-based attempts have been ineffective, due to the difficulties in reversing neuronal symptomatology, in finding appropriate gene transfection approaches, in inducing immune tolerance, reducing the risk of graft versus host disease (GVHD) when allogenic cells are used and that of immune response when engineered viruses are administered, coupled with a limited secretion and uptake of some enzymes. In the last decade, due to advances in our understanding of lysosomal biology and mechanisms of cross-correction, coupled with progresses in gene therapy, ongoing pre-clinical and clinical investigations have remarkably increased. Even gene editing approaches are currently under clinical experimentation. This review proposes to critically discuss and compare trends and advances in cell-based and gene therapy for LSDs. Systemic gene delivery and transplantation of allogenic stem cells will be initially discussed, whereas proposed brain targeting methods will be then critically outlined.