The stabilization of mutated glucocerebrosidase (GCase) in Gaucher disease (GD) remains an unresolved challenge in conventional therapies like enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), which are expensive and fail to treat neurological GD (nGD) forms. The misfolded enzyme fails to reach the lysosome and form aggregates, contributing to cellular stress. In the present work, a virtual screening of a metal ion library was reported, that enabled the identification of Ni2+ as the lead, demonstrating a high binding score to the active site of GCase. Nickel Prussian blue analogue nanoparticles (NiPB NPs) were synthesized, which showed an enhancement of GCase activity in the brain, liver, and spleen (∼35%, 25%, and 20%, respectively), higher than that of untreated CBE-induced GD mice. Improvement in the motor skills of GD mice highlights the potential of NiPB NP in managing nGD forms. The NiPB NP successfully elevated the residual activity of GCase (∼120% at 10 μg/mL dose) in the GBA1 siRNA knockdown HEK cell model. Finally, in an in vivo siRNA-mediated gene knockdown model, the NiPB NP enhanced the GCase activity in the organs significantly more than the untreated mice and alleviated GD symptoms.
Manna et al. (Mon,) studied this question.