Effective cell and gene therapy in a murine model of Gaucher disease

TLDR

Gaucher disease is a lysosomal storage disorder caused by GCase deficiency that leads to hepatosplenomegaly, cytopenias, and bone disease, yet existing mouse models are either lethal or lack these clinical features. The authors aim to develop a viable type 1 GD mouse model that can be used to evaluate safe and effective cell and gene therapies. They created mice by postnatal, conditional deletion of GCase exons 9‑11, producing animals that exhibit the characteristic clinical symptoms of type 1 GD. Transplantation of wild‑type bone marrow or retroviral gene‑edited bone marrow prevented disease onset and reversed established pathology, with gene therapy yielding higher GCase activity and complete clearance of Gaucher cells, proving the feasibility of in‑vivo gene therapy for type 1 GD.

Abstract

Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency in the enzyme glucosylceramidase (GCase) that causes hepatosplenomegaly, cytopenias, and bone disease as key clinical symptoms. Previous mouse models with GCase deficiency have been lethal in the perinatal period or viable without displaying the clinical features of GD. We have generated viable mice with characteristic clinical symptoms of type 1 GD by conditionally deleting GCase exons 9-11 upon postnatal induction. Both transplantation of WT bone marrow (BM) and gene therapy through retroviral transduction of BM from GD mice prevented development of disease and corrected an already established GD phenotype. The gene therapy approach generated considerably higher GCase activity than transplantation of WT BM. Strikingly, both therapeutic modalities normalized glucosylceramide levels and practically no infiltration of Gaucher cells could be observed in BM, spleen, and liver, demonstrating correction at 5-6 months after treatment. The findings demonstrate the feasibility of gene therapy for type 1 GD in vivo. Our type 1 GD mice will serve as an excellent tool in the continued efforts toward development of safe and efficient cell and gene therapy for type 1 GD.