Effect of Two Different Therapeutic Interventions: SRT in Comparison to ERT on Immune Aspects and Bone Involvement in Gaucher Disease

Introduction

Lysosomes are small, cytoplasmic organelles that contain several acid hydrolase enzymes. These enzymes break down foreign materials and cellular debris allowing the lysosomes to act as recycling centers for the cells. Following DNA transcription, lysosomal enzymes are produced in the endoplasmic reticulum and targeted to lysosomes by specific recognition markers. If one of the enzymes is absent or if its function is diminished due to either an altered amino acid sequence of the protein or defective intracellular trafficking, the macromolecules metabolized by the specific enzyme will gradually accumulate in the lysosomes. Abnormal substrate storage leads to cellular dysfunction followed by cell death ultimately manifesting as tissue damage and organ failure.

Gaucher disease (GD) is a lysosomal storage disorder caused by a genetic deficiency of the lysosomal enzyme glucocerebrosidase. GD leads to accumulation of glycosphingolipids in various tissue systems, most notably in cells of mononuclear phagocyte system resulting in a wide range of heterogenous phenotypic effects in the affected individuals. Clinical manifestations of GD affect across multiple organs ranging from immune dysregulations, splenomegaly to bone crises and osteoporosis. Carrier frequency is 1 in 200 for the general population with an incidence of 1 in 60,000. However, in certain populations, such as Ashkenazi Jews, the incidence could be as high as 1 in 1,000.

Background and Significance

Macrophage directed Enzyme replacement therapy (ERT) has been the most accepted form of treatment for GD. However there are still unmet needs in treating all aspects of GD using ERT. As an alternative to ERT, substrate reduction therapy (SRT) was developed using glucosylceramide synthase inhibitors. While ERT is devised to target macrophages which are the most affected cell types, SRT is meant to reach broad cell types. It is vital to know how each form of therapy acts on different cell types and tissues while choosing to administer either form of treatment on individual patients. Our preliminary immune phenotyping results reveal that patients with GD undergoing treatment manifest various kinds of persistent immune dysregulations. Information regarding which type of therapy works better in controlling these dysregulations would give valuable information in treatment options. In-depth analysis on peripheral blood would shed light as to how various components of immune system are being affected with either form of treatment.