Gaucher disease: Progress and ongoing challenges

Abstract

Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.

Treatment of profound thrombocytopenia in a patient with Gaucher disease type 1: Is there a role for substrate reduction therapy

“…However, there is a gap in the literature regarding individual drug effectiveness in treating specific symptoms and the potential benefits of combination treatment [11]. With five drugs currently approved for treatment of GD type 1, there is potential to tailor therapies to an individual patient's clinical concerns.…”

Electrostatic interactions drive native‐like aggregation of human alanine:glyoxylate aminostransferase

“…This phenomenon has important implications for the pharmaceutical industry, in particular for the formulation and manufacturing of therapeutic proteins [1][2][3]. The consequent reduction in the folding yield leads to a deficit in activity specific to the protein, such as chloride transport in the case of cystic fibrosis [6,7] or sphingolipid catabolism in the case of Gaucher's disease [8,9]. In age-related neurodegenerative disorders like Alzheimer's disease, a protein undergoes a conformational change favoring the formation of ordered oligomers and fibrillar aggregates that exert a toxic effect on a specific cell type [4,5].…”

“…In other cases, such as diseases caused by protein deficits, pathogenic mutations can promote the aggregation of the protein involved causing the formation of amorphous aggregates that undergo degradation. The consequent reduction in the folding yield leads to a deficit in activity specific to the protein, such as chloride transport in the case of cystic fibrosis [6,7] or sphingolipid catabolism in the case of Gaucher's disease [8,9].…”

Laboratory diagnosis and follow-up of Romanian Gaucher disease patients

“…Type 1 GD (the non-neuronopathic variant) is defined by the absence of primary neurological involvement, while a progressive neurodegenerative course is the hallmark of the disease in types 2 (the acute neuronopathic form) and 3 (the chronic neuronopathic subtype) (4). Current therapeutic options rely on enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase and substrate reduction therapy (SRT), monitored by several biomarkers, such as chemokines or enzymes produced by Gaucher cells (5,6).…”