Imiglucerase in the treatment of Gaucher disease: a history and perspective

Deegan, Patrick; Cox, Timothy M.

doi:10.2147/dddt.s14395

Cited by 27 publications

(7 citation statements)

References 170 publications

(197 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pharmacological chaperone (PC) therapy is a new strategy to increase residual activity by stabilizing misfolded mutant proteins, preventing endoplasmic-reticulum-associated degradation in proteasomes and allowing trafficking to lysosomes [73,74]. This approach is especially applicable in GD because only a modest increase in residual GBA should be sufficient to ameliorate the phenotype.…”

Section: Therapeutics Of Gdmentioning

confidence: 99%

Gaucher Disease: Clinical, Biological and Therapeutic Aspects

Dandana¹,

Khelifa²,

Chahed³

et al. 2015

Pathobiology

111

View full text Add to dashboard Cite

We present a brief review of Gaucher disease (GD), the most common lysosomal storage disease. GD is a rare autosomal recessive disorder characterized by the defective function of the catabolic enzyme β-glucocerebrosidase (GBA), leading to an accumulation of its substrate, glucocerebroside. Clinical signs and symptoms include neurological dysfunctions, bone infarcts and malformations, hepatosplenomegaly and hypersplenism leading to anemia, neutropenia and thrombocytopenia. Enzyme replacement therapy with recombinant GBA is the mainstay of treatment for GD, which became the first successfully managed lipid storage disease. Future treatments may include oral enzyme replacement and/or gene therapy interventions.

show abstract

Section: Therapeutics Of Gdmentioning

confidence: 99%

Gaucher Disease: Clinical, Biological and Therapeutic Aspects

Dandana¹,

Khelifa²,

Chahed³

et al. 2015

Pathobiology

111

View full text Add to dashboard Cite

show abstract

“…The mutations in glucocerebrosidase often cause decreased protein stability or enzymatic activity [ 2 – 5 ]. In Gaucher patients, glucocerebrosidase activity is decreased to ~ 5–20% of normal levels [ 3 ] and is accompanied by increased levels of its natural substrate, glucosylceramide [ 6 ]. The current treatment is peripheral administration of the active enzyme, glucocerebrosidase [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Tool Compounds Robustly Increase Turnover of an Artificial Substrate by Glucocerebrosidase in Human Brain Lysates

et al. 2015

View full text Add to dashboard Cite

Mutations in glucocerebrosidase (GBA1) cause Gaucher disease and also represent a common risk factor for Parkinson’s disease and Dementia with Lewy bodies. Recently, new tool molecules were described which can increase turnover of an artificial substrate 4MUG when incubated with mutant N370S GBA1 from human spleen. Here we show that these compounds exert a similar effect on the wild-type enzyme in a cell-free system. In addition, these tool compounds robustly increase turnover of 4MUG by GBA1 derived from human cortex, despite substantially lower glycosylation of GBA1 in human brain, suggesting that the degree of glycosylation is not important for compound binding. Surprisingly, these tool compounds failed to robustly alter GBA1 turnover of 4MUG in the mouse brain homogenate. Our data raise the possibility that in vivo models with humanized glucocerebrosidase may be needed for efficacy assessments of such small molecules.

show abstract

“…The clinical use of therapeutic proteins pre-dated today’s recombinant protein production technologies with early generations of these drugs obtained from natural sources; insulin is a well-known example initially derived from bovine and porcine pancreases. Additional examples from the current report include hyaluronidase obtained from mammalian sperm, β-glucocerebrosidase isolated from human placenta ( Deegan & Cox 2012 ), blood coagulation and clotting factors obtained from human plasma, and FSH prepared from human urine from postmenopausal women. In some cases, exemplified by β-glucocerebrosidase, glycoengineering was a critical enabling technology to turn this enzyme into a useful drug by installing high mannose N-glycans ( Figure 1B ) that enabled macrophage uptake to treat GD.…”

Section: Considerations For the Design And Production Of Glycoenginee...mentioning

confidence: 99%

Strategies for Glycoengineering Therapeutic Proteins

et al. 2022

View full text Add to dashboard Cite

Almost all therapeutic proteins are glycosylated, with the carbohydrate component playing a long-established, substantial role in the safety and pharmacokinetic properties of this dominant category of drugs. In the past few years and moving forward, glycosylation is increasingly being implicated in the pharmacodynamics and therapeutic efficacy of therapeutic proteins. This article provides illustrative examples of drugs that have already been improved through glycoengineering including cytokines exemplified by erythropoietin (EPO), enzymes (ectonucleotide pyrophosphatase 1, ENPP1), and IgG antibodies (e.g., afucosylated Gazyva®, Poteligeo®, Fasenra™, and Uplizna®). In the future, the deliberate modification of therapeutic protein glycosylation will become more prevalent as glycoengineering strategies, including sophisticated computer-aided tools for “building in” glycans sites, acceptance of a broad range of production systems with various glycosylation capabilities, and supplementation methods for introducing non-natural metabolites into glycosylation pathways further develop and become more accessible.

show abstract

Imiglucerase in the treatment of Gaucher disease: a history and perspective

Cited by 27 publications

References 170 publications

Gaucher Disease: Clinical, Biological and Therapeutic Aspects

Gaucher Disease: Clinical, Biological and Therapeutic Aspects

Tool Compounds Robustly Increase Turnover of an Artificial Substrate by Glucocerebrosidase in Human Brain Lysates

Strategies for Glycoengineering Therapeutic Proteins

Contact Info

Product

Resources

About