Last update 01 Nov 2024

GBA1 x GlcCer

Last update 01 Nov 2024

Basic Info

Related Targets

GBA1GlcCer

Drugs associated with GBA1 x GlcCer

GD-BT6822

Target

GBA1 x GlcCer

Mechanism

GBA stimulants [+1]

Active Org.

BioArctic AB

Originator Org.

BioArctic AB

Active Indication

Gaucher Disease

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GBA1 x GlcCer

100 Translational Medicine associated with GBA1 x GlcCer

0 Patents (Medical) associated with GBA1 x GlcCer

163

Literatures (Medical) associated with GBA1 x GlcCer

01 Sep 2024·Gene Therapy

Efficacy of an AAV vector encoding a thermostable form of glucocerebrosidase in alleviating symptoms in a Gaucher disease mouse model

Article

Author: Tsoory, Michael ; Hochfelder, Ariel ; Oren, Roni ; Biton, Inbal E ; Blumenreich, Shani ; Zerbib, Mirie ; Joseph, Tammar ; Fleishman, Sarel J ; Milenkovic, Ivan ; Futerman, Anthony H ; Azulay, Aviya

AbstractAlmost all attempts to date at gene therapy approaches for monogenetic disease have used the amino acid sequences of the natural protein. In the current study, we use a designed, thermostable form of glucocerebrosidase (GCase), the enzyme defective in Gaucher disease (GD), to attempt to alleviate neurological symptoms in a GD mouse that models type 3 disease, i.e. the chronic neuronopathic juvenile subtype. Upon injection of an AAVrh10 (adeno-associated virus, serotype rh10) vector containing the designed GCase (dGCase) into the left lateral ventricle of Gba−/−;Gbatg mice, a significant improvement in body weight and life-span was observed, compared to injection of the same mouse with the wild type enzyme (wtGCase). Moreover, a reduction in levels of glucosylceramide (GlcCer), and an increase in levels of GCase activity were seen in the right hemisphere of Gba−/−;Gbatg mice, concomitantly with a significant improvement in motor function, reduction of neuroinflammation and a reduction in mRNA levels of various genes shown previously to be elevated in the brain of mouse models of neurological forms of GD. Together, these data pave the way for the possible use of modified proteins in gene therapy for lysosomal storage diseases and other monogenetic disorders.

06 Aug 2024·Analytical Chemistry

Evaluation of a Liquid Chromatography–Tandem Mass Spectrometry Method for the Analysis of Glucosylceramide and Galactosylceramide Isoforms in Cerebrospinal Fluid of Parkinson’s Disease Patients

Article

Author: Carnicer-Caceres, Clara ; Camprodon-Gomez, Maria ; Hernández-Vara, Jorge ; Martinez-Vicente, Marta ; Pozo, Sara Lucas-Del ; Castillo-Ribelles, Laura ; Arranz-Amo, Jose Antonio ; Samaniego-Toro, Daniela ; Enriquez-Calzada, Silvia ; Ferrer, Roser ; Laguna, Ariadna ; Gonzalo, Mercedes Arrúe

Mutations in GBA1, encoding glucocerebrosidase beta 1 (GCase), are the most common genetic risk factor for Parkinson's disease (PD). GCase dysfunction leads to an accumulation of glucosylceramide (GluCer) substrates in different organs and fluids. Despite the challenges in quantifying GluCer isoforms in biological samples, their potential clinical interest as PD biomarkers justifies the development of robust assays. An extensively evaluated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for quantifying 14 GluCer and galactosylceramide (GalCer) isoforms in human cerebrospinal fluid (CSF) samples is presented. Sample pretreatment, HPLC, and MS/MS parameters were optimized. Evaluation was performed according to the recommendations of the Clinical and Laboratory Standards Institute and European Medicines Agency guidelines. Four 7-point calibration curves were generated, with a linearity interval from 2.5 to 200 nM (R² ≥ 0.995). The limit of quantification was set at 5 nM. Between-run precision and accuracy were up to 12.5 and 9%, respectively. After method validation, we measured the levels of GluCer and GalCer isoforms in CSF human samples, including 6 healthy controls (HC), 22 idiopathic GBA1 wild-type PD (iPD) patients, and 5 GBA1-associated PD (PD-GBA) patients. GluCer/GalCer median ratios were found to be higher in the CSF of PD-GBA patients, particularly in severe GBA1 mutations, than those in iPD and HC. The observed trends in GluCer/GalCer ratios among groups provide novel information for the comprehensive analysis of sphingolipids as potential biomarkers of PD.

01 Jul 2024·Advanced Science

Activation and Purification of ß‐Glucocerebrosidase by Exploiting its Transporter LIMP‐2 – Implications for Novel Treatment Strategies in Gaucher's and Parkinson's Disease

Article

Author: Chen, Jia‐Xuan ; Dobert, Jan Philipp ; Januliene, Dovile ; Bub, Simon ; Regensburger, Martin ; Steger, Lisa ; Hehr, Ute ; Zunke, Friederike ; Mächtel, Rebecca ; Arnold, Philipp ; Dejung, Mario ; Wilfling, Sibylle ; Plötz, Sonja ; Moeller, Arne

AbstractGenetic variants of GBA1 can cause the lysosomal storage disorder Gaucher disease and are among the highest genetic risk factors for Parkinson's disease (PD). GBA1 encodes the lysosomal enzyme beta‐glucocerebrosidase (GCase), which orchestrates the degradation of glucosylceramide (GluCer) in the lysosome. Recent studies have shown that GluCer accelerates α‐synuclein aggregation, exposing GCase deficiency as a major risk factor in PD pathology and as a promising target for treatment. This study investigates the interaction of GCase and three disease‐associated variants (p.E326K, p.N370S, p.L444P) with their transporter, the lysosomal integral membrane protein 2 (LIMP‐2). Overexpression of LIMP‐2 in HEK 293T cells boosts lysosomal abundance of wt, E326K, and N370S GCase and increases/rescues enzymatic activity of the wt and E326K variant. Using a novel purification approach, co‐purification of untagged wt, E326K, and N370S GCase in complex with His‐tagged LIMP‐2 from cell supernatant of HEK 293F cells is achieved, confirming functional binding and trafficking for these variants. Furthermore, a single helix in the LIMP‐2 ectodomain is exploited to design a lysosome‐targeted peptide that enhances lysosomal GCase activity in PD patient‐derived and control fibroblasts. These findings reveal LIMP‐2 as an allosteric activator of GCase, suggesting a possible therapeutic potential of targeting this interaction.

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