45 Mouse models of Gaucher disease: Insights into visceral and CNS disease progression

Abstract Gaucher disease type 1, a non-neuronopathic lysosomal storage disease, is caused by mutations at the acid β-glucosidase locus. Periodic infusions of macrophage-targeted acid β-glucosidase reverse hepatosplenomegaly, hematologic, and bony findings in many patients. Two patients receiving enzyme therapy developed neutralizing antibodies to acid β-glucosidase that were associated with a lack of improvement or progressive disease. After initial improvement, case 1 had no additional response to 2 years of high-dose (50 U/kg every 2 weeks) enzyme therapy. Similarly, case 2 initially showed a favorable response to enzyme therapy that plateaued after 1 year of treatment. Both patients developed minor allergic reactions and antibodies to acid β-glucosidase within the first 6 months of treatment. Enzyme therapy was discontinued in case 1, with resultant disease progression and need for splenectomy. An immunosuppression/tolerization protocol was initiated in case 2 because of disease progression and stable neutralizing antibody titers. The IgG neutralizing antibodies rapidly and completely inactivated the wild-type, but not the N370S, acid β-glucosidase in vitro. Antibodies to human serum albumin and chorionic gonadotropin also developed. The finding of neutralizing antibodies to acid β-glucosidase during enzyme therapy for Gaucher disease has significant implications for monitoring the therapeutic responses and for potential alternative future therapies for Gaucher disease.

Download Full-text

Abstract PO-060: Gna13 delays disease progression in mouse models of pancreatitis and pancreatic cancer

10.1158/1538-7445.panca20-po-060 ◽

2020 ◽

Author(s):

Mario A. Shields ◽

Christina Spaulding ◽

Mahmoud G. Khalafalla ◽

Thao D.N. Pham ◽

Hidayatullah G. Munshi

Keyword(s):

Pancreatic Cancer ◽

Disease Progression ◽

Mouse Models

Download Full-text

Dual BRAF/MEK blockade restores CNS responses in BRAF-mutant Erdheim–Chester disease patients following BRAF inhibitor monotherapy

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa024 ◽

2020 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Roei D Mazor ◽

Ran Weissman ◽

Judith Luckman ◽

Liran Domachevsky ◽

Eli L Diamond ◽

...

Keyword(s):

Disease Progression ◽

Therapeutic Strategy ◽

Braf Inhibitor ◽

Response To Therapy ◽

Cns Disease ◽

Erdheim Chester Disease ◽

Braf Mutant ◽

Erdheim Chester ◽

Chester Disease

Abstract Background Erdheim–Chester disease (ECD), a rare inflammatory myeloid neoplasm, is known to be fundamentally reliant on the constitutive activation of the MAPK signaling pathway in the majority of patients. Consequently, inhibition of the V600E-mutant BRAF kinase has proven to be a safe and efficacious long-term therapeutic strategy for BRAF-mutant ECD patients. Nevertheless, in a subset of patients with CNS disease, the efficacy of long-term treatment may diminish, facilitating suboptimal responses or disease progression. Methods We retrospectively describe 3 BRAF-mutant ECD patients whose treatment with Vemurafenib was upgraded to Vemurafenib/Cobimetinib due to either disease progression, insufficient response, or unacceptable toxicity. CNS response to therapy was evaluated using magnetic resonance imaging (MRI) and extra-cranial disease was monitored using 18F-fludeoxyglucose positron emission tomography/computed tomography (PET/CT). Results Three patients with a mean age of 52.6 years were treated with Vemurafenib for a mean duration of 26.6 months (range: 6–52). Monotherapies were upgraded to Vemurafenib/Cobimetinib dual therapy. The combination therapy was administered for a mean duration of 21 months (range: 19–23). All patients exhibited clinical and neurological improvement. Regression of lesions on MRI was noted in 2 patients. Both patients characterized by a PET-avid disease responded to the biological treatment regimen with complete metabolic remissions. Conclusion Dual inhibition of BRAF and downstream MEK may be a safe and effective therapeutic strategy for BRAF-mutant ECD patients for whom BRAF inhibitor therapy proved insufficient and as such appropriate for the long-term management of CNS disease in ECD.

Download Full-text

Frequency and Severity of Central Nervous System Lesions in Hemophagocytic Lymphohistiocytosis

Blood ◽

10.1182/blood.v89.3.794 ◽

1997 ◽

Vol 89 (3) ◽

pp. 794-800 ◽

Cited By ~ 155

Author(s):

Elie Haddad ◽

Maria-Luisa Sulis ◽

Nada Jabado ◽

Stephane Blanche ◽

Alain Fischer ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Disease Progression ◽

Hemophagocytic Lymphohistiocytosis ◽

Systemic Disease ◽

Neurological Symptoms ◽

Treatment Modalities ◽

Remission Induction ◽

Cns Involvement ◽

Cns Disease

Abstract We have retrospectively assessed the neurological manifestations in 34 patients with hemophagocytic lymphohistiocytosis (HLH) in a single center. Clinical, radiological, and cerebrospinal fluid (CSF ) cytology data were analyzed according to treatment modalities. Twenty-five patients (73%) had evidence of central nervous system (CNS) disease at time of diagnosis, stressing the frequency of CNS involvement early in the time course of HLH. Four additional patients who did not have initial CNS disease, who did not die early from HLH complications, and who were not transplanted, also developed a specific CNS disease. Therefore, all surviving and nontransplanted patients had CNS involvement. Initially, CNS manifestations consisted of isolated lymphocytic meningitis in 20 patients and meningitis with clinical and radiological neurological symptoms in nine patients. For these nine patients, neurological symptoms consisted of seizures, coma, brain stem symptoms, or ataxia. The outcome of patients treated by systemic and intrathecal chemotherapy and/or immunosuppression exclusively (n = 16) was poor, as all died following occurrence of multiple relapses or CNS disease progression in most cases. Bone marrow transplantation (BMT) from either an HLA identical sibling (n = 6) or haplo identical parent (n = 3) was performed in nine patients, once first remission of CNS and systemic disease was achieved. Seven are long-term survivors including three who received an HLA partially identical marrow. All seven are off treatment with normal neurological function and cognitive development. In four other patients, BMT performed following CNS relapses was unsuccessful. Given the frequency and the poor outcome of CNS disease in HLH, BMT appears, therefore, to be the only available treatment procedure that is capable of preventing HLH CNS disease progression and that can result in cure when performed early enough after remission induction.

Download Full-text

Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2010.12.014 ◽

2011 ◽

Vol 102 (4) ◽

pp. 436-447 ◽

Cited By ~ 88

Author(s):

Y.H. Xu ◽

Y. Sun ◽

H. Ran ◽

B. Quinn ◽

D. Witte ◽

...

Keyword(s):

Mouse Models ◽

Gaucher Disease

Download Full-text

A convenient approach to facilitate monitoring Gaucher disease progression and therapeutic response

The Analyst ◽

10.1039/c7an00938k ◽

2017 ◽

Vol 142 (18) ◽

pp. 3380-3387 ◽

Cited By ~ 4

Author(s):

Wujuan Zhang ◽

Melissa Oehrle ◽

Carlos E. Prada ◽

Ida Vanessa D. Schwartz ◽

Somchai Chutipongtanate ◽

...

Keyword(s):

Mass Spectrometry ◽

Tandem Mass Spectrometry ◽

Disease Progression ◽

Gaucher Disease ◽

Therapeutic Response ◽

Tandem Mass ◽

Convenient Approach ◽

Mass Spectrometry Assay

A robust and convenient tandem mass spectrometry assay is reported for the measurement of the GD biomarker, GlcS, in dried plasma spots.

Download Full-text

Global gene expression profile progression in Gaucher disease mouse models

BMC Genomics ◽

10.1186/1471-2164-12-20 ◽

2011 ◽

Vol 12 (1) ◽

Cited By ~ 20

Author(s):

You-Hai Xu ◽

Li Jia ◽

Brian Quinn ◽

Matthew Zamzow ◽

Keith Stringer ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profile ◽

Mouse Models ◽

Expression Profile ◽

Gaucher Disease ◽

Global Gene Expression ◽

Global Gene Expression Profile

Download Full-text

Disease Progression-Dependent Expression of CD200R1 and CX3CR1 in Mouse Models of Parkinson’s Disease

Aging and Disease ◽

10.14336/ad.2019.0615 ◽

2020 ◽

Vol 11 (2) ◽

pp. 254 ◽

Cited By ~ 2

Author(s):

Le Wang ◽

Yang Liu ◽

Shuxin Yan ◽

Tianshu Du ◽

Xia Fu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Progression ◽

Mouse Models

Download Full-text

Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

eLife ◽

10.7554/elife.64393 ◽

2021 ◽

Vol 10 ◽

Author(s):

Nicole R Gould ◽

Katrina M Williams ◽

Humberto C Joca ◽

Olivia M Torre ◽

James S Lyons ◽

...

Keyword(s):

Parathyroid Hormone ◽

Bone Formation ◽

Signaling Pathway ◽

Mouse Models ◽

Cell Lines ◽

Mechanical Loading ◽

Gaucher Disease ◽

Mechanical Load ◽

Lysosomal Degradation ◽

Rodent Cell

The down regulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minutes-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically- and hormonally-activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.

Download Full-text