Treatment Of Gaucher Disease Research Articles

Patients with Gaucher disease display systemic elevation of ACE2, which is impacted by therapy status and genotype

Gaucher disease (GD) has a high carrier rate among Ashkenazi Jews.The most common disease-causing variant in this population N370S, is also prevalent pan-ethnically. This has led to speculations of some protective effect for carriers of this variant. During the recent COVID-19 pandemic, GD patients reportedly had a surprisingly low infection rate and mild symptoms considering their disease status. As SARS-CoV-2 gains entry into the cell via membrane-bound angiotensin-converting enzyme 2 (ACE2), we speculated that differences in levels of soluble ACE2 in GD patients could contribute to this protective state. While ACE is known to be elevated in GD, to our knowledge, ACE2 levels have not been explored.We measured serum and macrophage-bound levels of ACE and ACE2 by ELISA and western blot, respectively, in GD patients and age- and sex-matched controls. Our results reveal a significant elevation of both serum and macrophage-bound ACE and ACE2 in GD patients compared to healthy controls. This elevation appears to be mitigated by GD treatment. Moreover, the most robust ACE2 elevation was observed in N370S homozygotes, and was not effected by treatment.Since coronaviruses use the ACE2 receptor as a gateway for host cell entry, we speculate that elevated circulating ACE2 may serve as a decoy. This might explain the observed mild infections in GD patients during the COVID-19 pandemic.

Abstract 4807: Gaucher disease treatment reduces the progression of smoldering myeloma

Abstract Background: Gaucher disease (GD), a hereditary condition characterized by glucocerebrosidase deficiency, results in the impaired degradation of glucocerebroside (GL1) and its deacetylated form, lyso-GL1 (LGL1). This leads to the accumulation of these substrates primarily in the bone marrow (BM), liver, and spleen. Notably, individuals with GD face an increased risk of plasma cell dyscrasias (PCD) by approximately nine-fold. We present two compelling cases of the regression of smoldering multiple myeloma (SMM) following GD treatment, substantiated by biochemical evidence of lipid-reactive clonal paraproteins (PP) in both patients. Methods: Peripheral blood samples were obtained with IRB approval from patients with concurrent SMM and GD at the Icahn School of Medicine at Mount Sinai. Utilizing C-18 beads coupled with gly-sphingosine-coated liposomes and Sphingosine-1 phosphate bead liposome-based pulldown, we established the binding of glycolipids to serum PP. Results: In a 66-year-old male, hepatosplenomegaly and pancytopenia revealed compound heterozygous N370S/V394L mutations and reduced β-glucosidase activity, confirming Type 1 GD. Laboratory findings included substantial pancytopenia (WBC 2.5 k/µL, Hgb 12.1 g/dL, platelet 44 k/µL) and myeloma markers (M spike 1.58 g/dL, monoclonal IgA λ). A BM biopsy indicated 30% λ-restricted plasma cells. PET-CT showed hepatosplenomegaly without FDG avid lytic lesions, consistent with SMM. Imiglucerase enzyme therapy improved GD biomarkers, decreased hepatosplenomegaly, and blood count improvement (WBC 4.7 k/µL, Hgb 13.6 g/dL, platelet 66 k/µL). Notably, myeloma burden significantly reduced (M-spike 0.94 g/dL, IgA 1373 g/dL and free lambda 26.1 mg/L). Similarly, a 41-year-old female with mild fatigue, Hgb levels of 10.9 g/dL, a platelet count of 169 k/µL, M spike of 0.9 g/dL, IgG κappa on immunofixation, and IgG levels at 1730 mg/dL, indicating SMM. GBA analysis showed homozygous N370S mutation and reduced beta-glucosidase activity consistent with Type 1 GD. Substrate reduction therapy with eliglustat alleviated fatigue, reduced GD biomarkers, normalized cytopenias, and gradually decreased myeloma markers. Laboratory results indicated an M spike of 0.5 g/dL, IgG levels at 1295 mg/dL, and free kappa at 31.3 mg/L. To explore the interaction between clonal immunoglobulins (Ig) and lyso-lipids, we utilized Gly-sphingolipids (see methods) and demonstrated a robust interaction with IgA (patient 1) and IgG (patient 2) paraprotein by western blotting. Conclusion: Our experimental findings confirm specific clonal Ig binding in SMM and GD patients and demonstrate potent and timely benefits from addressing GD in managing SMM patients. This holds significance amid ongoing clinical trials exploring aggressive interventions for SMM, including bispecific and CAR-T therapies. Citation Format: Ravi Prakash Shukla, Anshuman Parekh, Violetta V Leshchenko, Kevin Barley, Deepa Vatti, Daniel Verina, Manisha Balwani, Samir Parekh. Gaucher disease treatment reduces the progression of smoldering myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4807.

Advancements in Viral Gene Therapy for Gaucher Disease.

Gaucher disease, an autosomal recessively inherited lysosomal storage disorder, results from biallelic mutations in the GBA1 gene resulting in deficient activity of the enzyme glucocerebrosidase. In Gaucher disease, the reduced levels and activity of glucocerebrosidase lead to a disparity in the rates of formation and breakdown of glucocerebroside and glucosylsphingosine, resulting in the accumulation of these lipid substrates in the lysosome. This gives rise to the development of Gaucher cells, engorged macrophages with a characteristic wrinkled tissue paper appearance. There are both non-neuronopathic (type 1) and neuronopathic (types 2 and 3) forms of Gaucher disease, associated with varying degrees of severity. The visceral and hematologic manifestations of Gaucher disease respond well to both enzyme replacement therapy and substrate reduction therapy. However, these therapies do not improve the neuronopathic manifestations, as they cannot cross the blood-brain barrier. There is now an established precedent for treating lysosomal storage disorders with gene therapy strategies, as many have the potential to cross into the brain. The range of the gene therapies being employed is broad, but this review aimed to discuss the progress, advances, and challenges in developing viral gene therapy as a treatment for Gaucher disease.

Plain language summary of a study looking at the long-term benefits of enzyme replacement therapy in children and teenagers with Gaucher disease type 3

What is this study about? Gaucher disease is a rare genetic condition. There are three types of Gaucher disease: type 1, type 2, and type 3 (GD3). Symptoms of GD3 include problems with the brain and spinal cord, bones, blood, enlarged liver and spleen, and slow growth. Symptoms have a great impact on the quality of life of people with GD3 and are known to cause loss of life in childhood. In Gaucher disease, people have two non-working copies of a gene called GBA, which tells the body how to make an enzyme called beta-glucosidase (which breaks down excess fats called sphingolipids). In Gaucher disease, people do not make enough beta-glucosidase enzyme, meaning sphingolipids build up inside cells, affecting many organs and systems of the body. Enzyme replacement therapy (ERT) is a treatment for Gaucher disease. Previous studies looking at ERT showed that treatment can greatly improve most symptoms and quality of life in people with Gaucher disease. How ERT may help people with GD3 is only available in small studies. What was the aim of this study? Researchers looked at long-term changes in the blood, spleen, liver, and growth in children and teenagers living with GD3 and how long they survived once they had started an ERT called imiglucerase. Researchers used data from a large global database called the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The aim was to investigate if imiglucerase could improve long-term symptoms and prevent early loss of life. What were the results of this study? Low red blood cell counts (causing a condition called anaemia), low platelet (specialised blood cells that stop bleeding and bruising) counts, enlarged liver and spleen, and slow growth were the most common symptoms in people with GD3 before treatment. People with GD3 who had received imiglucerase had improved symptoms after 5 years of treatment. They also had a greater chance of living longer, with 92% of people alive after 5 years of treatment. These results show that the ERT imiglucerase helps to improve blood, spleen, liver, and growth symptoms, and most importantly that it is a life-prolonging treatment.

Regression of smoldering myeloma with treatment of Gaucher disease

Regression of smoldering myeloma with treatment of Gaucher disease

Overall assessment of patients with type 1 Gaucher disease: a single-centre’s experience

PurposeTo evaluate the demographic and clinical data of patients with type 1 Gaucher disease, a rare disease, at a single centre.MethodsThe data of patients with type 1 Gaucher disease who were followed up at the Endocrinology Department of Erciyes University’s Medical Faculty Hospital between 2019 and 2021 were evaluated.ResultsWe evaluated 13 patients with type 1 Gaucher disease who were diagnosed or followed up at our centre and whose data could be accessed. Four of the patients were male, and nine were female. The mean age at the time of diagnosis was 33 (± 11.32) years. Hepatomegaly was present in 11 of the 13 patients. Eight of the 13 patients had splenomegaly. Three patients had undergone splenectomy. The liver and spleen dimensions of two patients were normal. The platelet count was normal in three of the 10 patients without a history of undergoing splenectomy. Bone densitometry revealed that six patients had a lumbar z-score of ≤ − 2.5. Five patients had a score between − 1 and − 2.5, and two patients had a normal z-score. The mean treatment duration was 36 (± 19.46) months. All our patients were administered enzyme replacement therapy.ConclusionGaucher disease is a rare lysosomal storage disease that affects many systems. It causes irreversible morbidity in patients in whom diagnosis is delayed. The main treatment modality was enzyme replacement therapy. Because it is a rare and multisystemic disease, patients should be followed up at centres with experience in treating Gaucher disease.

Bone marrow adipocytes alteration in an in vitro model of Gaucher Disease

Gaucher disease (GD) is caused by biallelic pathogenic variants in GBA1 gene that encodes the lysosomal enzyme glucocerebrosidase. Up to now, specific treatment for GD cannot completely reverse bone complications. Bone is composed of different cell types; including osteoblasts, osteocytes and osteoclasts. Osteoblasts are present on bone surfaces and are derived from local mesenchymal stem cells (MSCs). Depending on environment conditions, MSCs could differentiate into osteoblasts and adipocytes. Mature adipocytes-secreted adipokines and free fatty acids affect both osteoblasts and osteoclasts formation/activity and therefore mediate skeletal homeostasis. The aim of this study was to evaluate possible alterations in GD adipocyte (GD Ad) that could contribute to bone complications. MSCs were grown in adipogenic media in order to evaluate expression of differentiation markers as PPAR-γ. PPAR-γ was observed into the nucleus of GD Ad, indicating that these cells are properly stimulated. However, these cells accumulate lesser lipid droplets (LDs) than Control Ad. In order to study lipid droplet metabolism, we evaluated the lipolysis of these structures by the measurement of free glycerol in culture supernatant. Our results indicated that GD Ad had an alteration in this process, evidenced by an increase in glycerol release. We have also evaluated two enzymes involved in LDs synthesis: fatty acid synthase (FASN) and stearoyl-coenzyme A desaturase 1 (SCD1). The transcription of these genes was decreased in GD Ad, suggesting a dysfunction in the synthesis of LDs. In conclusion, our results show an alteration in LDs metabolism of GD Ad, independent of adipocyte differentiation process. This alteration would be caused by an increase in lipolysis in early stages of differentiation and also by a reduction of lipid synthesis, which could contribute with the skeletal imbalance in GD.

In-Silico study of Cassia tora Linn in the treatment of Gaucher disease: A Scientific Ethnomedical Study

In-Silico study of Cassia tora Linn in the treatment of Gaucher disease: A Scientific Ethnomedical Study

SUCCESSFUL IMIGLUCERASE DESENSITIZATION IN A PATIENT WITH SEVERE ARTHRALGIA AND MYALGIA

<h3>Introduction</h3> A patient with Type I Gaucher disease experienced severe musculoskeletal pain within minutes upon first and second administration of imiglucerase, which is a rare adverse event. He underwent successful desensitization, which has only been reported in 3 cases, and continues to receive imiglucerase therapy. <h3>Case Description</h3> A 37-year-old male with Type I Gaucher disease developed severe arthralgias and myalgias without skin changes nor symptoms of anaphylaxis within 5 minutes of the first infusion of imiglucerase enzyme replacement therapy. The infusion was stopped, and he was treated with intravenous (IV) fluids, IV hydrocortisone, and acetaminophen. He experienced severe back pain at a second infusion a week later despite pretreatment with IV diphenhydramine and prednisolone. A desensitization procedure was performed using an intermediate risk (3 bag) protocol (44U, followed by 440U and 4400U). Premedication included intravenous (IV) dexamethasone twelve hours in advance, and IV dexamethasone, aspirin 325mg, IV diphenhydramine, and IV famotidine 30 minutes prior to the first bag. He tolerated the desensitization protocol without a reaction and has progressed to monthly infusions with pretreatment without adverse reactions. <h3>Discussion</h3> Adverse reactions to imiglucerase are an infrequent setback in Gaucher disease treatment, with mild cutaneous or respiratory symptoms primarily reported resolving with slowed infusion rates. Although hypersensitivity reactions suspected to be IgG-mediated have been described within the first six months of therapy, this case represents an even more rare immediate muscular hypersensitivity reaction upon first imiglucerase exposure with a successful model for desensitization and continued current tolerance of active therapy.

A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease.

Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment. Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted. Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R. The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values. This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups. The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.

Cross-sectional web-based survey among haematologists and gastroenterologists in Japan to identify the key factors for early diagnosis of Gaucher disease.

Gaucher disease (GD) is a rare, inherited metabolic disorder resulting from glucocerebrosidase deficiency. Patients benefit from early treatment as complications can arise from delayed diagnosis. To measure GD awareness among Japanese haematologists and gastroenterologists, who are the specialists most likely to encounter patients with symptoms recognised in the Gaucher Earlier Diagnosis Consensus (GED-C), such as hepatosplenomegaly and thrombocytopenia. Additionally, we aimed to determine key signs from the GED-C associated with early diagnosis. A quantitative web survey assessed Japanese haematologists and gastroenterologists for their (i) basic awareness of GD, (ii) explicit awareness of GD signs, (iii) explicit awareness of GD treatments and (iv) accuracy in suspecting GD in model patients. Survey results from 160 haematologists and 166 gastroenterologists indicated that more than 50% of haematologists were aware of GD symptoms, diagnostic criteria and/or treatments, and 38% of them had experienced or suspected GD. The majority of gastroenterologists were unaware of GD or knew the disease only by name, with 20% experiencing or suspecting GD in practice. Almost 70% of haematologists knew of enzyme replacement therapy, while 47% of gastroenterologists were not aware of any treatments for GD. Of the GED-C items, an awareness of bone-associated signs was correlated with accurate GD diagnosis in model patients and this awareness was greater among haematologists than gastroenterologists. The present study showed that haematologists had greater awareness of GD than gastroenterologists, and that bone pain may be a key sign of GD to enhance early diagnosis.

РЕДКОЕ НАБЛЮДЕНИЕ РЕАКЦИИ ГИПЕРЧУВСТВИТЕЛЬНОСТИ НА ПРЕПАРАТЫ ДЛЯ ФЕРМЕНТНОЙ ЗАМЕСТИТЕЛЬНОЙ ТЕРАПИИ У РЕБЕНКА С БОЛЕЗНЬЮ ГОШЕ 3-го ТИПА

Gaucher disease (GD) is an autosomal recessive disease that leads to excessive accumulation of glucocerebroside in the cells of the reticuloendothelial system, which leads to multiple organ damage with the development of cytopenia, hepatosplenomegaly, bone and neurological pathology. An effective and safe enzyme replacement therapy has been developed for the treatment of GD. However, there are rare cases of hypersensitivity reactions presented in the literature, requiring individualization of patient management with the search for alternative ways to continue therapy and prevent side effects. We present a rare clinical case of intolerance to imiglucerase and velaglucerase alfa in a child with GD type 3 and possible methods for continuing treatment, taking into account the hypersensitivity reaction.

M011: A novel highly phosphorylated β-glucocerebrosidase enzyme with broader tissue biodistribution for the treatment of Gaucher disease

M011: A novel highly phosphorylated β-glucocerebrosidase enzyme with broader tissue biodistribution for the treatment of Gaucher disease

Efficacy and Safety of Taliglucerase Alfa for the Treatment of Gaucher Disease: A 9-Year Experience

Efficacy and Safety of Taliglucerase Alfa for the Treatment of Gaucher Disease: A 9-Year Experience

Long-read single molecule real-time (SMRT) sequencing of GBA1 locus in Gaucher disease national cohort from Argentina reveals high frequency of complex allele underlying severe skeletal phenotypes: Collaborative study from the Argentine Group for Diagnosis and Treatment of Gaucher Disease

Gaucher disease is renowned for extreme phenotypic diversity that does not show consistent genotype/phenotype correlations. In Argentina, a national collaborative group, Grupo Argentino de Diagnóstico y Tratamiento de la Enfermedad de Gaucher, GADTEG, delineated uniformly severe type 1 Gaucher disease manifestations presenting in childhood with large burden of irreversible skeletal disease. Here using Long-Read Single Molecule Real-Time (SMRT) Sequencing of GBA1 locus, we show that the RecNciI allele is highly prevalent and it is associated with severe skeletal manifestations with onset in childhood or in young adults. Additionally, we described novel GBA1 variants not previously described.

Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease.

Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout (Gba-/-) mouse model. Gba-/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba-/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba-/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba-/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy–lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD.

Transient Production of Human β-Glucocerebrosidase With Mannosidic-Type N-Glycan Structure in Glycoengineered Nicotiana benthamiana Plants.

Gaucher disease is an inherited lysosomal storage disorder caused by a deficiency of functional enzyme β-glucocerebrosidase (GCase). Recombinant GCase has been used in enzyme replacement therapy to treat Gaucher disease. Importantly, the terminal mannose N-glycan structure is essential for the uptake of recombinant GCase into macrophages via the mannose receptor. In this research, recombinant GCase was produced using Agrobacterium-mediated transient expression in both wild-type (WT) and N-acetylglucosaminyltransferase I (GnTI) downregulated Nicotiana benthamiana (ΔgntI) plants, the latter of which accumulates mannosidic-type N-glycan structures. The successfully produced functional GCase exhibited GCase enzyme activity. The enzyme activity was the same as that of the conventional mammalian-derived GCase. Notably, N-glycan analysis revealed that a mannosidic-type N-glycan structure lacking plant-specific N-glycans (β1,2-xylose and α1,3-fucose residues) was predominant in all glycosylation sites of purified GCase produced from ΔgntI plants. Our research provides a promising alternative plant line as a host for the production of recombinant GCase with a mannosidic-type N-glycan structure. This glycoengineered plant might be applicable to the production of other pharmaceutical proteins, especially mannose receptor targeted protein, for therapeutic uses.

C-Abl activates RIPK3 signaling in Gaucher disease

Gaucher disease (GD) is caused by homozygous mutations in the GBA1 gene, which encodes the lysosomal β-glucosidase (GBA) enzyme. GD affects several organs and tissues, including the brain in certain variants of the disease. Heterozygous GBA1 variants are a major genetic risk factor for developing Parkinson's disease. The RIPK3 kinase is relevant in GD and its deficiency improves the neurological and visceral symptoms in a murine GD model. RIPK3 mediates necroptotic-like cell death: it is unknown whether the role of RIPK3 in GD is the direct induction of necroptosis or if it has a more indirect function by mediating necrosis-independent. Also, the mechanisms that activate RIPK3 in GD are currently unknown.In this study, we show that c-Abl tyrosine kinase participates upstream of RIPK3 in GD. We found that the active, phosphorylated form of c-Abl is increased in several GD models, including patient's fibroblasts and GBA null mice. Furthermore, its pharmacological inhibition with the FDA-approved drug Imatinib decreased RIPK3 signaling. We found that c-Abl interacts with RIPK3, that RIPK3 is phosphorylated at a tyrosine site, and that this phosphorylation is reduced when c-Abl is inhibited. Genetic ablation of c-Abl in neuronal GD and GD mice models significantly reduced RIPK3 activation and MLKL downstream signaling. These results showed that c-Abl signaling is a new upstream pathway that activates RIPK3 and that its inhibition is an attractive therapeutic approach for the treatment of GD.

Long-term treatment of Gaucher disease with velaglucerase alfa in a cohort of patients from Paraguay

Long-term treatment of Gaucher disease with velaglucerase alfa in a cohort of patients from Paraguay

Modeling potential interactions between oral Gaucher disease treatment and investigational COVID-19 therapies

Modeling potential interactions between oral Gaucher disease treatment and investigational COVID-19 therapies