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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. [ABSTRACT FROM AUTHOR]

Type 1 Gaucher’s disease (GD) is recognized for striking but unexplained phenotypic diversity. Rarely, severe pulmonary hypertension (PH) may occur in GD but its clinical spectrum, determinants or its response to enzyme replacement therapy (ERT) ± vasodilators is not known. One hundred and thirty-four consecutive patients with Type 1 GD were screened to estimate right ventricular systolic pressure (RVSP) by Doppler echocardiography. Ninety-four patients were on ERT and 40 were untreated. Eight additional GD patients were studied that represented consecutive tertiary referrals with severe PH. Angiotensin converting enzyme (ACE) gene polymorphisms and acid β-glucosidase gene (GBA) mutations were determined by DNA analysis. Mild, asymptomatic PH (RVSP > 35 < 50 mm Hg) was prevalent in Type 1 GD: 30% in untreated patients and 7.4% among patients receiving ERT (P<0.001). Splenectomy was strongly associated with severe, life-threatening PH: all patients with severe PH (RVSP 50–130 mm Hg) were asplenic compared to only 31% of patients with RVSP < 50 mm Hg (Odds ratio [OR] 28.8, 95% CI 1.6–531.6, P<0.001). Other characteristics of patients presenting with severe PH were poor compliance to ERT (4/9 patients) or no ERT (5/9 patients), a family history of a sib with GD and PH (2/2 patients), an excess of ACE I allele (OR 2.3, 95% CI 1.1–4.9, P=0.034) and an excess of non-N370S GBA mutation (OR 6.0, 95% CI 1.1–33, P=0.003). Severe PH was ameliorated by ERT ± vasodilators during 4.6±4.0 yr (range 1–12 yr) follow-up; three patients were initially considered for lung transplantation but improved such that they are no longer active transplant candidates. Our study reveals a remarkable predisposition for PH in type 1 GD. Progression to severe, life-threatening PH occurs in the presence of additional genetic factors (non-N370S GBA mutation, positive family history, and ACE I gene polymorphism) and epigenetic modifiers (i.e., asplenia and female sex). Splenectomy should be avoided and in high-risk patients, ERT ± vasodilators/coumadin should be initiated. [Copyright &y& Elsevier]

Eliglustat (Cerdelga, Sanofi Genzyme) is a first-line oral substrate reduction therapy for adults with Gaucher disease type 1 (GD1) with extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (>90% of patients). Clinical trials have demonstrated long-term clinical improvement in all major disease manifestations in treatment-naïve patients and long-term stability in patients switching from enzyme-replacement therapy (ERT). We report real-world data from treatment-naïve and ERT-switch patients enrolled in the International Collaborative Gaucher Group Gaucher (ICGG) Registry (NCT00358943/Sanofi Genzyme) who were treated with eliglustat for ≥1 year. Of 400 eliglustat-treated patients in the Registry as of July 2018, 238 had baseline and 2-year data (±1 year) for ≥1 key disease parameter: 15 treatment-naïve (0 splenectomized) and 223 switch (43 splenectomized). Overall, 213 were from the United States, the first country to approve eliglustat. In treatment-naïve patients, mean hemoglobin improved from 12.5 to 13.8 g/dL (p=0.004 n=14) mean platelet count improved from 113 to 158 x109/L (p=0.0002 n=13) mean spleen volume decreased from 9.4 to 4.2 multiples of normal (MN) (p=0.01, n=5), and mean liver volume was unchanged: 1.2 vs 1.1 MN (non-significant, n=5). In non‑splenectomized-switch patients, mean hemoglobin remained normal: 14.3 vs 14.1 g/dL (p=0.01, n=169) mean platelet count remained normal: 181 vs 184 x109/L (non-significant, n=169) mean spleen volume decreased from 2.9 to 2.5 MN (p=0.002, n=63), and mean liver volume remained stable at 0.9 MN (non-significant, n=63). In splenectomized-switch patients, mean hemoglobin remained stable: 13.5 to 13.4 g/dL (non-significant, n=36) mean platelet count increased from 295 to 319 x109/L (p=0.05, n=34) mean liver volume remained stable: 0.9 to 1 MN (non-significant, n=15). Mean chitotriosidase levels decreased in all groups, with significant reductions in treatment-naïve patients (1325 to 308 nmol/mL/hr, p=0.03, n=6) and non-splenectomized-switch patients (838 to 725 nmol/mL/hr p=0.02, n=86). These real-world results are consistent with those reported in eliglustat clinical trials. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection carries high morbidity and mortality in individuals with chronic disorders. Its impact in rare disease populations such as Gaucher disease (GD) is unknown. In GD, decreased acid β-glucosidase activity leads to the accumulation of inflammatory glycosphingolipids and chronic myeloid cell immune activation which a priori could predispose to the most severe effects of SARS-CoV-2. To evaluate the determinants of SARS-CoV-2 infection in GD, we conducted a cross-sectional study in a large cohort. 181 patients were enrolled, including 150 adults and 31 children, with a majority of patients on treatment (78%). Information on COVID-19 exposure, symptoms, and SARS-CoV-2 nucleic acid and/or antibody testing was obtained during the peak of the pandemic in the New York City metropolitan area. Forty-five adults reported a primary exposure to someone with COVID-19 and 17 (38%) of these patients reported at least one COVID-19 symptom. A subset of adults was tested (n = 88) and in this group 18% (16/88) were positive. Patients testing positive for SARS-CoV-2 had significantly more symptoms (4.4 vs 0.3, p < 0.001) than patients testing negative. Among patients who were antibody-positive, quantitative titers indicated moderate to high antibody response. In GD adults, male gender, older age, increased BMI, comorbidities, GBA genotype, prior splenectomy and treatment status were not associated with the probability of reporting symptoms or testing positive. No patient required COVID-19-specific treatments and there were no deaths. Our data suggests that GD does not confer a heightened risk for severe effects of SARS-CoV-2 infection feared based on the known chronic inflammatory state in these patients. [ABSTRACT FROM AUTHOR]

Acid sphingomyelinase deficiency (ASMD) also known as Niemann-Pick disease, is a rare lysosomal storage disorder with a diverse disease spectrum that includes slowly progressive, chronic visceral (type B) and neurovisceral forms (intermediate type A/B), in addition to infantile, rapidly progressive fatal neurovisceral disease (type A). We review the published evidence on the relevance of splenomegaly and reduced lung diffusion capacity to the clinical burden of chronic forms of ASMD. Targeted literature searches were conducted to identify relevant ASMD and non-ASMD studies for associations between diffusing capacity of the lungs for carbon monoxide (DL CO) and splenomegaly, with clinical parameters and outcome measures. Respiratory disease and organomegaly are primary and independent contributors to mortality, disease burden, and morbidity for patients with chronic ASMD. The degree of splenomegaly correlates with short stature, atherogenic lipid profile, and degree of abnormality of hematologic parameters, and thus may be considered a surrogate marker for bleeding risk, abnormal lipid profiles and possibly, liver fibrosis. Progressive lung disease is a prevalent clinical feature of chronic ASMD, contributing to a decreased quality of life (QoL) and an increased disease burden. In addition, respiratory-related complications are a major cause of mortality in ASMD. The reviewed evidence from ASMD natural history and observational studies supports the use of lung function and spleen volume as clinically meaningful endpoints in ASMD trials that translate into important measures of disease burden for patients. [ABSTRACT FROM AUTHOR]

In Gaucher disease type 1 (GD1), genetic deficiency of lysosomal glucocerebrosidase results in the accumulation of glucosylceramide and glucosylsphingosine (GlcSph), that underlie chronic lipid-mediated metabolic inflammation. An important age-related phenotype is high risk of monoclonal gammopathy (MG), including multiple myeloma. We identified GlcSph, a pathological lyso-sphingolipid exclusively elevated in GD, as a mediator of B cell activation and as an antigenic target for GD1-associated MG. Saposin C (SapC), is a lipid-binding protein and activator of lysosomal glucocerebrosidase, which when mutated, cause a rare variant of GD. Sera of GD1 patients with MG of diverse immunoglobulin types were compared to GD patients without gammopathy for reactivity against GlcSph and SapC. We show reactivity of clonal immunoglobulin in GD1 to GlcSph but not to SapC. In two patients with GD1 and gammopathy, GlcSph-reduction therapy with eliglustat resulted in reduction in clonal Ig. Together, our data show that GlcSph but not SapC is the antigenic target in GD1-associated MG and that therapy aimed at reducing the levels of immunogenic lipid resulted in reduction of clonal immunoglobulin in vivo. [ABSTRACT FROM AUTHOR]

In Gaucher disease, several macrophage-specific biomarkers have been validated for use in the clinic. However, Gaucher disease is more complex involving system-wide pathophysiology beyond the macrophage, and based on gene array analysis in our Gaucher disease mouse model and other emerging pathophysiologic insights, we evaluated serum levels of cathepsins D and S, YKL-40 and progranulin in Gaucher disease patients. We assessed their biomarker potential in Gaucher disease and compared them to established Gaucher disease biomarkers, chitotriosidase, chemokine ligand 18 (CCL18), and other indicators of disease severity and response to therapy. Mean YKL-40 and cathepsin D and S levels were significantly higher in Gaucher disease patients compared to healthy controls; in contrast, mean progranulin levels were lower in Gaucher disease patients compared to healthy controls. Enzyme replacement therapy resulted in a significant reversal of elevated cathepsin D and S but there was no change in progranulin and YKL-40 levels. Patients with persistent splenomegaly after long-term enzyme replacement therapy had significantly higher serum YKL-40 than patients with smaller spleens (63.0 ± 6.4 ng/ml vs. 46.4 ± 4.3 ng/ml, p =.03). Serum YKL-40 levels were higher in subjects with severe bone involvement (Hermann Score 3 to 5) compared to those with milder bone involvement (Hermann Score 1 to 2) (70.1 ± 4.3 ng/ml vs. 48.1 ± 3.7 ng/ml, p =.0002). YKL-40 was only weakly associated with chitotriosidase (r = 0.2, p =.008) and CCL18 (r = 0.3, p =.0004), and cathepsin S was moderately associated with chitotriosidase (r = 0.4, p =.01) and CCL18 (r = 0.6, p <.0001). Receiver operating curves for progranulin and YKL-40 demonstrated areas under the curves of 0.80 and 0.70, respectively. In conclusion, while these biomarkers do not meet robust properties of established macrophage-specific biomarkers, they may inform severity of skeletal disease, contribution of fibrosis to residual splenomegaly, and other disease manifestations. These findings, including markedly low progranulin levels that do not change upon enzyme replacement therapy, are intriguing to prompt further investigations to decipher their role in pathophysiology and relevance to diverse phenotypes of Gaucher disease. [ABSTRACT FROM AUTHOR]

Abstract Background Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, results from mutations in SMPD1 , the gene encoding acid sphingomyelinase (ASM). As a result, sphingomyelin accumulates in multiple organs including spleen, liver, lung, bone marrow, lymph nodes, and in the most severe form, in the CNS and peripheral nerves. Clinical manifestations range from rapidly progressive and fatal infantile neurovisceral disease, to less rapidly progressing chronic neurovisceral and visceral forms that are associated with significant morbidity and shorter life span due to respiratory or liver disease. Objectives To provide a contemporary guide of clinical assessments for disease monitoring and symptom management across the spectrum of ASMD phenotypes. Methods An international group of ASMD experts in various research and clinical fields used an evidence-informed consensus process to identify optimal assessments, interventions, and lifestyle modifications. Results Clinical assessment strategies for major organ system involvement, including liver, spleen, cardiovascular, pulmonary, and neurological/developmental are described, as well as symptomatic treatments, interventions, and/or life style modifications that may lessen disease impact. Conclusions There is currently no disease-specific treatment for ASMD, although enzyme replacement therapy with a recombinant human ASM (olipudase alfa) is in clinical development. Current monitoring addresses symptoms and multisystem involvement. Recommended interventions and lifestyle modifications are designed to address morbidity and disease complications and improve patient quality of life. While infantile neurovisceral ASMD is uniformly fatal in early childhood, patients with chronic visceral and chronic neurovisceral ASMD require appropriate management throughout childhood and adulthood by an interdisciplinary clinical team. [ABSTRACT FROM AUTHOR]

In Gaucher disease (GD), deficiency of lysosomal acid β-glucosidase results in a broad phenotypic spectrum that is classified into three types based on the absence (type 1 [GD1]) or presence and severity of primary central nervous system involvement (type 2 [GD2], the fulminant neuronopathic form, and type 3 [GD3], the milder chronic neuronopathic form). Enzyme replacement therapy (ERT) with imiglucerase ameliorates and prevents hematological and visceral manifestations in GD1, but data in GD3 are limited to small, single-center series. The effects of imiglucerase ERT on hematological, visceral and growth outcomes (note: ERT is not expected to directly impact neurologic outcomes) were evaluated during the first 5 years of treatment in 253 children and adolescents (< 18 years of age) with GD3 enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The vast majority of GBA mutations in this diverse global population consisted of only 2 mutations: L444P (77%) and D409H (7%). At baseline, GD3 patients exhibited early onset of severe hematological and visceral disease and growth failure. During the first year of imiglucerase treatment, hemoglobin levels and platelet counts increased and liver and spleen volumes decreased, leading to marked decreases in the number of patients with moderate or severe anemia, thrombocytopenia, and hepatosplenomegaly. These improvements were maintained through Year 5. There was also acceleration in linear growth as evidenced by increasing height Z-scores. Despite devastating disease at baseline, the probability of surviving for at least 5 years after starting imiglucerase was 92%. In this large, multinational cohort of pediatric GD3 patients, imiglucerase ERT provided a life-saving and life-prolonging benefit for patients with GD3, suggesting that, with proper treatment, many such severely affected patients can lead productive lives and contribute to society. [ABSTRACT FROM AUTHOR]

To celebrate the research visions and accomplishments of the late Roscoe O. Brady (1923–2016), remembrance commentaries were requested from several of his postdoctoral research fellows and colleagues. These commentaries not only reflect on the accomplishments of Dr. Brady, but they also share some of the backstories and experiences working in the Brady laboratory. They provide insights and perspectives on Brady's research activities, and especially on his efforts to develop an effective treatment for patients with Type 1 Gaucher disease. These remembrances illuminate Brady's efforts to implement the latest scientific advances with an outstanding team of young co-investigators to develop and demonstrate the safety and effectiveness of the first enzyme replacement therapy for a lysosomal storage disease. Brady's pursuit and persistence in accomplishing his research objectives provide insights into this remarkably successful physician scientist who paved the way for the development of treatments for patients with other lysosomal storage diseases. [ABSTRACT FROM AUTHOR]