Months Of Enzyme Replacement Therapy Research Articles

Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency

PurposePatients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi.MethodsWe report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data.ResultsRevcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2–3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred.ConclusionRevcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.

MO024: Effect of green tea on top of enzyme replacement therapy in patients with Fabry disease: a molecular biology approach

Abstract BACKGROUND AND AIMS Fabry disease (FD) is an X-linked rare disease characterized by deficient expression and activity of alpha-galactosidase A and consequent lysosomal accumulation of Gb3 and derivatives in various organs. Notwithstanding the first-line treatment with enzyme replacement therapy (ERT), FD progresses with serious cardiovascular, renal and cerebral implications in particular in case of late diagnosis. This suggests the involvement of secondary parallel mechanisms to Gb3 accumulation. We have shown that FD patients have increased and active oxidative stress (OxSt), which plays a primary role in the induction of cardiovascular–renal remodeling and contributes in these patients to the associated left ventricular hypertrophy (LVH). We have also shown that in dialysis and CKD stage 3–4 patients, another population with high cardiovascular risk, antioxidant treatment with green tea significantly reduced OxSt-related cell signaling mechanisms improving LVH. We have therefore hypothesized that inpatients with FD, green tea on top of ERT might have additive positive effects toward OxSt and OxSt-induced cardiovascular–renal remodeling using a molecular biologic approach. METHOD Ten naïve Fabry patients were enrolled and evaluated ex vivo in mononuclear cells the status of OxSt before ERT, after 12 months of ERT and after 6 months of the additional treatment with two capsules of green tea (600 mg Camellia Sinensis leaves dry extract, 40% Epigallocathechinegallate, Frama S.r.l., Noventa Padovana, Italy) per day taken in the morning at fast on top of ERT. The OxSt was evaluated and compared in the tree time periods in terms of protein expression of p22phox (subunit of NADH/NADPH oxidase essential for the production of superoxide), phosphorylation state of MYPT-1 (regulatory subunit of the myosin light chain phosphatase), ERK 1/2 (effectors at nuclear level of cardiovascular remodeling) and plasma levels of MDA (marker of lipid peroxidation). HO-1 levels (antioxidant and protective from OxSt) were also evaluated. RESULTS p22phox was significantly decreased after 12 months of enzymatic therapy and further decreased after 6 months of green tea treatment (1.91 ± 0.83 versus 1.10 ± 0.23 versus 0.83 ± 0.20 d.u.), same for MYPT-1 phosphorylation (0.81 ± 0.20 versus 0.68 ± 0.21 versus 0.52 ± 0.11 d.u.). The phosphorylation of ERK 1/2 remained unchanged after 12 months of ERT, but significantly decreased after 6 months of green tea supplementation (1.06 ± 0.24 versus 1.02 ± 0.27 versus 0.76 ± 0.14 d.u.) as well as MDA levels (5.50 ± 1.08 versus 5.10 ± 1.1 versus 4.16 ± 0.86 nmol/mL). Finally, HO-1 significantly increased with both ERT and green tea supplementation (1.37 ± 0.34 versus 1.67 ± 0.51 versus 1.96 ± 0.53 ng/mL). CONCLUSION This study provides data pointing toward an antioxidant effect exerted by ERT itself, which is further amplified by the treatment with green tea on top of ERT. These data while on one hand highlight the fundamental importance of an early diagnosis and treatment of FD, on the other hand suggest the need of adjuvant antioxidant treatments to prevent or improve specific disease manifestations.

Motor and respiratory decline in patients with late onset Pompe disease after cessation of enzyme replacement therapy during COVID‐19 pandemic

Data on interruption of enzyme replacement therapy (ERT) are scarce in late onset Pompe disease. Due to the COVID-19 crisis, eight neuromuscular reference centers in France were obligated to stop the treatment for 31 patients. We collected the motor and respiratory data from our French registry, before COVID-19 and at treatment restart. In 2.2months (mean), patients showed a significant deterioration of 37m (mean) in the 6-min walk test and a loss of 210ml (mean) of forced vital capacity, without ad integrum restoration after 3months of ERT restart. This national study based on data from the French Pompe Registry shows that the interruption of ERT, even as short as a few months, worsens Pompe patients' motor and respiratory function.

Allogeneic hematopoietic stem cell transplantation for treating severe lung involvement in Gaucher disease

ObjectiveTo provide strategies for monitoring and treating severe lung involvement in Gaucher disease. Study designWe reviewed the chart of a 5-year-old boy who developed rapidly progressive, severe infiltrative lung involvement of Gaucher disease (GD) and improved after allogeneic hematopoietic stem cell transplant (HSCT), along with other case studies reported before December 2019. He was diagnosed with GD (homozygous mutation at c.1448 T > C, p.L483P), and started receiving enzyme replacement therapy (ERT) at 17 months old. He developed respiratory distress symptoms after 45 months of ERT; chest imaging reported diffuse interstitial infiltration of the bilateral lungs and consolidations at the right lungs. Allogeneic HSCT using cells from a matched unrelated donor was performed four months upon progressive respiratory symptoms. ResultsHis respiratory symptoms subsided in one month; chest imaging improvement, pulmonary function test improvement, and normalized activity of β-glucocerebrosidase were reported in three months. ConclusionThis is the first report of a patient who received early and regular ERT but developed severe infiltrative lung involvement and recovered after allogeneic HSCT. Based on study results, we suggest regular chest imaging, even for asymptomatic patients. For patients with severe lung involvement, rapid deterioration, and unresponsive to higher ERT dosages, allogeneic HSCT should be considered.

Switch from enzyme replacement therapy to oral chaperone migalastat for treating fabry disease: real-life data

The treatment options for Fabry disease (FD) are enzyme replacement therapy (ERT) with agalsidase alfa or beta, and the oral pharmacological chaperone migalastat. Since few data are available on the effects of switching from ERT to migalastat, we performed a single-center observational study on seven male Fabry patients (18–66 years) to assess the effects of the switch on renal, cardiac, and neurologic function, health status, pain, lyso-Gb3, α-Gal A activity and adverse effects. Data were retrospectively collected at time of diagnosis of FD (baseline, T0), and after 12 months of ERT (T1), and prospectively after 1 year of therapy with migalastat (T2). No patient died or reported renal, cardiac, or cerebrovascular events during the study period. The predefined measures for cardiac, renal and neurologic function, and FD-related symptoms and questionnaires were stable between baseline and the switch, and remained unchanged with migalastat. However, a significant improvement was observed in left ventricular mass index from baseline to T2 (p = 0.016), with a significative difference between the treatments (p = 0.028), and in median proteinuria from T2 vs T1 (p = 0.048). Moreover, scores of the BPI improved from baseline to T1, and remained stable with migalastat. Plasma lyso-Gb3 levels significantly decreased from baseline to T1 (P = 0.007) and T2 (P = 0.003), while did not significantly differ between the two treatments. α-Gal A activity increased from T0 to T2 (p < 0.0001). The frequency of adverse effects under migalastat and ERT was comparable (28% for both drugs). In conclusion, switching from ERT to migalastat is valid, safe and well tolerated.

SAT-382 Pyridoxal 5’-Phosphate Cerebrospinal Fluid Abnormalities in Hyopophosphatasia Before and After Enzyme Replacement Therapy

Introduction: Hypophosphatasia (HPP) is an inborn error of metabolism due to deficiency of tissue non-specific alkaline phosphatase (TNSALP), characterized by a wide range of skeletal and neurological symptoms. Little is known about the mechanism of neurologic involvement, but it may result from inefficient hydrolysis of vitamin B6 (pyridoxal 5’-phosphate, PLP), which is involved in neurotransmitter synthesis and is markedly elevated in HPP. However, it remains unknown what PLP levels are in the cerebrospinal fluid (CSF) of patients with HPP. We report two cases: (1) one with pre- and post-treatment CSF PLP levels and (2) one with pre-treatment CSF PLP and neurotransmitter levels. Case 1: A 30-year-old woman with extensive fracture history presented with seizure-like activity. Laboratory evaluation while on no B6 supplementation was notable for low ALP (14 U/L, ref: 40-150), high plasma PLP (362 mcg/L, ref: 5-50), and high CSF PLP (16 mcg/L), with a low CSF/plasma PLP ratio (0.04, ref: 0.1-0.7[1]). Genetic testing showed a pathogenic variant of TNSALP (Het c.1133A>T, p.Asp378Val, rs 121918008). After initiation of enzyme replacement therapy (ERT), her plasma and CSF PLP levels normalized to 6.3 and 1.4 mcg/L, respectively, with a ratio of 0.23. She reported improvement in energy level and seizure-like activity after several months of ERT. Case 2: A 34-year-old man with no history of skeletal pathology presented with diffuse musculoskeletal pain, weakness, and loss of sensory function attributed to generalized peripheral neuropathy. Laboratory evaluation while on no B6 supplementation was notable for low ALP (23 U/L), high plasma PLP (496 mcg/L), and high CSF PLP (17 mcg/L) with a low CSF/plasma ratio (0.03). CSF neurotransmitter levels were also low, including 5-hydroxyindoleacetic acid (40 nmol/L, ref: 67-140) and homovanillic acid (115 nmol/L, ref: 145-324). Genetic testing showed heterozygous expression of a catastrophic frameshift mutation of TNSALP (c.662del, p.Gly221Valfs*56). ERT is being considered at this time. Conclusions: We report the novel findings that in these patients with HPP:1. CSF PLP levels are markedly elevated, though to a much lesser extent than plasma levels. Elevated CSF/plasma ratios suggest that transport of PLP and its metabolites across the blood brain barrier may be impaired in HPP.2. Decreased CSF neurotransmitter levels, as seen in our patient, may contribute to neurologic symptoms of HPP.3. Enzyme replacement therapy normalized both CSF and plasma PLP in case 1. Further studies are needed to understand how these changes affect patient symptoms and prognosis.Citation:1. Albersen, M., et al., Vitamin B-6 vitamers in human plasma and cerebrospinal fluid. Am J Clin Nutr, 2014. 100(2): p. 587-92

SUN-353 Physical and Cognitive Functioning Before and Six Months After Initiating Enzyme Replacement Therapy for an Adult with Hypophosphatasia: A Case Study

We present changes on physical therapy (PT), occupational therapy (OT), and speech-language pathology (SLP) assessments for a patient pre- and 6 months post-initiation of recombinant alkaline phosphatase therapy for hypophosphatasia (HPP).Our patient is a 30-year-old male diagnosed with pediatric onset HPP at the age of 28. Features of his HPP include skull deformities and scoliosis noted as a toddler, early loss of primary dentition with the root intact prior to the age of 4, severe bone and muscle pain described as “severe growing pain”, and fatigue as a teenager. He was noted to have arthritis in his feet requiring surgical fusion, which was complicated by nonunion. By the age of 30, he required the use of assistive devices for ambulation due to fatigue and pain. Biochemistry was notable for ALP 17U/L (40-150), serum PLP 241 mcg/L (5-50), urine phosphethanolamine 47 nmolmgCr (0-27), and genetic testing demonstrated a variant of undetermined significance of ALPL genet (Het. C.1364G>A p.Gly455Asp).PT and OT assessments included a thorough musculoskeletal and neurologic examination, as well as functional testing of mobility, balance, motor control, and activity of daily living tasks. After 6 months of enzyme replacement therapy (ERT), the patient’s scores on measures of body structure and function were grossly unchanged or diminished (muscle strength). However, activity-based measures of functional performance generally improved on ERT. Performance on the Five Times Sit to Stand Test (FTSTS), gait speed, Functional Gait Assessment, Sensory Organization Test, and Six-Minute Walk Test (6MWT) improved. His most significant improvements were on the FTSTS and 6MWT; his FTSTS improved from 15.4 seconds to 9.1 seconds, surpassing the cut-off for falls risk (12s), while his 6MWT improved from 1,228 feet to 1,541 feet, surpassing the minimal detectable change for individuals with osteoarthritis (201 ft).Cognitive testing revealed improvement in delayed memory (e.g., word-list recognition, story-retell) on the Repeatable Battery of the Assessment of Neuropsychological Status from baseline (7%tile) to 6 months post therapy (47%tile). He also demonstrated improvement in Trail Making Part A [TM A, cognitive processing speed] & TM B (executive functioning) from baseline (45s, 49s) to 6 months post therapy (21s, 38s). Mean performance on TM A&B for adults 25-34 yrs is 24.4s±8.71 and 50.7s±12.4, respectively.Overall, the patient demonstrated improvement in delayed memory, cognitive processing speed and executive functioning on ERT. Additionally, while his performance on bedside impairment-based testing generally declined or remained unchanged, his performance on standardized functional assessments improved on ERT. These functional improvements in physical and cognitive domains likely enable the patient to more fully participate in life roles to improve quality of life.

Psychological health in adults with Morquio syndrome type A after six months of enzyme replacement therapy

Vaccination is the primary strategy to prevent hepatitis B virus (HBV) infection in the United States. Prior to 2017, most standard hepatitis B vaccine schedules required 3 doses over 6 months. Heplisav-B, approved in 2017, is administered in 2 doses over a 1 month time period but has a higher per-dose cost ($115.75 per dose compared to $57.25 per Engerix-B dose, costs as of June 1, 2019). We aimed to assess the cost-utility of providing the two-dose Heplisav-B vaccine compared to a three-dose Engerix-B vaccine among adult populations currently recommended for vaccination against hepatitis B. We used a decision-tree model with microsimulation and a Markov disease progression process to assess the cost-utility separately for the following populations: adults with diabetes, obesity, chronic kidney disease, HIV; non-responders to previous hepatitis B vaccination; older adults; and persons who inject drugs (PWID). We modeled epidemiologic outcomes (incident HBV infections, sequelae and related deaths), costs (2019 USD) and benefits (quality-adjusted life years, QALYs) and compared them across strategies. Sensitivity analyses assessed the cost-utility at varying estimates of Heplisav-B efficacy. In the base case scenario for each population, vaccination with Heplisav-B resulted in fewer HBV infections (37.5–59.8% averted), sequelae, and HBV-related deaths (36.3–71.4% averted). Heplisav-B resulted in decreased costs and increased benefits compared to Engerix-B for all populations except non-responders. Incremental costs from the baseline strategy ranged from $4746.78 saved (PWID) to $14.15 added cost (non-responders). Incremental benefits per person ranged from 0.00005 QALYs (older adults) to 0.7 QALYs (PWID). For persons with HIV and PWID, Heplisav-B resulted in lower costs and increased benefits in all scenarios in which Heplisav-B series efficacy was at least 80%. Vaccination using Heplisav-B is a cost-saving strategy compared to Engerix-B for adults with diabetes, chronic kidney disease, obesity, and HIV; older adults; and PWID.

Widespread Valvular and Vascular Calcification in Type III Gaucher Disease

: A 13-year-old girl, as a known case of type III Gaucher disease, was referred to us for a cardiac assessment. Our investigations revealed wall thickening and calcification in the ascending thoracic aorta, transverse arch, and isthmus. Calcification was also present in the proximal portion of the brachiocephalic trunk while the osteal narrowing of right common carotid was also notable. The other finding included isolated thrombocytopenia. We decided to perform surgery after two months of enzyme replacement therapy.

Description of a patient with infantile onset Pompe disease after 45 months of enzyme replacement therapy

Description of a patient with infantile onset Pompe disease after 45 months of enzyme replacement therapy

CD77 levels over enzyme replacement treatment in Fabry Disease Family (V269M).

ABSTRACTIntroduction:Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT).Objective:The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation).Methods:We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types.Results:A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels.Conclusion:The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.

Divergent clinical outcomes of alpha-glucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state

Pompe disease is an autosomal recessive, lysosomal glycogen storage disease caused by acid α-glucosidase deficiency. Infantile-onset Pompe disease (IOPD) is the most severe form and is characterized by cardiomyopathy, respiratory distress, hepatomegaly, and skeletal muscle weakness. Untreated, IOPD generally results in death within the first year of life. Enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has been shown to markedly improve the life expectancy of patients with IOPD. However, the efficacy of ERT in patients with IOPD is affected by the presence of symptoms and cross-reactive immunologic material (CRIM) status.We have treated two siblings with IOPD with ERT at different ages: the first was symptomatic and the second was asymptomatic. The female proband (Patient 1) was diagnosed with IOPD and initiated ERT at 4months of age. Her younger sister (Patient 2) was diagnosed with IOPD at 10days of age and initiated ERT at Day 12. Patient 1, now 6years old, is alive but bedridden, and requires 24-hour invasive ventilation due to gradually progressive muscle weakness. In Patient 2, typical symptoms of IOPD, including cardiac failure, respiratory distress, progressive muscle weakness, hepatomegaly and myopathic facial features were largely absent during the first 12months of ERT. Her cardiac function and mobility were well-maintained for the first 3years, and she had normal motor development. However, she developed progressive hearing impairment and muscle weakness after 3years of ERT. Both siblings have had low anti-rhGAA immunoglobulin G (IgG) antibody titers during ERT and have tolerated the treatment well.These results suggest that initiation of ERT during the pre-symptomatic period can prevent and/or attenuate the progression of IOPD, including cardiomyopathy, respiratory distress, and muscle weakness for first several years of ERT. However, to improve the long-term efficacy of ERT for IOPD, new strategies for ERT for IOPD, e.g. modifying the enzyme to enhance uptake into skeletal muscle and/or to cross the blood brain barrier (BBB), will be required.

Oxidative and nitrative stress and pro-inflammatory cytokines in Mucopolysaccharidosis type II patients: effect of long-term enzyme replacement therapy and relation with glycosaminoglycan accumulation

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a deficient activity of iduronate-2-sulfatase, leading to abnormal accumulation of glycosaminoglycans (GAG). The main treatment for MPS II is enzyme replacement therapy (ERT). Previous studies described potential benefits of six months of ERT against oxidative stress in patients. Thus, the aim of this study was to investigate oxidative, nitrative and inflammatory biomarkers in MPS II patients submitted to long term ERT. It were analyzed urine and blood samples from patients on ERT (mean time: 5.2years) and healthy controls. Patients presented increased levels of lipid peroxidation, assessed by urinary 15-F2t-isoprostane and plasmatic thiobarbituric acid-reactive substances. Concerning to protein damage, urinary di-tyrosine (di-Tyr) was increased in patients; however, sulfhydryl and carbonyl groups in plasma were not altered. It were also verified increased levels of urinary nitrate+nitrite and plasmatic nitric oxide (NO) in MPS II patients. Pro-inflammatory cytokines IL-1β and TNF-α were increased in treated patients. GAG levels were correlated to di-Tyr and nitrate+nitrite. Furthermore, IL-1β was positively correlated with TNF-α and NO. Contrastingly, we did not observed alterations in erythrocyte superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities, in reduced glutathione content and in the plasmatic antioxidant capacity. Although some parameters were still altered in MPS II patients, these results may suggest a protective role of long-term ERT against oxidative stress, especially upon oxidative damage to protein and enzymatic and non-enzymatic defenses. Moreover, the redox imbalance observed in treated patients seems to be GAG- and pro-inflammatory cytokine-related.

Inflammasome during pregnancy in a Gaucher disease patient

Introduction: Pregnancy is marked by immunology alteration, with dynamic cytokine production, a decrease of the TH1 response and increase of the TH2 throughout the trimesters. Gaucher disease (GD) is caused by the deficiency of glucocerebrosidase enzyme, leading to lipid accumulation in macrophage lysosomes, culminating with chronic stimulation of the immune system. Objective: Characterize the inflammatory cytokine profile of a pregnant Gaucher patient, correlating to her clinical characteristics during and after pregnancy. Materials and Methods: Blood samples of the patient were collected before pregnancy (sample 1), during each pregnancy trimester (samples 2, 3, and 4), and 2 and 6 months after delivery (samples 5 and 6). The inflammatory cytokines were analyzed and their logarithmic values were compared to the healthy pregnant values (American Journal of Immunology 2010, 64:411–426). Case Report: The patient, genotype p.N370S/L444P, has had the Gaucher diagnosis since 15 years of age when she presented hepatosplenomegaly, pancytopenia, and bone pain. She has been through 11 months of enzyme replacement therapy (ERT) with Imiglucerase (30 UI/kg/inf), showing improvement of visceromegaly and pancytopenia, but bone pain persisted. At 18 years old, the patient became pregnant and continued the ERT at a dose of 30 UI/kg/infusion. The patient reported total improvement of bone pain after the first trimester of pregnancy. There were no complications throughout the gestational period nor during labor. After delivery, she remained 2 months without ERT by choice, experienced worsening of the visceromegaly, and the bone pain returned. After 4 months of ERT (6 months after delivery) she was referred for spontaneous bleeding and persistence of bone pain with improvement of the visceromegaly. Results: Each cytokine profile can be seen in Table 1. Most of the cytokine progressed in accordance to the literature. Interestingly, the cytokines INFγ, TNFα, IL-6, and IL-8, besides having their levels decreased during pregnancy, progressed differently from the expected when compared to the values of healthy pregnant women (Fig. 1). Discussion: Literature data indicate that pregnant patients with Gaucher disease may have exacerbations. In contrast, this pregnant Gaucher patient, appeared to have improvement of her disease, with total resolution of bone pain, which returned after delivery. The hypothesis raised is that her immunology alterations during pregnancy can interfere in the activity of GD, as seen in other autoimmune diseases like rheumatoid arthritis, multiple sclerosis, and uveitis. Clinical worsening after delivery contributes to the hypothesis, since there was an increase in the cytokine levels right after delivery. Conclusion: Those who are pregnant and have GD may not have the same inflammatory cytokine profile as the healthy pregnant women. The cytokine variation during pregnancy may explain clinical improvement of the Gaucher patient, while the elevation of these levels during the post-partum period may explain clinical worsening.

T.P.19: Effects of antibody formation during enzyme replacement therapy in 73 adult patients with Pompe disease

High sustained antibody titers against enzyme replacement therapy (ERT) with alglucosidase alfa adversely affect clinical outcome in classic-infantile Pompe disease. The long-term effects of antibody formation on therapeutic efficacy in non-classic Pompe disease are yet unknown. We studied whether the presence of anti-alglucosidase alfa antibodies has an impact on treatment outcome and occurrence of infusion-associated reactions (IARs) in a large cohort of adult patients. This prospective single-centre cohort study included 73 adult patients who were treated with 20 mg/kg alglucosidase alfa every other week and started to receive ERT at least 3 years ago. Antibody titers were measured at approximately 6, 12 and 36 months of ERT using ELISA and their effects on enzyme activity were measured in the medium and in cultured fibroblasts in vitro . Clinical parameters included muscle strength (MRC sumscore), pulmonary function (FVC in upright and supine positions), and IARs. 71 of the 73 (97%) patients developed antibodies against alglucosidase alfa. The mean titer peaked at 6 months to 1:1259 and thereafter declined to 1:270 at 36 months of treatment. Individual titers and titer courses varied, but in the majority (93%) of patients titers decreased or stabilized with continued ERT. Patients with high peak titers showed moderate to high levels of in vitro enzyme inhibition. An increased risk for IARs was found in patients with higher antibody peak titers as 7 (44%) of 16 patients with high titers (⩾1:31,250) experienced IARs, 5 (19%) of 27 patients with intermediate titers (1:1250 to p = 0.001). No relation was found with antibody titer and poorer clinical outcome for MRC sumscore and FVC in upright and supine positions after a 36 months treatment period. Antibody formation to alglucosidase alfa in non-classic Pompe patients increases the risk for infusion-associated reactions, but is not associated with unfavorable clinical outcome during 3 years of treatment.

Rapid improvement of respiratory parameters in a MPS II patient after 6 months of enzyme replacement therapy

Rapid improvement of respiratory parameters in a MPS II patient after 6 months of enzyme replacement therapy

Clinical observations on enzyme replacement therapy in patients with Fabry disease and the switch from agalsidase beta to agalsidase alfa

BackgroundFabry disease is an X-linked inherited lysosomal storage disease that can be treated with the enzymes of agalsidase beta (Fabrazyme) and agalsidase alfa (Replagal). Since June 2009, viral contamination of Genzyme's production facility has resulted in a worldwide shortage of agalsidase beta, leading to the switch to agalsidase alfa for patients with Fabry disease in Taiwan. MethodsThe medical records were retrospectively reviewed for nine male patients with Fabry disease from the start of agalsidase beta treatment until the switch to agalsidase alfa for at least 1 year. ResultsAfter 12–112 months of enzyme replacement therapy (ERT), decreased plasma globotriaosylsphingosine (lyso-Gb3) was found in five out of seven patients, indicating improvement in disease severity. Among the six patients with available echocardiographic data at baseline and after ERT, all six experienced reductions of left ventricular mass index. Renal function, including microalbuminuria and estimated glomerular filtration rate, showed stability after ERT. Mainz Severity Score Index scores revealed that all nine patients remained stable at 12 months after switching to agalsidase alfa. ERT improved or stabilized cardiac status and stabilized renal function, while reducing plasma lyso-Gb3. ERT was well tolerated, even among the three patients who had hypersensitivity reactions. ConclusionThe switch of ERT from agalsidase beta to agalsidase alfa appears to be safe after 1 year of follow-up for Taiwanese patients with Fabry disease.

Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

BackgroundGaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.MethodologyHere, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).FindingsOnly GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.InterpretationIn summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD.

Enzyme replacement therapy in two Japanese siblings with Fabry disease, and its effectiveness on angiokeratoma and neuropathic pain

Enzyme replacement therapy (ERT) for Fabry disease does not show a clear benefit in angiokeratoma. We describe two Japanese siblings with Fabry disease, who were diagnosed when angiokeratomas were found on the older sibling at the age of 13years. Neither of the boys complained of pain, while both suffered from hypohidrosis. We evaluated the safety and efficacy of ERT with recombinant human agalsidase alfa (Replagal®, Dainippon-Sumitomo Pharma. Co., Osaka, Japan) in these siblings over a 5-year period.In both siblings, sweating was observed 3months after the initiation of ERT, which motivated them to adhere to ERT. Pain sensation was regained after 12 to 36months of ERT, followed by a decrease after 48 to 60months. Angiokeratomas on the lateral side of the knee of the older sibling partially disappeared after 48months of ERT. Although the height of both siblings at baseline was lower than the corresponding average age-related heights in the normal Japanese population, during ERT they were within, or close to, the average +1 standard deviation in the non-Fabry population. Their growth rate seemed to indicate catch-up growth. Other clinical symptoms were maintained at baseline levels.Immunoglobulin G anti-agalsidase alfa antibodies were not detected in both sibling during ERT, and no infusion-associated reaction was observed. The treatment was generally well tolerated.ERT was a safe and effective treatment for angiokeratoma and neuropathic pain for these two siblings with Fabry disease.

Plasmatic kinetics of dermatan sulfate during enzyme replacement therapy with iduronate-2-sulfatase in a mucopolysaccharidosis II Patient

Enzyme replacement therapy (ERT) is the worldwide standard of care for a number of mucopolysaccharidosis (MPS) diseases. We report a kinetic study of plasmatic dermatan sulfate (DS) in a 3-year-old subject affected by a severe form of MPS II during the first 10months of ERT with Idursulfase. A strong increase in the DS plasmatic concentration was measured immediately after the first enzyme infusion, with a maximum after 3h, followed by a continuous decrease in the 8-15days following the beginning of treatment. After this, a constant plasmatic content of DS concentration was observed. Overall, during the 10-month treatment period, ERT reduced the plasmatic concentration of DS up to ~80-85%, but it was unable to totally remove it from the blood. We can suppose that immediately after the first enzyme administrations, a large amount of abnormal DS is removed from tissues reaching the blood compartment and eliminated via the urine, and thereafter only minimal changes are observed. The persistency of the residual amounts of DS with the actually recommended dosage in our Patient may suggest the opportunity to promote further studies with increased enzyme dosages to completely remove the accumulation of lysosomal DS.