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PubMed2006

In vivo transduction by intravenous injection of a lentiviral vector expressing human ADA into neonatal ADA gene knockout mice: a novel form of enzyme replacement therapy for ADA deficiency.

Using a mouse model of adenosine deaminase-deficient severe combined immune deficiency syndrome (ADA-deficient SCID), we have developed a noninvasive method of gene transfer for the sustained systemic expression of human ADA as enzyme replacement therapy. The method of delivery is a human immunodeficiency virus 1-based lentiviral vector given systemically by intravenous injection on day 1 to 2 of life. In this article we characterize the biodistribution of the integrated vector, the expression levels of ADA enzyme activity in various tissues, as well as the efficacy of systemic ADA expression to correct the ADA-deficient phenotype in this mouse model. The long-term expression of enzymatically active ADA achieved by this method, primarily from transduction of liver and lung, restored immunologic function and significantly extended survival. These studies illustrate the potential for sustained in vivo production of enzymatically active ADA, as an alternative to therapy by frequent injection of exogenous ADA protein.

Adenosine Deaminase↗

PubMed2005

Monitoring enzyme replacement therapy in Fabry disease--role of urine globotriaosylceramide.

Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb(3) concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant alpha-galactosidase A. The marked decline in urine Gb(3) on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment.

Adult↗

PubMedDate not supplied

Immune response to enzyme replacement therapy: single epitope control of antigen distribution from circulation.

Immune response to replacement therapy has been reported for a range of therapeutic strategies being developed for the treatment of patients with genetic disease. The potential problem of immune response to enzyme replacement therapy has been investigated in alpha-L-iduronidase immunized rats, representing a model of the lysosomal storage disorder Hurler syndrome (alpha-L-iduronidase deficiency). The antibody response to alpha-L-iduronidase showed that the positional location of antibody reactivity was similar for different immunized rats, but the precise linear sequence epitopes identified, varied between rats. A monoclonal antibody reacting to an epitope in close proximity to one high antigenicity site on alpha-L-iduronidase was used to reproduce the in vivo effect of altered enzyme tissue distribution, previously observed in immunized rats infused with alpha-L-iduronidase. The study demonstrated that during an immune response, antibody reacting to a single epitope could partially control the tissue distribution of antigen from circulation.

Amino Acid Sequence↗

PubMed2004

Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial of enzyme replacement therapy.

Mucopolysaccharidosis type VI (MPS VI), or Maroteaux-Lamy syndrome, is a lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (ARSB). Seven MPS VI patients were chosen for the initial clinical trial of enzyme replacement therapy. Direct sequencing of genomic DNA from these patients was used to identify ARSB mutations. Each individual exon of the ARSB gene was amplified by PCR and subsequently sequenced. Nine substitutions (c.289C>T [p.Q97X], c.629A>G [p.Y210C], c.707T>C [p.L236P], c.936G>T [p.W312C], c.944G>A [p.R315Q], c.962T>C [p.L321P], c.979C>T [p.R327X], c.1151G>A [p.S384N], and c.1450A>G [p.R484G]), two deletions (c.356_358delTAC [p.Y86del] and c.427delG), and one intronic mutation (c.1336+2T>G) were identified. A total of 7 out of the 12 mutations identified were novel (p.Y86del, p.Q97X, p.W312C, p.R327X, c.427delG, p.R484G, and c.1336+2T>G). Two of these novel mutations (p.Y86del and p.W312C) were expressed in Chinese hamster ovary cells and analyzed for residual ARSB activity and mutant ARSB protein. The two common polymorphisms c.1072G>A [p.V358M] and c.1126G>A [p.V376M] were identified among the patients, along with the silent mutation c.1191A>G. Cultured fibroblast ARSB mutant protein and residual activity were determined for each patient, and, together with genotype information, were used to predict the expected clinical severity of each MPS VI patient.

Alternative Splicing↗

PubMed2002

Agalsidase alfa--a preparation for enzyme replacement therapy in Anderson-Fabry disease.

Anderson-Fabry disease is an X-linked multisystemic disorder caused by a genetic deficiency of the lysosomal enzyme a-galactosidase A. The enzyme is responsible for degradation of glycolipids inside the lysosomes. Lack of catalytic activity leads to progressive depositions of undegraded glycolipids in a large number of organs. Crises of severe pain in the extremities (acroparesthesias), hypohidrosis, corneal opacities and dysfunction of several organs (kidney, brain, heart) are the leading symptoms in patients with Anderson-Fabry disease. Females may have the same symptoms as males but to a more variable degree. The variable manifestations seen in heterozygotes can be explained by the Lyon hypothesis. This hypothesis predicts that in X-linked diseases, the carriers are a mosaic of normal and mutant cells in varying proportions and hence have variable expression. As in Gaucher's disease, enzyme replacement therapy recently became available for Anderson-Fabry disease. Two drugs have gained approval in the EU by the European Agency for the Evaluation of Medicinal Products. These are agalsidase beta (Fabrazyme, Genzyme Corporation) and agalsidase alfa (Replagal, Transkaryotic Therapies, Inc.). This review will describe clinical efficacy, safety and tolerability of agalsidase alfa.

Animals↗

PubMed2004

Clinical benefit in Fabry patients given enzyme replacement therapy--a case series.

Fabry disease is a rare lysosomal storage disorder resulting from deficient activity of alpha-galactosidase A and subsequent pathological accumulation of glycosphingolipids throughout the body. Traditionally, Fabry disease was managed symptomatically, but the introduction of enzyme replacement therapies (ERTs) (agalsidase beta (Fabrazyme); agalsidase alfa (Replagal)) has transformed treatment of this disorder. Clinical studies of both compounds have demonstrated clearance of glycosphingolipds from key tissues. To explore whether substrate clearance translates into clinical benefit, a retrospective survey of 17 patients (mean age 34.7 years) treated with agalsidase beta (1 mg/kg every 2 weeks) was undertaken, using an eight-item retrospective questionnaire developed specifically to assess the effect of ERT on the symptoms of Fabry disease. Pain severity, heat tolerance, physical activity, fatigue and psychological status were scored using a 10-point visual analogue scale (e.g. for pain severity: 1=none, 10=strong). Answers to all other questions were quantitative. Changes in mean scores were 4.69 to 2.25 (p =0.012) for pain severity; 4.38 to 2.21 (p =0.019) for number of pain crises per month; 8.69 to 2.98 (p =0.097) for duration of pain crises in hours; 2.76 to 5.76 (p =0.002) for heat tolerance; 3.28 to 2.51 (p =0.058) for bowel movements per day; 2.47 to 4.47 (p =0.007) for frequency of physical activity; 5.53 to 3.71 (p =0.046) for fatigue, and 5.82 to 8.12 (p =0.005) for psychological status. All patients improved in at least one aspect, although the degree of improvement across patients and aspects varied widely; reasons for this remain unclear. Despite the inherent bias involved in retrospective questionnaires, we believe that the findings are encouraging. A prospective version of the questionnaire is currently under validation.

Adolescent↗

PubMedDate not supplied

Enzyme replacement therapy in Fabry's disease: recent advances and clinical applications.

Fabry's disease is a rare X-linked recessive disorder resulting from deficient lysosomal enzyme, alpha-galactosidase A (alpha-Gal A) activity. The deficiency leads to progressive glycosphingolipid globotriaosylceramide (Gb3) accumulation in fluids and tissues, including vascular endothelium, connective tissue, kidney, heart, brain and peripheral nerves. Classic Fabry's disease in hemizygous males has high morbidity and mortality due to end-stage renal disease (ESRD) requiring hemodialysis (HD) or kidney transplantation, myocardial involvement and central nervous system (CNS) complications. Most heterozygous females can also suffer from this severe disease deterioration. Until recently, Fabry's disease management consisted of symptomatic and palliative treatment, but this has changed with the availability of the recombinant human alpha-Gal A enzyme, agalsidase. Two different agalsidase formulations have been obtained: one from human fibroblast (agalsidase alpha), and one from Chinese hamster ovary (CHO) cells (agalsidase beta). Both preparations underwent clinical trials that documented the feasibility, efficacy and safety of the treatment. In addition, several clinical observations have proved that agalsidase reduces the storage of the substrate from several organs and tissues and, consequently, improves signs and symptoms of Fabry's disease. Additional clinical experiences have confirmed the initial clinical trial results, but further studies are needed to evaluate the long-term outcome of enzyme replacement therapy (ERT). We reviewed the clinical trial observations, as well as subsequent clinical experiences with ERT in patients with Fabry's disease.

Animals↗

PubMed2004

Effect of enzyme-replacement therapy on gastrointestinal symptoms in Fabry disease.

Fabry disease is an X-linked recessive lysosomal storage disorder caused by deficiency of lysosomal alpha-galactosidase A. The disease affects not only kidney, myocardium, central nervous system and the skin but also, in many patients, the gastrointestinal tract. The recent advent of enzyme-replacement therapy has been reported to show beneficial effects on cardiomyopathy, renal function and autonomous nervous function. We report on a 34-year-old patient with Fabry disease in whom gastrointestinal symptoms were major complaints. Enzyme replacements led to remarkable improvement of diarrhoea and constipation. Abdominal pain, the feeling of fullness and meteorism improved, and metoclopramide, which previously had been used regularly, could be discontinued. There were also marked improvements of appetite, body weight, body mass index, physical activity and overall wellbeing. This observation should prompt further investigations into the pathophysiology of gastrointestinal manifestations in Fabry disease and the mechanisms of enzyme-replacement effects on gut function.

Adult↗

PubMed2003

[Effect of enzyme replacement therapy on lipid profile in patients with Gaucher's disease].

BACKGROUND AND OBJECTIVE: Gaucher's disease (GD) is a lysosomal storage disorder, caused by a deficiency of the acid -glucocerebrosidase enzyme, which results in accumulation of lipids within macrophages. GD patients show decreased plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels, as well as decreased apolipoprotein (apo) A-I and B. Conversely, concentrations of plasma apo E and the chitotriosidase (ChT) activity, a chitinase synthesized by activated macrophages, are increased. Enzyme replacement therapy (ERT) is effective and safe in reversing the clinical manifestations in symptomatic patients. The aim of this study was to evaluate the effect of ERT on the lipid profile of GD patients. PATIENTS AND METHOD: 70 patients, from the Spanish Registry of Gaucher's disease (REEG), were divided into two groups: 54 under ERT, according to stablished criteria, and 16 without ERT. Plasma apolipoprotein, lipoprotein and lipid concentrations, and chitotriosidase activity were analyzed in both groups. Statistical analysis was carried out with the U-Mann Whitney non-parametric test for comparison of data. RESULTS: The group of GD patients under ERT showed significant increases of HDL-c (+38%) and apo A-I (+18%) levels, whereas no changes were observed in LDL-c and apo B levels. Conversely, chitotriosidase activity (-58%), plasma-apo E (-32%) and HDL-apo E (-26%) levels were dramatically reduced after ERT. No significant modifications were observed in the group without ERT. CONCLUSIONS: ERT in GD patients displays significant effects on the concentration of plasma lipoproteins, resulting in a less atherogenic lipid profile and in a reduction of activated macrophages.

Adolescent↗

PubMed1991

Hematologic improvement in a patient with Gaucher disease on long-term enzyme replacement therapy: evidence for decreased splenic sequestration and improved red blood cell survival.

We describe here an investigation of the hematologic response of a child with Gaucher disease to a six-year therapeutic trial of human placental mannose-terminated glucocerebrosidase. While on enzyme replacement therapy, the patient's hemoglobin and platelet count significantly increased (6.9 g/dl to 12.2 g/dl, and 39,000/microliters to 74,000/microliters, respectively). Over the same time interval his absolute reticulocyte count decreased (88.1 x 10(3)/microliters to 31.5 x 10(3)/microliters). The patient's splenic volume decreased by over 60% (2108ml to 797ml) and his bone marrow demonstrated a dramatic clearing of Gaucher cell infiltration. Serum erythropoietin levels were at the lower range of normal at points in time when he was severely anemic and did not change with improvement in hemoglobin. Coincident with the improvement in the patient's hemoglobin, in vivo survival of autologous radiolabeled RBCs increased 34%. The improved hematopoietic profile appeared to result primarily from an increase in the in vivo survival of mature hematopoietic elements secondary to a decrease in splenic sequestration. Improved marrow function secondary to the clearing of Gaucher cell infiltrates may also play a role in his improved hematologic status.

Biopsy↗

PubMed2006

Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome.

Hurler syndrome (MPS 1H) is the severe form of mucopolysaccharidosis type 1 (MPS 1). Haematopoietic cell transplantation (HCT) is the treatment of choice, but carries a high incidence of graft failure and morbidity. The use of enzyme replacement therapy (ERT) might improve the clinical signs and symptoms before HCT, resulting in less transplantation-related complications. Moreover, clearance of glycosaminoglycans (GAG's) from the bone marrow might improve engraftment. Twenty-two patients with MPS 1H received one or more HCT procedures in combination with ERT. One patient with severe cardiomyopathy improved significantly after ERT. All children were in a relatively good clinical condition before HCT. Of patients 59, 82 and 86% were alive and engrafted after one, two and three HCT procedures, respectively. Two patients died after repetitive HCT. No serious ERT-infusion-related toxicity occurred. ERT with HCT was well tolerated. Neither a positive nor a negative effect on the number of patients who are alive and engrafted after receiving ERT before HCT as compared to a historic cohort was noted. However, patients in a poor clinical condition before HCT might benefit from ERT.

Child, Preschool↗

PubMedDate not supplied

Metaphyseal undertubulation in gaucher disease: resolution at MRI in a patient undergoing enzyme replacement therapy.

Gaucher disease is a sphingolipid storage disorder that results in the accumulation of Gaucher cells within the reticuloendothelial system. The life span can be near normal in the most common form. Our case illustrates the resolution of the skeletal findings in Gaucher disease following enzyme replacement therapy. We also report the correlation of these findings with clinical improvement.

Acetabulum↗

PubMed2000

Enzyme replacement therapy in a mouse model of aspartylglycosaminuria.

Aspartylglycosaminuria (AGU), the most common lysosomal disorder of glycoprotein degradation, is caused by deficient activity of glycosylasparaginase (AGA). AGA-deficient mice share most of the clinical, biochemical and histopathologic characteristics of human AGU disease. In the current study, recombinant human AGA administered i.v. to adult AGU mice disappeared from the systemic circulation of the animals in two phases predominantly into non-neuronal tissues, which were rapidly cleared from storage compound aspartylglucosamine. Even a single AGA injection reduced the amount of aspartylglucosamine in the liver and spleen of AGU mice by 90% and 80%, respectively. Quantitative biochemical analyses along with histological and immunohistochemical studies demonstrated that the pathophysiologic characteristics of AGU were effectively corrected in non-neuronal tissues of AGU mice during 2 wk of AGA therapy. At the same time, AGA activity increased to 10% of that in normal brain tissue and the accumulation of aspartylglucosamine was reduced by 20% in total brain of the treated animals. Immunohistochemical studies suggested that the corrective enzyme was widely distributed within the brain tissue. These findings suggest that AGU may be correctable by enzyme therapy.-Dunder, U., Kaartinen, V., Valtonen, P., Väänänen, E., Kosma, V.-M., Heisterkamp, N., Groffen, J., Mononen, I. Enzyme replacement therapy in a mouse model of aspartylglycosaminuria.

Acetylglucosamine↗

PubMed2005

Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) or Krabbe disease is a devastating, degenerative neurological disorder caused by mutations in the galactosylceramidase (GALC) gene that severely affect enzyme activity. Currently, treatment options for this disorder are very limited. Enzyme replacement therapy (ERT) has been shown to be effective in lysosomal storage disorders with predominantly peripheral manifestations such as type I Gaucher's and Fabry's disease. Little however is known about the possible benefit of ERT in GLD, which has a substantial central nervous system component. In this study, we examined the effect of peripheral GALC injections in the twitcher mouse model of the disease. Although we were unable to block the precipitous decline that normally occurs just before death, we did observe significant early improvements in motor performance, a substantial attenuation in the initial failure to thrive, and an increase in life span. Immunohistochemical and activity analyses demonstrated GALC uptake in multiple tissues, including the brain. This was associated with a decrease in the abnormal accumulation of the GALC substrate psychosine, which is thought to play a pivotal role in disease pathology. These results indicate that peripheral ERT is likely to be beneficial in GLD.

Animals↗

PubMed2001

Lung involvement and enzyme replacement therapy in Gaucher's disease.

Symptomatic lung involvement in Gaucher's disease is relatively rare, being restricted to patients with other severe manifestations. We describe our experience in eight of 411 patients in our referral clinic, who presented with prominent pulmonary signs or symptoms. There were four adults and four children; all have been successfully treated with enzyme replacement therapy. Routine means of monitoring pulmonary status including clinical assessment, chest X-ray, pulmonary function tests, and high-resolution CT (HRCT) were used. Enzyme treatment resulted in decreased hepatosplenomegaly, improved haematological parameters, and increased well-being; There was decreased clubbing and decreased dyspnoea in some of the patients, although on radiology, lung pathology had not normalized. All four children showed improved respiratory compliance, with significant improvement of the radiological findings in one and unchanged disease in the others. Two adults showed improvement in oxygen saturation but worsening of pulmonary hypertension. On chest X-ray, both had increased interstitial markings; one had gradual progression of pulmonary artery accentuation and fine interstitial stable pattern on HRCT. The other two adults had no change in lung function or on chest X-ray, but on HRCT there was apparent improvement in one patient. There is great heterogeneity in presentation and response to enzyme therapy in patients with Gaucher's disease and symptomatic lung involvement. Clinically, some benefited significantly from enzyme therapy, but in contrast to the dramatic reduction in organomegaly, there was no normalization in pulmonary function or lung architecture.

Adolescent↗

PubMed2005

Individualization of long-term enzyme replacement therapy for Gaucher disease.

Gaucher disease, the most common lysosomal storage disorder, is a heterogeneous condition affecting multiple organ systems. Patients with nonneuronopathic (type 1) Gaucher disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase (imiglucerase, Cerezyme, Genzyme Corporation, Cambridge, MA) reverses or ameliorates many of the manifestations of type 1 Gaucher disease. However, due to the variable pattern and severity of disease, and the uncertain manner of progression, implementation of treatment, choice of initial and maintenance imiglucerase dose, and evaluation of the therapeutic response must be tailored to the individual patient. For the past 14 years, the US Regional Coordinators of the International Collaborative Gaucher Group have individually and collectively developed extensive clinical experience in managing patients with Gaucher disease. In this review, we present recommendations for initial imiglucerase treatment and subsequent dose adjustments based on a schedule of regular assessment and monitoring, and achievement and maintenance of defined therapeutic goals.

Disease Progression↗

PubMed2006

Enzyme replacement therapy and renal function in 201 patients with Fabry disease.

AIM: Fabry disease is a rare lysosomal storage disorder caused by deficient activity of alpha-galactosidase A, resulting in progressive cellular accumulation of glycolipids, which may ultimately result in endstage renal disease. We examined the effects of enzyme replacement therapy (ERT) with Agalsidase-alpha on renal function using data from a large international database, the Fabry Outcome Survey (FOS). METHODS: This analysis was based on 1,040 serum creatinine measurements in 201 patients with Fabry disease, aged 20 - 60 years, with serum creatinine concentrations of less than 2 mg/dl and duration of ERT of up to 4.7 years. Both pretreatment and treatment data were used to examine independent predictors of changes in serum creatinine. In a second approach longitudinal serum creatinine measurements from 1 year before treatment, at baseline and 1 and 2 years after the start of treatment were analyzed in 20 patients with chronic kidney disease (CKD) Stage 2 and 3. RESULTS: We found an independent negative association between serum creatinine and time on Agalsidase-alpha treatment (p < 0.05). Renal function declined significantly (p < 0.05) in the year before treatment. After 1 year of treatment, however, the decline in estimated glomerular filtration rate had been halted, and renal function was preserved for up to 2 years. CONCLUSIONS: In conclusion, ERT with Agalsidase-alpha is associated with decrease of serum creatinine and may prevent the deterioration of renal function in patients with Fabry disease.

Adult↗

PubMed1980

alpha1,4-Glucosidase-albumin polymers: in vitro properties and advantages for enzyme replacement therapy.

Soluble polymers of rat (or human) albumin and alpha-1,4-glucosidase are prepared using the cross-linking agent glutaraldehyde. The resulting polymer has an average molecular weight of 800 000 indicating an average composition of 12 albumin molecules for each enzyme molecule. Compared with an equivalent amount of free enzyme, the enzyme-albumin polymer has an increased resistance to heat denaturation (half-life of 15 h compared with 1 h for free enzyme at 37 degrees C) and to proteolysis by trypsin (half-life of 180 min compared with 10 min). The high degree of resistance to bioinactivation of the enzyme-albumin polymer is discussed in relation to requirements for enzyme replacement therapy in a range of metabolic diseases including type II glycogenosis (Pompe's disease) where alpha-1,4-glucosidase is the defective enzyme.

Animals↗