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PubMed1999

Pancreatic enzyme replacement therapy in cystic fibrosis: Australian guidelines. Pediatric Gastroenterological Society and the Dietitians Association of Australia.

Pancreatic enzyme replacement therapy (PERT) is a major factor associated with achieving optimum growth and nutritional status in cystic fibrosis (CF) patients with pancreatic insufficiency and consequent malabsorption. Currently in Australian CF clinics policies for the usage of PERT vary considerably. This paper highlights the current issues related to fat absorption and use of PERT in CF. It also provides evidence to support the recommendation of a PERT dose based on a standard ratio of lipase units per gram of dietary fat consumed for individual patients. A consistent approach to PERT doses will facilitate identification of patients whose PERT intake increases their risk of fibrosing colonopathy and for whom gastroenterological review is warranted. Recent reports indicate that PERT intake can be reduced with a secondary improvement in growth and nutrition status as a consequence of increased dietetic input. These Australian guidelines for the judicious use of PERT in CF should lead not only to a refinement in nutritional management of patients with CF but should also facilitate an improvement in compliance with therapy due to sophistication in patient education materials. The Australian guidelines for the use of PERT in CF if correctly applied, will also provide patients and their families with a better understanding of the relationship between PERT and nutritional status.

Adolescent↗
PubMed2002

Enzyme replacement therapy for Gaucher Disease: the only experience in Malaysia.

Gaucher Disease may now be treated with enzyme replacement therapy (ERT) or bone marrow transplantation (BMT). Both have their advantages and disadvantages. Results with BMT are curative when successful but limited by the scarcity of an appropriate donor. ERT offers very good relief of symptoms but treatment is lifelong and cost of treatment exorbitant. Patients in developing countries are particularly disadvantaged and management remains a dilemma for both doctor and patient.

Child↗
PubMed2004

[First Polish experience with enzyme replacement therapy in patients with Fabry disease].

We report here the course and outcomes of 18-month enzyme replacement therapy in two 43 and 41-year-old brothers with Fabry disease. At 18 months of recombinant alpha-galactosidase A (Fabrazyme) infusions, we observed in the older patient: weight gain, decreased proteinuria (from 4 to 1.5 g/d), stabilization of creatinine clearance, much lower frequency and intensity of angina, and in the younger brother: weight gain, stabilization of creatinine clearance and proteinuria, prolongation of PQ interval and improvement of hearing. However, neurologic manifestations deteriorated over treatment period in both patients. No serious infusion-related side effects were observed.

Adult↗
PubMed1980

Partial resolution of bone lesions. A child with severe combined immunodeficiency disease and adenosine deaminase deficiency after enzyme-replacement therapy.

A child with severe combined immunodeficiency disease and adenosine deaminase deficiency, with characteristic bone dysplasia, was treated with transfusions of frozen irradiated RBCs as a means of enzyme replacement. This therapy resulted in restoration of immunologic competence and partial resolution of the bone lesions. Although the natural history of these lesions without therapy is not known, enzyme-replacement therapy may have played a role in the resolution of this patient's bone lesions.

Adenosine Deaminase↗
PubMed1999

Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to beta-glucuronidase requires early initiation of enzyme replacement therapy.

We have previously shown that mucopolysaccharidosis type VII (MPS VII) mice receiving six weekly injections of recombinant beta-glucuronidase from birth had improved cognitive ability and reduced central nervous system lysosomal storage. However, a single beta-glucuronidase injection at 5 wk of age did not correct neuronal storage. We define the age at which central nervous system storage in MPS VII mice becomes resistant to beta-glucuronidase therapy and determine the effect of enzyme on other tissues by comparing the histology of mice begun on therapy at various times after birth. MPS VII mice received injections on the day of birth and then weekly for 5 wk with 16,000U/g beta-glucuronidase had reduced lysosomal storage in brain. The same therapy begun on d 14 of life or thereafter failed to correct neuronal storage, even when treatment was continued for six doses. Glial responsiveness or accessibility to enzyme also depended on early treatment. In contrast, leptomeningeal, osteoblast, and retinal pigment epithelial storage reduction depended on enzyme dose rather than age at initiation of therapy. Fixed tissue macrophage storage was reduced in all treated MPS VII mice, even those receiving a single dose. These observations indicate that fixed tissue macrophages in MPS VII mice remain sensitive to enzyme replacement therapy well into adulthood although neurons are responsive or accessible to enzyme therapy early in life. Because early initiation of enzyme replacement is important to achieve a central nervous system response, these studies emphasize the importance of newborn screening for lysosomal storage diseases so that early treatment can maximize the likelihood of a favorable therapeutic response.

Anaphylaxis↗
PubMed2004

Enzyme replacement therapy for Fabry disease: lessons from two alpha-galactosidase A orphan products and one FDA approval.

Two virtually identical products have been developed for enzyme replacement therapy for the treatment of Fabry disease, which is a rare and debilitating genetic disease caused by decreased activity of the lysosomal enzyme alpha-galactosidase A. Lack of this enzyme results in progressive tissue accumulation of globotriaosylceramide (GL-3), resulting in life-threatening renal, cardiac and cerebrovascular complications. Both enzyme replacement products, agalsidase alfa (Replagal; Transkaryotic Therapies, Cambridge, MA, USA) and agalsidase beta (Fabrazyme; Genzyme Corporation, Cambridge, MA, USA), were approved by the European Agency for the Evaluation of Medicinal Products in 2001; agalsidase alfa at a recommended dose of 0.2 mg/kg and agalsidase beta at a recommended dose of 1 mg/kg. In the US, however, orphan drug laws dictated that only one of these products could be approved. In April 2003, after a rigorous evaluation of both products by the US FDA, this approval was granted to agalsidase beta. This decision reflected clinical trial design, how dosages were determined, antibody effects and the ability of each product to demonstrate either clinical efficacy or reduction of tissue storage of GL-3 in major organs of pathology when administered at the recommended dosage. The process also highlighted important issues in the evaluation of drugs to treat life-threatening genetic diseases for which the pathological basis is well-defined.

Adult↗
PubMed2006

Enzyme replacement therapy in alpha-mannosidosis guinea-pigs.

alpha-Mannosidosis is a lysosomal storage disorder caused by deficient activity of lysosomal alpha-mannosidase and is characterised by massive accumulation of mannose-containing oligosaccharides in affected individuals. Patients develop behaviour and learning difficulties, skeletal abnormalities, immune deficiency and hearing impairment. Disease in alpha-mannosidosis guinea-pigs resembles the clinical, histopathological, biochemical and molecular features of the human disease. We have used the guinea-pig model to investigate efficacy of enzyme replacement therapy as a treatment for alpha-mannosidosis. Intravenous recombinant human lysosomal alpha-mannosidase, administered at a dose of 1mg/kg, was cleared from circulation with a half-life of 53 h, with significant enzyme activity (1.4x normal levels) detected in circulation one week post-injection. alpha-Mannosidase administered to alpha-mannosidosis guinea-pigs at 1mg/kg (onset at birth or approximately 30 days) and 10mg/kg (at birth) was distributed widely amongst tissues, including to capillary depleted brain. By monitoring with tandem mass spectrometry, enzyme replacement therapy was found to be effective in reducing stored substrates in peripheral tissues at both dose rates, and in brain by up to 39% at the 10mg/kg dose, compared with untreated alpha-mannosidosis controls. Reductions of up to 60% of urinary mannose containing oligosaccharides were also observed. No histological improvements were seen in the brain at either dose, however marked decreases in lysosomal vacuolation in liver, kidney, spleen and endocrine pancreas, as well as a significant reduction in trigeminal ganglion neurons were observed. Multiple injections of 1mg/kg recombinant enzyme in alpha-mannosidosis guinea-pigs induced a very rapid humoral immune response precluding long-term intravenous treatment.

Animals↗
PubMed2006

Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease.

CONTEXT: Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease. OBJECTIVES: Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease. METHODS: We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5-18) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies. RESULTS: Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics. CONCLUSIONS: Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.

Adolescent↗
PubMed2004

Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow-up.

Pompe's disease is an autosomal recessive myopathy. The characteristic lysosomal storage of glycogen is caused by acid alpha-glucosidase deficiency. Patients with late-onset Pompe's disease present with progressive muscle weakness also affecting pulmonary function. In search of a treatment, we investigated the feasibility of enzyme replacement therapy with recombinant human alpha-glucosidase from rabbit milk. Three patients (aged 11, 16, and 32 years) were enrolled in the study. They were all wheelchair-bound and two of them were ventilator dependent with a history of deteriorating pulmonary function. After 3 years of treatment with weekly infusions of alpha-glucosidase, the patients had stabilized pulmonary function and reported less fatigue. The youngest and least affected patient showed an impressive improvement of skeletal muscle strength and function. After 72 weeks of treatment, he could walk without support and finally abandoned his wheelchair. Our findings demonstrate that recombinant human alpha-glucosidase from rabbit milk has a therapeutic effect in late-onset Pompe's disease. There is good reason to continue the development of enzyme replacement therapy for Pompe's disease and to explore further the production of human therapeutic proteins in the milk of mammals.

Adolescent↗
PubMed2006

Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease.

In Pompe disease, a genetic deficiency of lysosomal acid alpha-glucosidase, glycogen accumulates abnormally in the lysosomes of skeletal, cardiac and smooth muscle, and contributes to clinically progressive and debilitating muscle weakness. The present study involved 8 infantile-onset Pompe patients, treated weekly with 10 mg/kg of recombinant human acid alpha-glucosidase (rhGAA). Muscle biopsies were obtained at baseline, 12 and 52 weeks post-treatment to establish an indicator of efficacy. Several histologic strategies were employed to characterize changes in pre- and post-treatment samples, including high-resolution light microscopy and digital histomorphometry, electron microscopy, capillary density and fiber type analysis, and confocal microscopy for satellite cell activation analysis. Histomorphometric analysis was performed on muscle samples to assess glycogen depletion in response to enzyme replacement therapy (ERT). The extent of glycogen clearance varied widely among these patient samples, and correlated well with clinical outcome. Low glycogen levels, mild ultrastructural damage, a high proportion of type I fibers, and young age at baseline were all features associated with good histologic response. There was no correlation between capillary density and glycogen clearance, and activated satellite cell levels were shown to be higher in post-treatment biopsies with poor histologic responses. This histopathologic study of infantile Pompe disease provides detailed insight into the cellular progression of the disease and its response to therapy while highlighting a number of methodologies which may be employed to assess regression or progression of the associated pathology. As enzyme replacement therapy becomes more prevalent for the treatment of lysosomal storage diseases, such evaluation of post-treatment pathology will likely become a more common occurrence in the daily practice of pathologists.

Capillaries↗
PubMed1998

Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease.

The issue of the interplay of optimal dosage and frequency regimens for enzyme replacement therapy in type I Gaucher disease has been a source of controversy during the 7 years since the introduction of the placenta-derived enzymatic preparation in 1991. We present the results of treatment with the human recombinant form of the enzyme in 28 type I Gaucher patients, who have been treated for 6 to 24 months. As long as cost is an important factor in the management of patients with Gaucher disease, low-dose low-frequency imiglucerase promises satisfactory clinical improvement without compromising quality of life.

Adolescent↗
PubMed2006

Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis.

Dosing of enzyme replacement therapy (ERT) for Gaucher disease type 1 is still a subject of debate and varies from 15 to 130 U/kg/mo, making a huge economic difference of 70,000 US dollars to 380,000 US dollars(euro55,000-300,000) per patient per year. To investigate whether this difference in dosing ultimately translates into a different response, we retrospectively compared long-term outcome of ERT at 2 large European treatment centers, Academic Medical Center, Amsterdam, The Netherlands (n = 49, median dose, 15-30 U/kg/4 wks) and Heinrich-Heine University, Duesseldorf, Germany (n = 57, median dose, 80 U/kg/4 wks). These adult cohorts had a similar genetic background. All follow-up parameters were matched separately at baseline, to avoid bias with respect to disease severity. Improvement in hemoglobin, platelet count, and hepatosplenomegaly was not significantly different between both cohorts, whereas plasma chitotriosidase and bone marrow involvement by magnetic resonance imaging improved more quickly and was more pronounced in the higher-dosed group. Major bone complications rarely occurred in both groups. In conclusion, different dosing regimens of ERT do not affect outcome of hematologic and visceral parameters, but higher dosing leads to accelerated decrease of chitotriosidase and better objective bone response in adult type 1 Gaucher disease.

Adult↗
PubMed1997

Enzyme replacement therapy from birth in a feline model of mucopolysaccharidosis type VI.

We report evidence of a dose responsive effect of enzyme replacement therapy in mucopolysaccharidosis type VI cats from birth, at the clinical, biochemical, and histopathological level. Cats treated with weekly, intravenous recombinant human N-acetylgalactosamine-4-sulfatase at 1 and 5 mg/kg, were heavier, more flexible, had greatly reduced or no spinal cord compression, and had almost normal urinary glycosaminoglycan levels. There was near normalization or complete reversal of lysosomal storage in heart valve, aorta, skin, dura, liver, and brain perivascular cells. No reduction in lysosomal vacuolation was observed in cartilage or cornea; however, articular cartilage was thinner and external ear pinnae were larger in some treated cats. Degenerative joint changes were not obviously delayed in treated cats. Skeletal pathology was reduced, with more normalized bone dimensions and with more uniform bone density and trabecular pattern clearly visible on radiographs by 5 to 6 mo; however, differences between 1 and 5 mg/kg dose rates were not clearly distinguishable. At a dose of 0.2 mg/kg, disease was not significantly altered in the majority of parameters examined. Lysosomal storage was present in all tissues examined in the midterm mucopolysaccharidosis type VI fetus and increased rapidly in extent and severity from birth.

Animals↗
PubMed1999

Immune response to enzyme replacement therapy in lysosomal storage disorder patients and animal models.

The lysosomal storage disorders (LSD) are a group of severe multiple pathology disorders characterized by enzyme deficiencies which cause the lysosomal accumulation of undegraded or partially degraded macromolecules. Enzyme replacement therapy (ERT) has been developed as a therapy for LSD patients. However, immune responses to ERT have been reported in some individuals from LSD animal model and LSD human patient studies. Antibodies can have adverse effects during ERT, which include hypersensitivity/anaphylactic reactions, enzyme inactivation, altered targeting, and increased enzyme turnover. The monitoring of antibody production during replacement therapy is an important consideration for patient management, as high-titer antibodies can affect the safety and efficacy of the therapy.

Animals↗
PubMed2001

The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease.

OBJECTIVE: To assess the long-term systemic and neurologic responses to enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease. STUDY DESIGN: Patients with type 3 Gaucher's disease (n = 21), aged 8 months to 35 years, were enrolled in a prospective study. Enzyme dose was adjusted to control systemic manifestations. Clinical and laboratory evaluations were performed at baseline and every 6 to 12 months thereafter. Patients were followed up for 2 to 8 years. RESULTS: Significant improvement in hemoglobin levels, platelet count, and acid phosphatase values occurred. Liver and spleen volume markedly decreased, and bone structure improved. Nineteen patients had asymptomatic interstitial lung disease unresponsive to ERT. Supranuclear gaze palsy remained stable in 19 patients, worsened in one patient, and improved in one. Cognitive function remained unchanged or improved over time in 13 patients but decreased in 8 patients, 3 of whom developed progressive myoclonic encephalopathy accompanied by cranial magnetic resonance imaging and electroencephalographic deterioration. CONCLUSIONS: At relatively high doses, ERT reverses almost all the systemic manifestations in patients with type 3 Gaucher's disease. Most treated patients do not deteriorate neurologically. Novel therapeutic strategies are required to reverse the pulmonary and neuronopathic aspects of the disease.

Adolescent↗