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PubMed1995

[Enzyme replacement therapy of patients with lysosomal storage disease].

The history and bases of enzyme replacement therapy are briefly reviewed. The enzyme replacement therapy for Gaucher disease type 1, which has been developed for clinical use and is about to be introduced in our country, was described somewhat in detail under the items of the modification of human placental glucocerebrosidase into the macrophage-terminated enzyme, its clinical usage, effects and their evaluations, adverse effects, and new attempts of its application for Gaucher disease types II and III, now being under clinical trials. Also touched are developments of other enzymes for such lysosomal diseases as Fabry disease, Pompe disease, Hurler syndrome, Hunter disease, and Sly disease.

Carbohydrate Sequence↗
PubMed2003

Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis.

GOALS: To evaluate the quality of life (QoL) of patients with chronic pancreatitis before and after pancreatic enzyme replacement therapy in a prospective, multicentre, follow-up study. STUDY: Two groups of patients were evaluated. Group 1 consisted of 31 patients with newly diagnosed chronic pancreatitis who had never been treated with pancreatic enzyme preparations. Group 2 consisted of 39 patients whose disease was diagnosed on average 3.4 years before the start of the study. The latter group of patients had undergone pancreatic enzyme replacement therapy, but during follow-up this treatment proved to be insufficient. The dose of pancreatic enzyme replacement therapy was tailored in accordance with the degree of pancreatic exocrine insufficiency measured by means of exocrine pancreatic function tests. A modified European Organizaton for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was used to assess QoL. RESULTS: The social functioning and financial strain were significantly better, while the levels of hope and confidence were significantly reduced in group 1 compared with group 2. A significant gain in body weight and a significantly reduced defecation rate were found in both groups one month after the beginning of the pancreatic enzyme replacement therapy when compared with the pretreatment values. The prevalence of general and disease-specific symptoms and the intensity of pain were reduced in both groups after one month of enzyme substitution therapy. The working ability, the financial strain and the overall QoL scores were improved significantly in both groups, while the cognitive functioning score was found to be significantly improved during the follow-up only in group 1. The overall increase in the QoL score correlated significantly with the increase in body weight and the decrease in defecation number in both groups. CONCLUSIONS: Pancreatic enzyme replacement therapy in patients with chronic pancreatitis not only reduced the extent of steatorrhea and pain, but also significantly improved a variety of other symptoms and the patient's QoL. Individually tailored enzyme replacement therapy improved the QoL not only in the untreated chronic pancreatitis patients, but also in the inadequately treated group. This study demonstrated that the EORTC QLQ-C30 questionnaire, with the addition of two further questions about steatorrhea, is a useful tool for the evaluation of QoL in patients with chronic pancreatitis.

Abdominal Pain↗
PubMed2006

Outcome after three years of laronidase enzyme replacement therapy in a patient with Hurler syndrome.

Enzyme replacement therapy (ERT) with laronidase, recombinant alpha-L-iduronidase, for mucopolysaccharidosis type I (MPS I) has been clinically available since April 2003. Pre-approval studies were performed on patients with the more attenuated forms of MPS I, Hurler-Scheie and Scheie syndromes. The clinical efficacy of laronidase on the severe form of MPS I, Hurler syndrome, is not well known. We present a patient with Hurler syndrome who has been treated with laronidase for 3 years. Clinically, the patient demonstrated improvement in urinary glycosaminoglycan (GAG) levels and hepatomegaly, but continued to experience decline in respiratory status, musculoskeletal and spinal involvement, and developmental skills. Overall, the benefit of ERT with laronidase in advanced Hurler syndrome appeared to be minimal in this patient.

Disease Progression↗
PubMed1998

Enzyme replacement therapy for Gaucher's disease: the early Canadian experience.

BACKGROUND: The management of severe Gaucher's disease was dramatically improved by the development of enzyme replacement therapy. However, this treatment is very costly (currently about $21,000 per infusion for adults at the starting dose recommended by the manufacturer). The goal of this study was to determine how enzyme replacement therapy was being prescribed and financially supported in various parts of Canada. In addition, demographic and outcome information was elicited. METHODS: Prescribing physicians were identified through professional associations and with the help of the manufacturer of the enzyme preparations used for the treatment of Gaucher's disease. The physicians were surveyed by questionnaire in July 1995. The study included all patients in Canada who had received enzyme replacement therapy for Gaucher's disease before July 1, 1995. RESULTS: A total of 25 patients (15 children and 10 adults) with type 1 Gaucher's disease, the common nonneuronopathic variant of the disease, were receiving enzyme replacement therapy by the end of 1995. The indications for treatment included massive splenomegaly, growth failure, and severe bony, hematologic and pulmonary complications of the disease; no patients with mild disease were receiving treatment. Treatment regimens varied markedly (from 12 to 160 units of enzyme/kg per month). All the patients were reported to have responded well to therapy, based on serial measurements of hematologic indices, liver and spleen volumes, and numbers of bony crises as well as patients' subjective impressions. Financial support for therapy varied markedly from one province to another. None of the reporting physicians was aware of any patients with severe Gaucher's disease who were denied therapy as a result of inability to pay for the medication. Various agencies provided financial support for therapy, including both federal and provincial governments, private insurance carriers and the commercial supplier of the enzyme. In Ontario provincial health care officials accepted the development, by a multidisciplinary panel of medical experts, of formal guidelines for determining eligibility, on the basis of objective medical criteria, for reimbursement for enzyme replacement treatment. INTERPRETATION: Although some differences were found across the country with respect to the details of treatment, the indications for enzyme replacement therapy and the selection of severely affected patients were similar in the various provinces. However, financial support was inconsistent and varied among provinces and patients. This will prove to be a challenge in future, not only with respect to this disease but also for other diseases for which effective, expensive therapy has been developed.

Adult↗
PubMed1998

Total glycolipid and glucosylceramide content in serum and urine of patients with Gaucher's disease type 3 before and after enzyme replacement therapy.

The follow-up of Gaucher's patients under enzyme replacement therapy is generally based both on the clinical aspects and the evaluation of haematological parameters: haemoglobin level, platelet count, acid and alkaline phosphatase activities. Spleen and liver volumes are also reliable criteria for evaluating the improvement of the patients. The determination of glycolipid excretion in the urine and/or the quantification of glycolipids in serum can also be a useful tool for the screening and the follow up of patients with lysosomal storage disease including Gaucher's disease. In this paper we report the follow-up of three patients with Gaucher type 3; in order to test the efficacy of the enzyme replacement therapy with alglucerase in these patients, we evaluated the urine and plasma glucosylceramide content as a marker parallel to the clinical improvement and the decreased organomegaly.

Child↗
PubMed1998

Immune response to enzyme replacement therapy: clinical signs of hypersensitivity reactions and altered enzyme distribution in a high titre rat model.

Immune responses to enzyme replacement therapy (ERT) have been reported and can result in a hypersensitivity/anaphylactic reaction during or immediately after enzyme infusion. We have investigated the infusion of the lysosomal enzyme N-acetylgalactosamine 4-sulphatase (4-sulphatase) into immunized, high titre rats as a model of immune response to ERT. To simulate ERT, high and low titre rats were infused with different doses of radiolabelled recombinant human 4-sulphatase (3H-rh4S). There was evidence of altered targeting, inactivation and degradation of 4-sulphatase in high titre (titre 1024000) compared to low titre (titre 64) rats. There was more 4-sulphatase enzyme activity detected in 5 mg/kg high titre rats when compared to 1 mg/kg high titre rats, suggesting that the antibodies could be saturable in vivo. However, the rats treated with 5 mg/kg 3H-rh4S all had clinical signs of hypersensitivity reactions to 4-sulphatase infusion. There were no apparent signs of adverse reactions in either the high titre 1 mg/kg rats or the low titre rats (1, 5 mg/kg). The high titre 5 mg/kg rats also had changes in 3H-rh4S distribution, with lower levels delivered to the liver and a marked increase in the level remaining in plasma, when compared to either 1 mg/kg high titre rats or low titre rats (1, 5 mg/kg).

Anaphylaxis↗
PubMed1994

Enzyme replacement therapy for Gaucher disease: critical investigations beyond demonstration of clinical efficacy.

Enzyme replacement therapy is highly effective for patients with Type 1 Gaucher disease. In order to estimate the quantity of enzyme that would be necessary for clinical benefit, we conducted a single-infusion, dose-response study in nonsplenectomized patients with Gaucher disease. Biochemical and histologic changes were compared in liver biopsy specimens obtained before and 44 h following the infusion of varying quantities of enzyme. Based on the information obtained from this investigation, patients in our initial clinical efficacy trial were given 60 IU of macrophage-targeted glucocerebrosidase/kg body wt every other week. All patients had significant improvement of their anemia and reduction of splenomegaly after 6 months of treatment. In a subsequent investigation, 10 moderately symptomatic patients with intact spleens were given 10 IU of glucocerebrosidase/kg body wt every other week. After 6 months of treatment, only a portion of these patients had beneficial responses. We concluded that the rate and extent of response to enzyme replacement therapy in patients with Gaucher disease are dependent upon the quantity of enzyme administered. When treatment is initiated in patients with mild to moderately severe disease, a lower dose of enzyme can be selected. Moreover, the maintenance dose of glucocerebrosidase has been shown to be much less than the amount initially required to reduce the accumulated lipid. Some patients require enzyme infusions on only a monthly basis, require enzyme infusions on only a monthly basis, and it is possible that even this frequency may eventually be reduced. These refinements in treatment strategy merit serious consideration for the long-term management of patients with Gaucher disease.

Enzyme Therapy↗
PubMed2001

Enzyme replacement therapy in Fabry disease.

Recent clinical trials have demonstrated that enzyme replacement therapy with alpha-galactosidase A (alpha-Gal A) constitutes a major clinical advance in the treatment of patients with Fabry disease. This new therapeutic approach has been shown to be well tolerated and effective in reducing levels of the storage product globotriaosylceramide and in normalizing many of the debilitating manifestations of the disorder. A double-blind placebo-controlled trial in 26 hemizygous male patients showed that agalsidase alfa (human alpha-Gal A) significantly reduced neuropathic pain (p = 0.02), increased creatinine clearance (p = 0.02), improved glomerular histology, reduced the QRS interval on electrocardiography and increased weight gain. Positron emission tomography also revealed normalization of cerebrovascular flow. After the 6-month controlled period, all patients were given agalsidase alfa for a further 12 months. At the end of this period, all patients had a decrease in neuropathic pain, and there was a significant improvement in their ability to sense heat and cold. In addition, renal function stabilized, even in patients with renal insufficiency at the onset of treatment, and patients reported a normalization of sweating and improvements in their level of energy and sense of well-being. These findings show that enzyme replacement therapy offers promise as an effective management strategy for patients with Fabry disease.

Animals↗
PubMed1999

Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids.

BACKGROUND: Pancreatic enzyme replacement therapy frequently fails to correct intestinal fat malabsorption completely in cystic fibrosis (CF) patients. The reason for this failure is unknown. OBJECTIVE: We investigated whether fat malabsorption in CF patients treated with pancreatic enzymes is caused by insufficient lipolysis of triacylglycerols or by defective intestinal uptake of long-chain fatty acids. DESIGN: Lipolysis was determined on the basis of breath 13CO2 recovery in 10 CF patients receiving pancreatic enzyme replacement therapy after they ingested 1.3-distearoyl,2[1-13C]octanoyl glycerol ([13C]MTG). Intestinal uptake of long-chain fatty acids was determined by analyzing plasma [13C]linoleic acid ([13C]LA) concentrations after patients ingested [13C]LA. For 3 d, dietary intakes were recorded and feces were collected. RESULTS: Fecal fat excretion ranged from 5.1 to 27.8 g/d (mean+/-SD: 11.1+/-7.0 g/d) and fat absorption ranged from 79% to 93% (89+/-5%). There was no relation between breath 13CO2 recovery and dietary fat absorption (r = 0.04) after ingestion of [13C]MTG. In contrast, there was a strong relation between 8-h plasma [13C]LA concentrations and dietary fat absorption (r = 0.88, P < 0.001). CONCLUSION: Our results suggest that continuing fat malabsorption in CF patients receiving enzyme replacement therapy is not likely due to insufficient lipolytic enzyme activity, but rather to incomplete intraluminal solubilization of long-chain fatty acids, reduced mucosal uptake of long-chain fatty acids, or both.

Adolescent↗
PubMed2000

Comparative efficacy of dose regimens in enzyme replacement therapy of type I Gaucher disease.

Gaucher disease is caused by a deficiency of beta-glucocerebrosidase activity. The optimum dose and frequency of enzyme replacement therapy for Gaucher patients have not been determined. We set to compare the therapeutic effects of initiating treatment with macrophage-targeted glucocerebrosidase at a high dose followed by progressive dose reductions with that produced by initial treatment at a low dose in patients with type I Gaucher disease. The study included two parts: (i) Twelve patients received every 2 weeks enzyme replacement therapy at 60 IU/kg body wt for 24 months followed by sequential dose reduction every 6 months to 30 and then to 15 IU/kg body wt. (ii) Thirty-two patients received enzyme replacement therapy at 10 IU/kg every 2 weeks for 12 months. Hematologic parameters and liver and spleen volume were monitored in all patients. All patients had intact spleens. In patients who were started on high-dose enzyme replacement therapy, hemoglobin, acid phosphatase, and organ volume improved or remained unchanged at the end of each dose reduction. Platelet count decreased significantly when the dose of enzyme was reduced from 30 to 15 IU/kg body wt. Initiation of therapy at a low dose led to a significant improvement in all measured parameters at the end of 1 year. We conclude that the minimal effective dose for the nonskeletal manifestations of Gaucher disease can be achieved either by initiating enzyme replacement therapy with a high dose followed by a stepwise dose reduction or by starting treatment at the minimal dose. High dose provides a faster clinical response and should be considered for patients with more aggressive disease. The therapeutic threshold for macrophage-targeted glucocerebrosidase appears to be 10-15 IU/kg body wt every 2 weeks.

Adolescent↗
PubMed1993

Home treatment with intravenous enzyme replacement therapy for Gaucher disease: an international collaborative study of 33 patients.

Intravenous enzyme replacement therapy (Alglucerase; Ceredase; Genzyme Corp, Boston, MA) is an effective and safe treatment for patients with type 1 Gaucher disease. In an attempt to reduce its high cost, a "low-dose high-frequency" protocol (30 U/kg/mo, 3 times a week) was introduced and found to be as effective as the original high-dose protocol (60 U/kg every 2 weeks). Because receiving frequent infusions creates a burden for many patients, we have implemented a program of home treatment for our patients. We now report the safety and feasibility of low-dose/high-frequency home intravenous enzyme-replacement therapy in 33 patients with Gaucher disease. The chronic nature of the treatment, its safety, lack of adverse effects, the stable condition of most patients, and the need to reduce the high cost make enzyme replacement for Gaucher disease a good candidate for intravenous home therapy.

Adolescent↗
PubMed2002

[Quality of life in the course of enzyme replacement therapy for chronic pancreatitis].

AIM: The ultimate goal of any treatment in chronic pancreatitis is to maximize the patient's quality of life. The authors evaluated the QoL of patients with chronic pancreatitis prior to and after pancreatic enzyme replacement therapy in a prospective, multicenter, follow-up study. PATIENTS AND METHODS: Two groups of patients were evaluated. Group 1: 31 patients with newly diagnosed chronic pancreatitis who had never been treated with pancreatic enzyme preparations; Group 2: 39 patients whose disease was diagnosed on average 3.4 years before the start of the study. The latter group of patients had undergone pancreatic enzyme replacement therapy, but during the follow-up this proved to be insufficient. The dose of pancreatic enzyme replacement therapy was tailored in accordance with the degree of pancreatic exocrine insufficiency measured by means of exocrine pancreatic function tests. RESULTS: A significant gain in body weight and a significantly reduced defecation rate were found in both groups 1 month after the beginning of the pancreatic enzyme replacement therapy as compared to the pretreatment values. The prevalence of general and disease-specific symptoms, and the intensity of pain were reduced in both groups after 1 month of enzyme substitution therapy. The working ability, the emotional functioning, the financial strain and the overall QoL score were improved significantly in both groups, while the cognitive functioning was found to be significantly improved during the follow-up only in Group 1. The overall increase in the QoL score correlated significantly with the increase in body weight and the decrease in defecation number in both groups. CONCLUSIONS: Individually-tailored enzyme replacement therapy improved the QoL, reduced the extents of steatorrhea and pain, increased the body weight, not only in the untreated chronic pancreatitis patients, but even in the inadequately treated group.

Adult↗
PubMed2005

Short-term, high dose enzyme replacement therapy in sialidosis mice.

Given the success of enzyme replacement therapy (ERT) in treating the systemic manifestations in a number of lysosomal storage disorders (LSDs), we evaluated the effect of ERT on the mouse model of sialidosis. This glycoproteinosis, which affects primarily the reticuloendothelial (RE) system, is caused by deficiency of lysosomal neuraminidase (NEU1) and consequent accumulation of sialylated glycoconjugates. NEU1 lacks a functional mannose-6-phosphate recognition marker and is not endocytosed by mammalian cells. However, the enzyme produced in insect cells has features that allow its effective uptake by RE cells and macrophages via the mannose receptor, and therefore represent an alternative method of therapy. In this study we tested the therapeutic efficacy of baculovirus (BV) expressed mouse neuraminidase (Neu1) in sialidosis mice. Four-week-old Neu1-/- mice were first injected intravenously with a single dose of the recombinant enzyme for assessment of the half-life of mannosylated Neu1 in vivo. Afterwards, a short-term ERT with a total of five enzyme injections over a 2-week period was performed for evaluation of phenotype correction. Neu1 infused alone or co-administered with its associated protein, protective protein/cathepsin A (PPCA) was effectively taken up by resident macrophages in many tissues. Restored Neu1 activity persisted for up to 4 days, depending on the tissue, and resulted in a significant reduction of lysosomal storage. However, beyond 2 weeks of treatment, ERT mice developed a severe immune response towards the exogenous Neu1 enzyme. These results may have important implications for ERT in sialidosis patients.

Animals↗
PubMedDate not supplied

Decreased bone density in splenectomized Gaucher patients receiving enzyme replacement therapy.

Little is known about the effect of enzyme replacement therapy (ERT) on the bone abnormalities in Gaucher disease. Splenectomized Gaucher patients tend to suffer the most severe skeletal complications. We hypothesized that vitamin D supplementation would act synergistically with glucocerebrosidase infusions to increase bone density in splenectomized Gaucher patients. In a 24-month study, 29 splenectomized Gaucher patients were randomized to three groups: Group 1, calcitriol (1,25-dihydroxyvitamin D3; 0.25-3.0 microg/day) alone for the first 6 months with the addition of ceredase/cerezyme at 60 IU/kg every 2 weeks during months 7-12; Group 2, calcitriol together with ceredase/cerezyme at 60 IU/kg every 2 weeks during months 1-6; and Group 3, enzyme only at 60 IU/kg body wt every 2 weeks. In all three groups, enzyme dose was halved after the first 6 months of therapy. The primary outcome measure was bone mineral density of the lumbar spine measured by single-energy quantitative CT. Bone density by single-energy CT (P = 0.001) and by dual-energy CT (P = 0.06) declined overall, but there was no significant difference between the groups. Calcitriol had no significant effect on bone density. Fat fraction in lumbar spine increased (P = 0.000) and skeletal MRI scores improved. Bone-specific alkaline phosphatase (P = 0.002) and serum osteocalcin increased (P = 0.008), while blood cyclic AMP and urinary deoxypyridinoline did not change appreciably. Hemoglobin, platelet counts, and liver volume significantly improved. We conclude that ERT alone, or in combination with calcitriol, cannot repair the bone composition in splenectomized adult Gaucher patients. Alternatively, measuring trabecular bone density may be an inadequate marker of clinical efficacy for treating skeletal involvement in Gaucher disease.

Adult↗
PubMed2000

Enzyme replacement therapy in a feline model of MPS VI: modification of enzyme structure and dose frequency.

Enzyme replacement therapy (ERT) in the MPS VI cat is effective at reducing or eliminating pathology in most connective tissues. One exception is that cartilage and chondrocytes remained distended with extensive lysosomal vacuolation after long-term, high-dose ERT. In this study, we demonstrate that recombinant human N-acetylgalactosamine-4-sulphatase (4S) is taken up by chondrocytes via a mannose-6-phosphate-dependent mechanism and is effective at removing MPS storage. In vitro, the penetration of 4S into articular cartilage is low (partitioning coefficient = 0.06) and i.v. administered enzyme does not distribute significantly into articular cartilage in vivo. To alter the tissue distribution of 4S, the enzyme was coupled to ethylene diamine or poly-L-lysine, increasing its overall charge and diffusion into cartilage, and the dosing frequency of unmodified 4S was increased. Modification resulted in active 4S that maintained its ability to correct MPS storage and increased the partitioning coefficient of 4S into cartilage by 77% and 50% for ethylene diamine and poly-L-lysine, respectively. However, in vivo ERT studies demonstrated that response to therapy was not significantly improved by either the enzyme modifications or change to the dosing regimen, when compared with ERT with unmodified enzyme. Distribution experiments indicated the majority of enzyme is taken up by the liver irrespective of modification. To optimize therapy and improve the amount of enzyme reaching cartilage and other tissues demonstrating poor uptake, it may be necessary to bypass the liver or prolong plasma half-life so that proportionately more enzyme is delivered to other tissues.

Animals↗
PubMed1975

Investigations in enzyme replacement therapy in lipid storage diseases.

Enzyme replacement appears to offer much promise as specific therapeutic procedures for patients with Fabry's disease and Gaucher's disease. However, enzyme replacement in patients with Tay-Sachs disease and other heritable metabolic disorders where the central nervous system is affected will require first the development of effective methods for the delivery of exogenous enzymes to the brain; such methods are not yet available.

Adolescent↗
PubMed1989

Enzyme-replacement therapy: problems and prospects.

Several diseases can, at least in theory, be treated by the administration of an enzyme, the deficiency of which is the cause of the disease. Various attempts have been made to correct enzymatic deficiencies responsible for the clinical manifestation of diseases for which prevention cannot be achieved by modification of the diet or by supportive therapy with drugs. Except for treating certain digestive disorders, enzyme-replacement therapy has not yet found a broad application. In this review article a compilation is given of the problems and prospects of enzyme-replacement therapy in diseases caused by the deficiency of an enzyme.

Enzyme Therapy↗
PubMed2003

Enzyme replacement therapy in Fabry disease: clinical implications.

PURPOSE OF REVIEW: Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A. The lack of enzyme activity results in an intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide, in various tissues. Significant morbidity is caused by progressive effects on the vascular endothelium, heart, brain and kidney leading to end-stage renal disease. In this review we would like to give a current overview on recent advances in therapy and an outlook on future aspects in the management of Fabry disease. RECENT FINDINGS: Besides symptomatic management, enzyme replacement therapy with recombinant alpha-galactosidase A is the only specific treatment currently available. Clinical trials using recombinant alpha-galactosidase A showed safety and efficacy in reversing substrate storage in different tissues. Short-term response on clinical manifestations such as impaired kidney function demonstrates a clear potential to improve and stabilize symptoms of the disease. In patients with residual enzyme activity enzyme enhancement therapy with pharmacological chaperones seems to be an attractive approach. Enzyme replacement therapy mediated by gene transfer may become a promising alternative treatment strategy in the future. SUMMARY: Remarkable advances in the treatment of patients with Fabry disease have been made with the introduction of enzyme replacement therapy in clinical use. Although lysosomal globotriaosylceramide deposits are cleared very effectively, longer term experience on clinical outcome in patients with severe vital organ involvement is still limited.

Clinical Trials as Topic↗