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PubMed2001

Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

CONTEXT: Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. OBJECTIVE: To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease. DESIGN AND SETTING: Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health. PATIENTS: Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay. INTERVENTION: A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total). MAIN OUTCOME MEASURE: Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI). RESULTS: Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight. CONCLUSION: Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.

Adult↗
PubMed1999

Enzyme replacement therapy improves reproductive performance in mucopolysaccharidosis type VII mice but does not prevent postnatal losses.

Mice with mucopolysaccharidosis type VII (MPS VII) are devoid of beta-glucuronidase and accumulate glycosaminoglycans in lysosomes resulting in bone dysplasia, learning disabilities, and decreased mobility. MPS VII males do not breed and, while MPS VII females occasionally mate with heterozygous males, they do not maintain their young postnatally. Heterozygous matings produce less than 25% MPS VII offspring, but until now it was unclear whether this results from prenatal or postnatal losses. The administration of recombinant beta-glucuronidase from birth significantly reduces glycosaminoglycan storage in most tissues, increases life span, and improves the animal's cognitive ability and mobility. To determine whether reproductive failure is corrected by such therapy, male and female MPS VII mice were injected with enzyme at weekly intervals from birth to 5 wk of age (6xinj). Enzyme-replaced MPS VII mice bred when mated together. The 6xinj MPS VII males mated repeatedly until they were killed 135 d postinjection. All mated 6xinj MPS VII females gave birth to two litters, but maintained few of their young. Selective loss of MPS VII offspring was observed in matings between heterozygotes. Analysis of 379 preterm fetuses from heterozygous matings showed a frequency of 24.6% MPS VII pups, indicating that the decreased number of MPS VII pups produced by mating heterozygotes results from postnatal losses. The ovaries of young adult MPS VII mice have follicles and corpora lutea, and the testes generate sperm. Results suggest that the reproductive failure in MPS VII mice is related to impaired mobility and/or impaired cognitive function, and enzyme replacement restores mating capacity.

Animals↗
PubMed2001

Production and characterization of recombinant human CLN2 protein for enzyme-replacement therapy in late infantile neuronal ceroid lipofuscinosis.

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal recessive childhood disease caused by mutations in the CLN2 gene, which encodes the lysosomal enzyme tripeptidyl peptidase I. As a step towards understanding the protein and developing therapeutics for the disease, we have produced and characterized recombinant human CLN2 (ceroid lipofuscinosis, neuronal 2) protein from Chinese-hamster ovary cells engineered to secrete high levels of the enzyme. The protein was secreted as an inactive soluble proenzyme of approximately 65 kDa that appears as a monomer by gel filtration. Upon acidification, the protein is processed to mature form and acquires activity. The enzyme is efficiently delivered to the lysosomes of LINCL fibroblasts by mannose 6-phosphate-receptor-mediated endocytosis (EC(50) approximately 2 nM), where it remains active for long periods of time (t(1/2) approximately 12 days). In addition, the enzyme is taken up by rat cerebellar granule neurons by mannose 6-phosphate-dependent and -independent mechanisms. Treatment of LINCL fibroblasts with recombinant CLN2 protein restores normal enzyme activity and ameliorates accumulation of the major storage protein, mitochondrial ATP synthase subunit c.

Aminopeptidases↗
PubMed1991

Enzyme replacement therapy for Gaucher disease.

Four patients with moderately severe type I Gaucher disease were treated with commercially available mannose terminated glucocerebrosidase (Ceredase; Genzyme, Boston, MA) for up to 13 months. The enzyme was administered at the rate of three to four times weekly at one fourth the total recommended dosage, greatly decreasing the cost. Marked regression of hepatomegaly and improvement in liver function tests, peripheral blood counts, and serum angiotensin-converting enzyme levels were documented. The two patients with pulmonary involvement manifested improvement in pulmonary function tests. Skeletal disease remained unchanged.

Adult↗
PubMed1989

Management of chronic pancreatitis. Focus on enzyme replacement therapy.

The goals of treatment with pancreatic extracts in patients with chronic relapsing pancreatitis are twofold: pain relief and control of maldigestion caused by exocrine pancreatic insufficiency. Experience with the use of pancreatic enzymes for analgesic purposes suggests that the less severe the pain, the greater the analgesic effect of these enzymes. However, the number of trials, as well as the number of patients treated, is fairly small and more studies in larger patient populations are needed. The use of pancreatic enzymes for maldigestion owing to exocrine pancreatic insufficiency which is secondary to chronic pancreatitis, pancreatectomy, cystic fibrosis, or GI bypass surgery incurs several problems. These problems are primarily caused by gastric inactivation of the enzymes, low enzyme activity of many commercial preparations and/or poor patient compliance. Treatment with conventional enzyme products (powdered extracts, enteric-coated tablets or capsules) has been disappointing. At best, results were inconsistent, showing a high degree of individual variation. The introduction of enzyme preparations in the form of pH-sensitive enteric-coated microspheres in hard gelatin capsules represents a significant advance. These microspheres are superior to conventional enzyme preparations in improving the symptoms of pancreatic insufficiency, particularly steatorrhea, where low doses of microspheres are as effective as large doses of conventional enzyme preparations. Steatorrhea, however, is rarely completely resolved. In cases refractory to therapy, treatment with the combination of pH-sensitive enteric-coated microspheres and H2-antagonists or prostaglandins has met with some success.

Chronic Disease↗
PubMed1994

Enzyme replacement therapy for murine mucopolysaccharidosis type VII.

Recombinant mouse beta-glucuronidase administered intravenously to newborn mice with mucopolysaccharidosis type VII (MPS VII) is rapidly cleared from the circulation and localized in many tissues. Here we determine the tissue distribution of injected enzyme and describe its effects on the histopathology in 6-wk-old MPS VII mice that received either one injection of 28,000 U recombinant beta-glucuronidase at 5 wk of age or received six injections of 28,000 U given at weekly intervals beginning at birth. These mice were compared with untreated 6-wk-old MPS VII mice. The single injection decreased lysosomal distention in the fixed tissue macrophage system. MPS VII mice that received multiple injections had 27.8, 3.5, and 3.3% of normal levels of beta-glucuronidase in liver, spleen, and kidney, respectively. Brain had detectable beta-glucuronidase, ranging from 2.0-12.1% of normal. Secondary elevations of alpha-galactosidase and beta-hexosaminidase in brain, spleen, liver, and kidney were decreased compared with untreated MPS VII mice. Although no improvement was observed in chondrocytes, glia, and some neurons, the skeleton had less clinical and pathological evidence of disease and the brain had reduced lysosomal storage in meninges and selected neuronal groups. These data show that recombinant beta-glucuronidase treatment begun in newborn MPS VII mice provides enzyme to most tissues and significantly reduces or prevents the accumulation of lysosomal storage during the first 6 wk of life. Whether therapy begun later in life can achieve this level of correction remains to be established.

Animals↗
PubMedDate not supplied

Correlation of bone marrow response with hematological, biochemical, and visceral responses to enzyme replacement therapy of nonneuronopathic (type 1) Gaucher disease in 30 adult patients.

PURPOSE: This investigation correlates the marrow response with the degree of increase in hemoglobin (Hb) and platelet count (Plt); decrease in concentrations of plasma tartrate-resistant acid phosphatase, serum angiotensin-converting enzyme (ACE), serum ferritin, and plasma chitotriosidase; and decrease in liver and spleen size, measured by ultrasonography. METHODS: Thirty adult patients with nonneuronopathic (type 1) Gaucher disease (23% splenectomized) were followed for mean periods of 12 and 36 months. RESULTS: The series achieved highly significant mean responses in all hematological, biochemical, and visceral parameters over both observation periods; over a mean 36 months, 19 (63%) had a marrow response, 11 (37%) did not. Six of 7 splenectomized patients attained a marrow response. There were no significant differences between the marrow responders and nonresponders in age, sex, spleen status, Gaucher genotype distribution, mean baseline hematological or biochemical values or liver size, or mean follow-up. At a mean follow-up of 12 months, no significant differences yet were evident between marrow responders and nonresponders in seven of eight response parameters, but marrow responders had a significantly greater reduction in plasma chitotriosidase and a trend toward significantly greater reduction in serum ACE. At a mean follow-up of 36 months, marrow responders had a significantly greater mean increase in Plt and mean decrease in serum ferritin concentration and liver size than did marrow nonresponders; the trend toward greater ACE reduction in marrow responders deepened. However, chitotriosidase response now was equivalent in both subgroups. Marrow nonresponders had a significantly greater mean diminution in spleen size than did marrow responders, but the marrow nonresponders had significantly larger mean spleen size at baseline. Marrow nonresponders also had a greater mean increase in Hb than did marrow responders, but the difference was not significant. The two subgroups had equivalent mean reductions of plasma TRAP. CONCLUSIONS: The clinical relevance of qualitative MRI of the bone marrow in monitoring patients receiving ERT for nonneuronopathic Gaucher disease show that marrow nonresponders can derive considerable benefit from ERT across a variety of other response parameters and suggest an influence of spleen size on marrow response to ERT.

Adult↗
PubMed1988

In situ activation of human erythrocyte prolidase: potential for enzyme replacement therapy in prolidase deficiency.

Deficiency of prolidase is frequently associated with skin lesions and mental retardation. Biochemically, the condition is marked by iminodipeptiduria. We have investigated the feasibility of using donor erythrocytes to replace the deficient enzyme. Prolidase occurs in erythrocytes in an inactive form. If erythrocytes are incubated overnight at 37 degrees C in the presence of 1 mM MnCl2, the intracellular Mn++ concentration increases from 0.014 to 2.04 micrograms/ml. As a consequence, the activity of prolidase in hemolysates increases to 159 mumol glycyl-L-proline hydrolyzed/h/ml compared to 5 mumol/h/ml for hemolysates of cells incubated in the absence of Mn++. Hydrolysis of glycyl-L-proline by intact erythrocytes is reduced by the slow rate of iminodipeptide transport into the cell; however, intact cells hydrolyzed this substrate at a rate 10-20 times faster after preincubation with MnCl2. After exogenous MnCl2 is removed from the storage buffer, high levels of erythrocyte prolidase activity persist for at least 13 days. The kinetic parameters for intact activated erythrocyte-catalyzed hydrolysis of glycyl-L-proline have been estimated. These values predict that donor erythrocytes, activated with Mn++ before transfusion could play a significant role in the recovery of proline from dietary sources of iminodipeptides in patients with prolidase deficiency.

Dipeptidases↗
PubMed1992

Enhanced intracellular stability of dextran-horse radish peroxidase conjugate: an approach to enzyme replacement therapy.

Horse radish peroxidase (HRP), a mannose-containing glycoprotein was covalently modified by conjugation with dextran. The rapid uptake of HRP by the liver is markedly inhibited by mannan. The uptake of dextran-HRP conjugate by the liver, though lower compared to that of the free enzyme, is also partially inhibited by mannan. Liposomes were therefore used as carriers for delivering the free and the modified HRP to the liver. The dextran-HRP conjugate showed greater stability intracellularly as compared to the free enzyme. The enhanced stability of enzymes upon their extensive glycosylation with nondegradable sugar polymers would be of importance in extending the catalytic life of therapeutically active enzymes and thereby improve their therapeutic potential for the treatment of certain enzyme deficiency disorders.

Chromatography, Gel↗
PubMed1980

Severe combined immunodeficiency and adenosine deaminase deficiency: failure of enzyme replacement therapy.

A first-born baby boy presented at age 3 months with persistent diarrhoea, failure to thrive, and recurrent bacterial and fungal infections. Severe combined immunodeficiency was demonstrated. A deficiency of adenosine deaminase (ADA) activity was suggested by the presence of extensive skeletal abnormalities, and the ADA activity in erythrocyte and leucocyte lysates was < 0.005 nmol/h per mg protein. Culture of ADA-negative peripheral blood mononuclear cells, together with purified calf ADA, did not alter the absent phytohaemagglutinin response. Treatment with immunoglobulin, pentamidine, and co-trimoxazole was started and a programme of ADA enzyme replacement, with infusions of plasma and frozen irradiated erythrocytes, was begun at age 4 months and achieved blood ADA levels in excess of 30 nmol/h per mg haemoglobin. Although resolution of the interstitial pneumonitis and skeletal abnormalities was observed, there was no evidence of immunological reconstitution. The patient died at age 17 months after a parainfluenza pneumonitis. Features of importance in predicting lack of benefit from enzyme replacement by erythrocyte infusion in ADA-negative severe combined immunodeficiency appear to be early clinical presentation with associated severe skeletal abnormalities, a very low level of residual ADA activity in peripheral blood mononuclear cells, and lack of effect of exogenous ADA on the absent in vitro mitogen response of ADA-negative blood mononuclear cells.

Adenosine Deaminase↗
PubMed1989

Pancreatic enzyme replacement therapy in post-pancreatectomy patients.

The occurrence of malnutrition and maldigestion was studied in nine patients who underwent pancreatoduodenectomy and sclerosis of the residual pancreatic stump with neoprene. The operation causes a complete loss of exocrine pancreatic function, but spares islet cell function. Upon discharge from the hospital, patients received pancreatin powder as a dietary enzyme supplement (18,000 lipase U/meal). Patients were again hospitalized 2 y after surgery for evaluation of nutritional status and digestive function (hospital checkup). Nutritional status was evaluated by measuring serum albumin, total iron binding capacity, and total lymphocytes. Digestive function was assessed by the D-xylose tolerance test and determination of fecal fat excretion. Patients were then discharged with pancrelipase enteric-coated microspheres (ECM) as a dietary enzyme supplement (16,050 lipase U/meal). Malnutrition, defined as the occurrence of at least two abnormal nutritional parameters, was observed in three patients at the time of the hospital checkup. Upon reevaluation of nutritional status after 6 mo on pancrelipase ECM, all patients were well nourished. The mean body weight, which had been 52.8 Kg immediately after surgery, increased to 54.9 Kg at the time of the hospital checkup (p less than 0.01) and to 58.0 Kg after six months of pancrelipase ECM therapy (p less than 0.05). At the hospital checkup, the D-xylose test was normal in all patients and steatorrhea had decreased from a mean of 32.8 g/d without enzyme supplementation to 16.7 g/d with pancrelipase therapy (16,050 lipase U/meal). The complete loss of exocrine pancreatic function following surgery was well tolerated. In fact, when patients were on pancrelipase therapy, much of the original body weight was recovered and the biochemical indices of malnutrition were normalized.

Adult↗
PubMed1990

[Requirements for successful pancreatic enzyme replacement therapy (comparative study of Kreon and Panpur)].

Factors influencing the effectivity of replacement therapy with Panpur and Creon were controlled by in vivo and in vitro investigations. Both enteric coated preparations were equally acid protected, they even seemed to be more effective in hyperacid than in anacid chronic pancreatitis patients. Thus the uneven results of Panpur treatment in pancreatic steatorrhea cannot be explained by acid inactivation of the enzymes. Creon dose-dependently ameliorated the steatorrhea as well as vitamin B12 absorption while crushed but not the intact Panpur has only some insignificant effect. Good mixing of pancreatin with the B12-intrinsic factor - R protein complex and with the protein containing meal seems to be important for digestion of protein as well as fat. Unbound, overflowing trypsin activity of Panpur resulted in fast proteolytic inactivation of lipase. This could be diminished by soybean trypsin inhibitor which increased the in vivo effectiveness of the preparate. In summary Creon fulfilled two important factors of replacement therapy more successfully than Panpur: good mixing with meals and stability of lipase against proteolytic splitting, that is why it proved to be more effective for replacement therapy of pancreatic insufficiency.

Celiac Disease↗
PubMed1983

Enzyme replacement therapy in porphyrias--IV. First successful human clinical trial of delta-aminolevulinate dehydratase-loaded erythrocyte ghosts.

A patient with chronic lead intoxication was treated with only one course of highly purified human blood aminolaevulinate dehydratase entrapped in autologous erythrocyte ghosts given intravenously. No untoward effects were observed during or after infusion. An immediate increase in the patient's erythrocyte dehydratase activity was detected 1 hr after enzyme administration, reaching its maximum and nearly normal level 2 days later, values remained unchanged for a week, to slowly diminish after 2 weeks of initiated the treatment, and finally recovered activity was kept practically leveled off for weeks. This novel therapeutic trial produced complete improvement both clinical and biochemical, showing that enzyme infusion has been beneficial and can be safely and successfully used in the treatment of human lead intoxication.

Adult↗