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PubMed2004

Toward PKU enzyme replacement therapy: PEGylation with activity retention for three forms of recombinant phenylalanine hydroxylase.

Phenylketonuria (PKU) is a disease in which phenylalanine and phenylalanine-derived metabolites build up to neurotoxic levels due to mutations in the phenylalanine hydroxylase gene (PAH). Enzyme replacement therapy is a viable option to supply active PAH. However, the inherent protease sensitivity and potential immunogenicity of PAH have precluded adoption of this approach. In this report, we have used polyethylene glycol derivatization (PEGylation) to produce protected forms of PAH for potential therapeutic use. Three recombinantly produced PAH enzymes were reacted with activated PEG species, with the aim of developing a stable and active PKU enzyme replacement. Tetrameric full-length human PAH, dimeric double-truncated (DeltaN102-DeltaC428) human PAH, and monomeric Chromobacterium violaceum PAH were PEGylated with succinimidyl succinate polyethylene glycol of molecular weight 5000 or 20,000 Da. Characterization of the PEGylated species was accomplished with MALDI-TOF mass spectrometry, SDS-PAGE, and specific activity measurements using ESI mass spectrometry. All PEG-derivatized PAH species retained catalytic activity, and, at low numbers of PEG molecules attached, these PEGylated PAH proteins were found to be more active and more stable than their non-derivatized PAH counterparts.

Bacterial Proteins↗
PubMed2003

[Gaucher's disease in children: first clinical signs, natural course and benefits of enzyme replacement therapy].

OBJECTIVES: Gaucher's disease is a rare genetic disease. Paediatric patients present with highly severe disease and, until now, literature does not provide many descriptions in children only. A specific enzyme replacement therapy has been available for the last decade. Quality of life has been improved by the treatment. POPULATION AND METHODS: We studied 17 Gaucher patients (14 type 1 and 3 type 3) diagnosed before the age of 15 and treated afterwards. The first clinical signs and the course of the disease are described before and during treatment. To appreciate the impact of the treatment on quality of life, we established a clinical score with the functional symptoms of the patients. RESULTS: The mean age was 6.4 years at diagnosis and 18.3 years at the beginning of the treatment. With specific treatment, all clinical and biological symptoms dramatically improved but some specific organic damages were irreversible. CONCLUSION: The comparison of our patients with other reported paediatric cases confirm that Gaucher's disease in children is severe and has to be precociously diagnosed and treated. Clinical scores appeared to be helpful to choose the moment for treating and to follow-up the patients under treatment.

Adolescent↗
PubMed2002

Enzyme replacement therapy for the mucopolysaccharide storage disorders.

The mucopolysaccharide storage disorders are a group of lysosomal storage disorders associated with deficiencies of lysosomal enzymes required for the normal sequential degradation of glycosaminoglycans, formerly known as mucopolysaccharides. The accumulation of glycosaminoglycans in a wide variety of tissues results in a complex and progressive disease leading to death in the first or second decade in most patients. Studies of enzyme replacement in animal models of mucopolysaccharide disorders have demonstrated the potential of parenterally administered enzyme to reduce glycosaminoglycan storage and microscopic pathology. Clinical studies of enzyme replacement therapy are currently underway for mucopolysaccharidosis I, mucopolysaccharidosis VI and mucopolysaccharidosis II. The complexity and heterogeneity of the mucopolysaccharide disorders provide significant challenges for clinical study design and evaluation. Innovative clinical development strategies may be needed to lower the development cost and time for complex rare disease therapies to assure that such patients receive therapies they deserve.

Animals↗
PubMed1976

Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency.

To evaluate their role as a form of replacement therapy, frozen irradiated red blood cells were administered to a child with adenosine deaminase deficiency associated with severe combined immunodeficiency disease. In vitro lymphocyte responses to mitogens and allogeneic cells were restored. Subsequently, a "thymus shadow" appeared, and immunoglobulin synthesis was demonstrated. Frozen irradiated plasma, which alone had no effect on lymphocytes numbers or responses, promoted lymphocytosis when given with frozen irradiated red blood cells. The patient received the transfusions with or without irradiated plasma at four-week intervals and remained free of infection for 17 months. The patient's lymphocyte adenosine triphosphate levels were elevated before therapy, which consistently reduced them without altering the lymphocyte adenosine deaminase activity. Enzyme replacement therapy may provide a way to treat patients with adenosine deaminase deficiency associated with severe combined immunodeficiency disease who do not have histocompatible bone-marrow donors.

Adenosine Deaminase↗
PubMed2004

Enzyme replacement therapy administered during hemodialysis in patients with Fabry disease.

BACKGROUND: Enzyme replacement treatment with recombinant human alpha-galactosidase A (r-halphaGalA) is now available for patients with Fabry disease, many of whom are on maintenance hemodialysis. Because r-halphaGalA must be infused over several hours, administering the enzyme during dialysis would save a day of treatment for patients receiving both therapies. However, these procedures have never been combined due to concerns about possible loss of enzyme in the dialysate. METHODS: Ten Fabry patients received r-halphaGalA (1 mg/kg body weight continuously infused over 4 hours) during dialysis and separately in the interval between dialysis treatments. Plasma activity of r-halphaGalA was measured at baseline and then every hour for both procedures. In two patients, a third r-halphaGalA infusion during dialysis with a high-flux membrane was followed. RESULTS: The rise in plasma concentrations of r-halphaGalA during infusion and the steady-state levels reached were comparable for enzyme administrations with or without dialysis. The trend for the somewhat higher activities during hemodialysis was explained by volume contraction due to ultrafiltration. With the use of a high-flux dialyzer, the plasma r-halphaGalA activities were identical to those that were observed during low-flux dialysis. CONCLUSIONS: Administration of r-halphaGalA during hemodialysis is not associated with a reduced activity of r-halphaGalA therapy in patients with Fabry disease. Replacement therapy with r-halphaGalA may therefore be performed during hemodialysis without apparent loss of enzyme into the dialysate.

Fabry Disease↗
PubMed2001

Enzyme replacement therapy in mucopolysaccharidosis type I: progress and emerging difficulties.

Mucopolysaccharidosis type I is due to a deficiency of the lysosomal enzyme alpha-L-iduronidase (EC 3.2.1.76) and is associated with a defect in the catabolism of the glycosaminoglycans heparan and dermatan sulphate. The clinical picture produced by this abnormal storage is diverse and ranges from a disorder that is fatal in the early months of life, due to cardiomyopathy, to a condition compatible with a normal life-span. It has become usual to describe the phenotypes associated with this spectrum of disorders after their eponymous names, Hurler (MPS IH, severe), Scheie (MPS IS, mild) and Hurler/Scheie (MPS IH/S, intermediate). Severely affected patients have progressive learning difficulties, facial and skeletal deformities, cardiac disease, corneal clouding, respiratory compromise and joint stiffness. Patients with MPS IH typically die in the first decade of life. MPS IH/S usually have normal intelligence and die in their twenties of cardiorespiratory disease. Patients with MPS IS may have joint stiffness, aortic valve disease and corneal clouding, but are often able to live a normal life-span. Enzyme replacement therapy has been developed as a potential therapy for some patients with MPS I. This process has been helped by the study of a naturally occurring canine model of the disease, which produces a phenotype similar to MPS IH/S in the human. This review details the progress that has been made in this area and also highlights some potential problems with the introduction of therapy.

Animals↗
PubMed2006

[Manifestation of Fabry disease in a heterozygous female patient. New perspectives using enzyme replacement therapy].

HISTORY AND ADMISSION FINDINGS: A 32-year-old woman with bilateral corneal opacities was at 9 years of age diagnosed to have reduced activity of the enzyme alpha-galactosidase A. She was admitted to our hospital because of skin lesions that had developed over the last 8 years. INVESTIGATIONS: The clinical features included angiokeratomas on the buttocks, hips, and periumbilical region, whorl-like corneal opacity (cornea verticillata), and mitral valve prolapse. Activity of alpha-galactosidase A was reduced to about a quarter of the normal value. Histological examination revealed lipid deposits within the endothelial cells of the skin. Molecular analysis of the alpha-galactosidase A gene revealed a point mutation at nucleotide-position 691 in exon 5 (p.Asp231Asn). TREATMENT AND COURSE: Enzyme replacement therapy with agalsidase alfa 0.2 mg/kg body-weight, infused over 40 min every other week, was initiated. So far no side effects due to the infusion therapy have been noted. The therapeutic success (reduction of lipid storage) cannot be assessed as yet. CONCLUSION: Fabry disease results from deficient activity of the enzyme alpha-galactosidase A. Affected (hemizygous) males often show the complete spectrum of symptoms and signs and have a deficient alpha-galactosidase A activity. Occasionally milder oligosymptomatic courses are observed, when residual enzyme activity is present. In contrast to previous belief, heterozygous females may be affected in the same manner as hemizygotes and may also have a significantly reduced enzyme activity.

Abdomen↗
PubMed2005

[Outcome of two patients with Hurler's syndrome under enzyme replacement therapy with human recombinant alpha-L-iduronidase].

We performed a prospective study of two patients with Hurler's syndrome (aged 4.8 years and 17 months at the beginning of the intervention) under enzyme replacement therapy with human recombinant alpha-L-iduronidase for 452 and 28 weeks respectively. The aim of this study was to analyze the safety and efficacy of the intervention during the treatment periods. Several diagnostic imaging tests, clinical examinations, and serial laboratory determinations were performed to demonstrate the effectiveness of the therapy in both patients. In patient 1 (a boy aged 4.8 years, homozygote W402X), the treatment was always intended to be palliative because of the advanced stage of the disease. In patient 2 (a 17-month-old girl, heterozygote W402X) the treatment was initiated early with subsequent clinical stabilization without acquisition of regressive factors. Bone marrow transplantation from an unrelated donor was successful. Currently, because of the lack of histocompatible bone marrow donors, transplantation of hematopoietic stem cells from umbilical cord blood or peripheral blood are being performed with satisfactory results. In the future, gene therapy may be able to prevent the diseases associated with Hurler's syndrome and halt the neurocognitive deterioration characteristic of these patients.

Child, Preschool↗
PubMed2003

[Enzyme replacement therapy in Gaucher disease: monitoring visceral and bone changes with MRI].

INTRODUCTION: Gaucher disease (GD) is the most common lysosomal storage disorder. It can be successfully treated with infusion of the modified deficient enzyme. AIM: Visceral and skeletal changes during enzyme replacement therapy (ERT) in patients with type 1 Gaucher disease (GD) were studied by radiological methods. METHODS: Eight patient with GD (8-39 years) were examined, who underwent ERT for 1-8 years (30-80 IU/bwkg/months Ceredase or Cerezyme). MRI from the upper abdomen were made before ERT was started and once a year during ERT, that allowed measurement of hepatic and splenic volume. The bone changes were depicted by MRI and conventional X-ray images. Bone marrow infiltration was estimated by MRI scans of femora with semiquantitative method. RESULTS: Hepato- and splenomegaly were detected before ERT, which decreased in each patient during therapy. Decrease of liver volume was more expressed in patients with splenectomy. The infiltration of the bone marrow with Gaucher cells has reduced during treatment in six cases. Decreases of hepatosplenomegaly occured earlier and faster, than the improvement of bone disorders. Two splenectomised patients exhibited 4 episodes of bone crisis diagnosed by MRI. Their symptoms regrediated on increased enzyme doses. The grade of bone marrow infiltration and concurrent bone complications could not be detected by conventional X-ray films. CONCLUSIONS: We conclude that the use of ERT in all patients leads to marked improvements in visceral and skeletal pathology of patients with Gaucher disease. The volume of the liver and the spleen, and the extension of bone marrow infiltration can be measured precisely by MRI, so it can be the method of choice in the diagnosis and in the monitoring of response to ERT. MRI helps to determine the appropriate enzyme dosage and to establish the necessity of elevation the enzyme dose. MRI can be practicable in the differential diagnosis of bone crisis and osteomyelitis.

Adolescent↗
PubMed2002

Fabry disease: recent advances in enzyme replacement therapy.

Fabry disease is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the systemic accumulation of incompletely metabolised glycosphingolipids, primarily globotriaosylceramide, in plasma and lysosomes within various tissues. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity, associated with significant impact on quality of life and diminished lifespan from early onset strokes, heart attack and progressive renal failure. The disease manifests primarily in hemizygous males; however, there is increasing recognition that heterozygous (carrier) females may also develop disease-related complications. Indeed, most heterozygotes present with cardiac, renal or neurological symptoms, although with later-onset and to a lesser extent than is observed in hemizygotes. Until recently, medical management was symptomatic, consisting of partial pain relief with analgesic drugs (carbamazepin, gabapentin), kidney and vascular protection with angiotensin-converting enzyme inhibitors, statins and folic acid, whereas renal transplantation or dialysis is available for patients experiencing end stage renal failure. The ability to produce high doses of alpha-galactosidase A has opened the way to preclinical studies, and enzyme replacement therapy has recently been validated as a therapeutic agent in clinical trials. Long-term safety and efficacy of replacement therapy are currently being investigated. Increasing knowledge of the natural history of Fabry disease and greater experience with enzyme therapy should enable optimal patient care. The complexity and relative rarity of Fabry disease necessitates a multi-disciplinary team approach that may be facilitated by a disease registry.

Animals↗
PubMed2006

Pompe disease (glycogen storage disease type II): clinical features and enzyme replacement therapy.

Pompe disease (glycogen storage disease type II, acid maltase deficiency) is a progressive metabolic myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase. This leads to an accumulation of glycogen in various tissues of the body, most notably in skeletal muscle. The disease has an autosomal recessive inheritance with a predicted frequency of 1 :40.000. Pompe disease is a continuous spectrum but for clinical practice different subtypes are recognized. The classic infantile form of the disease occurs in infants (shortly after birth) and is characterized by generalized hypotonia, failure to thrive, and cardiorespiratory failure. Patients usually die within the first year of life. The non-classic or late-onset form of the disease may occur at any age in childhood or adulthood. It presents predominantly as a slowly progressive proximal myopathy, with or without respiratory failure. Enzyme replacement therapy (ERT) is under study as treatment for the disease. The first results with recombinant human alpha-glucosidase are promising and a registered therapy seems near. Beneficial effects of ERT have been reported both in patients with the classic infantile form as well as in patients with the non-classic or late-onset form of the disease. The best therapeutic results are achieved when ERT is started early in the course of symptom development and before irreversible muscular damage has occurred. Detailed knowledge about the natural course of the disease becomes more and more essential to determine the indication and timing of treatment.

Animals↗
PubMed2004

Numerous transcriptional alterations in liver persist after short-term enzyme-replacement therapy in a murine model of mucopolysaccharidosis type VII.

The lysosomal storage disease MPS VII (mucopolysaccharidosis type VII) is caused by a deficiency in beta-glucuronidase activity, and results in the accumulation of partially degraded glycosaminoglycans in many cell types. Although MPS VII is a simple monogenetic disorder, the clinical presentation is complex and incompletely understood. ERT (enzyme replacement therapy) is relatively effective at improving the clinical course of the disease; however, some pathologies persist. In order to clarify the molecular events contributing to the disease phenotype and how ERT might impact upon them, we analysed liver tissue from untreated and treated MPS VII mice at both 2 and 5 months of age using biochemical assays and microarray analysis. Overall, as the disease progresses, more genes have altered expression and, at either age, numerous transcriptional changes in multiple pathways appear to be refractory to therapy. With respect to the primary site of disease, both transcriptional and post-transcriptional mechanisms are involved in the regulation of lysosomal enzymes and other lysosome-associated proteins. Many of the changes observed in both lysosome-associated mRNAs and proteins are normalized by enzyme replacement. In addition, gene expression changes in seemingly unrelated pathways may account for the complex metabolic phenotype of the MPS VII mouse. In particular, beta-glucuronidase deficiency appears to induce physiological malnutrition in MPS VII mice. Malnutrition may account for the pronounced adipose storage deficiency observed in this animal. Studying the molecular response to lysosomal storage, especially those changes recalcitrant to therapy, has revealed additional targets that may improve the efficacy of existing therapies.

Animals↗
PubMed2005

Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID).

Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (ADA-deficient SCID) is characterized by impaired lymphocyte development and function resulting from the adenosine metabolism defect. Enzyme replacement therapy with polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) minimizes infectious complications of ADA-deficient patients who have not received bone marrow transplantation. In PEG-ADA therapy, enzymatically active ADA continuously circulates to act as a metabolic sink, detoxifying the adenosine and deoxyadenosine metabolites that accumulate to high levels in the absence of ADA. Studies have shown that upon the initiation of PEG-ADA therapy, the absolute numbers of circulating T and B lymphocytes and NK cells increase and protective immune function develops. However, the long-term efficacy is unknown. This retrospective study was designed to assess the long-term effectiveness of PEG-ADA treatment, based on evaluation of the immune function of nine ADA-deficient SCID patients (age 5-15) treated over the past decade. The results showed that the lymphocyte counts of all of the PEG-ADA treated patients were below the normal range at all times, despite initial improvements. A gradual decline of mitogenic proliferative responses occurred after a few years of treatment and normal antigenic response occurred less than expected. To this date, these low numbers and functions of lymphocytes had been adequate to provide protective immunity. These patients should be followed closely to detect a premature decline in immune function with aging in future decades of PEG-ADA therapy.

Adenosine Deaminase↗
PubMed2005

Pharmacokinetic profile of recombinant human N-acetylgalactosamine 4-sulphatase enzyme replacement therapy in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): a phase I/II study.

AIM: Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme-N-acetylgalactosamine 4-sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double-blind, two-dose (0.2 and 1.0 mg/kg/week) phase I/II study (n = 7) followed by an open-label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. METHODS: Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp-up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. RESULTS: The area under the plasma concentration-time curve (AUC(0-t)) for the high-dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC(0-t) was observed between the low- and high-dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high-dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations. CONCLUSION: Pharmacokinetic parameters appear to be independent of the duration of treatment and are not linear between the 0.2 and 1.0 mg/kg/week doses. Antibodies to rhASB develop in most patients, but their concentration decreases over time. Antibody formation may influence pharmacokinetic parameters during the early phases of treatment, although it appears to have limited impact on biochemical efficacy.

Adolescent↗
PubMed1997

Plasma chitotriosidase activity in Gaucher disease patients who have been treated either by bone marrow transplantation or by enzyme replacement therapy with alglucerase.

A marked elevation in plasma chitotriosidase (chitinase) activity has recently been observed in patients with Gaucher disease (Hollak et al 1994). It has been suggested that this phenomenon may serve as a useful marker for the efficacy of treatment with enzyme replacement therapy. We report our findings on the comparison of plasma chitotriosidase levels in 8 patients treated with the modified human placental enzyme alglucerase and 8 patients treated by allogeneic bone marrow transplantation (BMT). Two years after transplantation the activity in the BMT patients had fallen by over 93% and has continued to fall. Now, 5-12 years post-BMT, 6 patients have normal levels of plasma chitotriosidase and 2 patients have activities slightly above the reference range. Patients have been treated with alglucerase for a considerably shorter time than the BMT patients. The chitotriosidase activities have fallen and are continuing to fall in 7 patients but at a slower rate than in the BMT group. In one patient there has been no appreciable change in activity over the last 6 months, which would suggest that she may be on too low a dosage.

Adolescent↗