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PubMed2003

Enzyme therapy for lysosomal storage disease: principles, practice, and prospects.

Over the past three decades, enzyme therapy for lysosomal storage diseases has moved from an academic pursuit to direct delivery of effective clinical care for affected patients and families. This success is based on understanding the complexities of lysosomal biogenesis, lysosomal hydrolase sorting and hydrolytic requirements, and the target sites of pathology of these diseases. This article reviews these concepts and their application to the treatment of affected patients with Gaucher disease, Fabry disease, and mucopolysaccharidosis I. The principles, progress, and practice in these diseases provide prototypes for expansion of enzyme therapy to a growing set of these diseases.

Humans↗
PubMed1955

[Enzyme therapy].

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Enzyme Therapy↗
PubMed2001

Enzyme therapy for lysosomal acid lipase deficiency in the mouse.

Lysosomal acid lipase (LAL) is the critical enzyme for the hydrolysis of the triglycerides (TG) and cholesteryl esters (CE) delivered to lysosomes. Its deficiency produces two human phenotypes, Wolman disease (WD) and cholesteryl ester storage disease (CESD). A targeted disruption of the LAL locus produced a null (lal( -/-)) mouse model that mimics human WD/CESD. The potential for enzyme therapy was tested using mannose terminated human LAL expressed in Pichia pastoris (phLAL), purified, and administered by tail vein injections to lal( -/-) mice. Mannose receptor (MR)-dependent uptake and lysosomal targeting of phLAL were evidenced ex vivo using competitive assays with MR-positive J774E cells, a murine monocyte/macrophage line, immunofluorescence and western blots. Following (bolus) IV injection, phLAL was detected in Kupffer cells, lung macrophages and intestinal macrophages in lal( -/-) mice. Two-month-old lal( -/-) mice received phLAL (1.5 U/dose) or saline injections once every 3 days for 30 days (10 doses). The treated lal( -/-) mice showed nearly complete resolution of hepatic yellow coloration; hepatic weight decreased by approximately 36% compared to PBS-treated lal( -/-) mice. Histologic analyses of numerous tissues from phLAL-treated mice showed reductions in macrophage lipid storage. TG and cholesterol levels decreased by approximately 50% in liver, 69% in spleen and 50% in small intestine. These studies provide feasibility for LAL enzyme therapy in human WD and CESD.

Animals↗
PubMed1999

[Systemic enzyme therapy in osteosynthesis of the long bones].

The authors focused their attention on the application of systemic enzyme therapy in traumatology, in particular on its anti-oedematous, fibrinolytic and analgetic effects during the postoperative period in osteosyntheses of the long bones. In a group of 40 patients they investigated postoperative changes of the volume of operated extremities. They found a very marked anti-oedematous effect of Phlogenzym. The authors draw attention to the great importance of anti-oedematous treatment and mention also possibilities of systemic enzyme therapy in this indication.

Adolescent↗
PubMed1986

Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis.

The symptomatic effect of pancreatic enzyme substitution therapy was examined in a 4-week double-blind crossover study. Twenty patients, 11 with and 9 without steatorrhoea, were examined. Pancreatic steatorrhoea was reduced from a median of 24 g/day to 10 g/day by the enzyme therapy (P less than 0.01). No significant pain reduction was found in either of the two groups, although there was a tendency to reduction in pain and analgetic consumption in the patients with steatorrhoea when treated with pancreatic enzymes. It is concluded that pancreatic steatorrhoea is still the only indication for pancreatic enzyme therapy.

Adult↗
PubMed1998

Enzyme therapy in Gaucher disease type 2: an autopsy case.

A Japanese patient with Gaucher disease type 2 was treated with enzyme therapy, alglucerase, from 7 to 22 months of age. Whereas hematologic parameters were normalized and hepatosplenomegaly was alleviated, no improvement in neurologic symptoms occurred, and the patient died of respiratory failure at age 22 months. Postmortem examination revealed massive intra-alveolar infiltration of Gaucher cells in lungs and in the central nervous system, i.e., the presence of Gaucher cells in the perivascular Virchow-Robins spaces in the cortex and deep white matter and extensive lamilar necrosis with reactive proliferation of blood vessels and macrophage infiltration of the cerebral cortex. It is suggested that enzyme therapy, with thus far recommended dose, does not prevent long-term respiratory and central nervous system involvement in severe varients of Gaucher disease.

Brain↗
PubMedDate not supplied

[Experimental development of a method of enzyme therapy in eye burns].

The proposed method of enzyme therapy of eye burns consists in instillations of a proteolytic drug for the first two days after burn and instillations of an antiproteolytic agent for the next 12 days. Experimental trials of the method in a rabbit with an alkaline burn of the cornea, including assessment of clinical manifestations of disease and investigation of the proteinase-inhibitor balance in the lacrimal fluid demonstrated a high efficacy of the new treatment.

Animals↗
PubMed1999

[Reducing pain by oral enzyme therapy in rheumatic diseases].

Proteolytic enzymes have analgesic, effects, besides the wellknown antiinflammatory and edema-reducing properties. These analgesic effects are based on the inhibition of inflammation and in addition to that on direct influences on the nociceptors. All that explains the therapeutical effects of such enzymes in degenerative-rheumatic and soft tissue rheumatic diseases in which inflammatory or immunologic processes are not in the forefront. In recent years a significant reduction of pain in various rheumatic diseases, concerning these aspects, was shown in several clinical studies. The clinical trial in patients with periarthritis of shoulder showed statistical equivalence of pain reduction, whether they were treated with phlogenzym or diclofenac. Likewise in the trial of patients suffering from painful osteoarthritis of the knee, there was a statistical equivalence of the pain-scores, comparing diclofenac and enzymes. The study of painful vertebral syndromes again resulted in equivalence of the treatment with NSAIDs compared to therapy with enzymes.

Adult↗
PubMed1995

Pathological findings in Gaucher disease type 2 patients following enzyme therapy.

The pathological outcomes following intravenous acid beta-glucosidase (alglucerase) infusions were compared in two siblings with Gaucher disease type 2, the acute neuronopathic variant. In case 1 enzyme infusions (four doses at 7 months) had no effect when severe progressive visceral and neuronopathic disease were present. Death from progressive disease occurred at 9 months. Case 2 was prenatally diagnosed. Enzyme infusions were initiated presymptomatically at 4 days of age and continued until death at 15.2 months. Development progressed satisfactorily, albeit at a slower than normal rate until age 10 months when progressive brain stem involvement became evident. Death occurred after slowly progressive brain stem dysfunction, but gross motor and cognitive skills were nearly normal. Postmortem light and electron microscope (EM) studies in both cases showed typical central nervous system (CNS) findings and massive infiltration of the lungs and lymph nodes by Gaucher cells. The liver, spleen, and bone marrow, except that in the temporal bone, in case 2 were normal. These studies show that enzyme therapy may slow but does not prevent the development of lethal CNS disease in Gaucher disease type 2, even when initiated presymptomatically. These findings also indicate the nonuniformity of tissue responses to enzyme therapy implying the existence of therapeutically inaccessible compartments that, in less severe variants, may create unexpected long-term disease complications.

Fatal Outcome↗
PubMed1980

Enzyme therapy XIV. Comparison of methods for enzyme entrapment in human erythrocytes.

Seven methods of erythrocyte entrapment--six by hypotonic exchange loading and one by chlorpromazine-induced endocytosis--were evaluted for (1) efficiency of incorporation of beta-glucuronidase, inulin, and glucose; (2) presence of beta-glucuronidase on the erythrocyte surface, as detected by hemagglutination or complement-dependent lysis in the prsence of antibody to beta-glucuronidase; (3) in vitro leakage of entrapped markers; and (4) morphologic alterations by scanning electron microscopy. Dependent on the method of entrapment, the incorporation of markers ranged from 0.7% to 6.2% for beta-glucuronidase, 3.4% to 31% for inulin, and 1.2% to 12.2% for glucose. Maximal incorporation by hypotonic exchange loading occurred when the initial concentration of sodium chloride (150 mM) was reduced to 50 or 75 mM. However, beta-glucuronidase was detected on the erythrocyte surface by hemagglutination for these methods as well as a dialysis method of loading. Essentially no leakage of entrapped enzyme was detected (< 1%) for all methods, although up to 11% of entrapped glucose was released during a 3 hr incubation at 37 degrees C in buffered whole blood. Finally, entrapment methods requiring the greatest reduction in salt concentration resulted in the formation of echinocytes, whereas stomatocytes were observed after entrapment by methods requiring lesser salt dilutions. These results demonstrate the efficiency of entrapment and relative integrity of erythrocytes following various loadng procedures and suggest that in vitro assessment may provide a useful predictor of the imunogenicity and in vivo fate of erythrocyte-entrapped enzymes or other therapeutic agents.

Antigens, Surface↗
PubMed1996

Enzyme therapy of xeroderma pigmentosum: safety and efficacy testing of T4N5 liposome lotion containing a prokaryotic DNA repair enzyme.

Xeroderma pigmentosum (XP) is a rare genetic disease in which patients are defective in DNA repair and are extremely sensitive to solar UV radiation exposure. A new treatment approach was tested in these patients, in which a prokaryotic DNA repair enzyme specific for UV-induced DNA damage was delivered into the skin by means of topically applied liposomes to supplement the deficient activity. Acute and chronic safety testing in both mice and humans showed neither adverse reactions nor significant changes in serum chemistry or in skin histology. The skin of XP patients treated with the DNA repair liposomes had fewer cyclobutylpyrimidine dimers in DNA and showed less erythema than did control sites. The results encourage further clinical testing of this new enzyme therapy approach.

Adolescent↗
PubMed2001

Enzyme therapy for pompe disease with recombinant human alpha-glucosidase from rabbit milk.

Pompe disease is a metabolic myopathy caused by deficiency of lysosomal acid alpha-glucosidase. In this report we review the first 36 weeks of a clinical study on the safety and efficacy of enzyme therapy aimed at correcting the deficiency. Four patients with infantile Pompe disease were enrolled. They received recombinant human alpha-glucosidase from transgenic rabbit milk. The product is generally well tolerated and reaches the primary target tissues. Normalization of alpha-glucosidase activity in skeletal muscle was obtained and degradation of PAS-positive material was seen in tissue sections. The clinical condition of all patients improved. The effect on heart was most significant, with an impressive reduction of the left ventricular mass index (LVMI). Motor function improved. The positive preliminary results stimulate continuation and extension of efforts towards the realization of enzyme therapy for Pompe disease.

Animals↗
PubMed1994

Enzyme therapy for pancreatic insufficiency: present status and future needs.

Pancreatic enzyme extracts have been used for several decades to decrease maldigestion of macro- and micronutrients due to pancreatic insufficiency and to alleviate various abdominal symptoms, including the pain of alcohol-induced chronic pancreatitis and distal intestinal obstruction. Decreasing nutrient maldigestion and malabsorption in pancreatic insufficiency is of additional critical importance because improvement in nutritional status reduces morbidity and mortality. For example, pancreatic sufficient patients with cystic fibrosis (CF) demonstrate a slower decline in pulmonary function. In spite of the recognized importance of pancreatic enzymes, several problems exist with current preparations, and as newer enzyme preparations are marketed, proper evaluation becomes critical. There is a clear need to optimize the constituents of enzyme preparations, improve manufacturing processes, and find better sources of enzymes. Other issues that need addressing include standardization of the ratios of enzymes (lipase, amylase, protease) in these products; the stability of the enzymes at room temperature; the shelf life of the finished product; whether there are significant batch-to-batch differences; and the need for a USP reference standard.

Enzyme Therapy↗