Lysosomal storage disorders (LSDs) are a group of single-gene inherited metabolic diseases caused by defects in lysosomal enzymes or function-related proteins. Enzyme replacement therapy is the main treatment method in clinical practice, but it has a poor effect in patients with neurological symptoms. With the rapid development of multi-omics, sequencing technology, and bioengineering, gene therapy has been applied in patients with LSDs. As one of the vectors of gene therapy, adeno-associated virus (AAV) has good prospects in the treatment of genetic and metabolic diseases. More and more studies have shown that AAV-mediated gene therapy is effective in LSDs. This article reviews the application of AAV-mediated gene therapy in LSDs.
Humans ; Dependovirus/genetics* ; Genetic Therapy/methods* ; Lysosomal Storage Diseases/therapy* ; Enzyme Replacement Therapy ; Proteins/genetics*

PURPOSE: Mucopolysaccharidosis II (MPS II) is a lysosomal storage disorder caused by a deficiency of iduronate-2 sulfatase (IdS), which is involved in the degradation of glycosaminoglycan (GAG). In this study, the frequency of fasting hypoglycemia in patients with MPS II was investigated and changes in accumulation of glycogen and GAG in the hepatocytes of IdS-knockout (KO) mice were evaluated before and after recombinant IdS enzyme replacement therapy (ERT). MATERIALS AND METHODS: Plasma glucose levels were evaluated after an 8-hour fast in 50 patients with MPS II. The IdS-KO mice were divided into three groups (group 2; saline, group 3; 0.15 mg/kg of IdS, and group 4; 0.5 mg/kg of IdS); wild-type mice were included as controls (group 1). ERT was initiated intravenously at four weeks of age, and continued every week until 20 weeks of age. RESULTS: The mean glucose level after an 8-hour fast was 94.1 +/- 23.7 mg/dL in the patients with MPS II. Two (4%) out of 50 patients had fasting hypoglycemia. For the mice, GAG in the lysosomes nearly disappeared and glycogen particles in the cytoplasm were restored to the normal range in group 4. CONCLUSION: Glucose metabolism in patients with MPS II appeared to function well despite hepatocytic GAG accumulation and hypothetical glycogen depletion. A higher dose of IdS infusion in MPS II mice led to disappearance of lysosomal GAG and restoration of glycogen to the cytoplasm of hepatocytes.
Animals ; Blood Glucose/analysis ; Enzyme Replacement Therapy/methods ; Glycogen/*analysis ; Glycosaminoglycans/*analysis ; Hepatocytes/chemistry/*enzymology ; Humans ; Hypoglycemia/enzymology/physiopathology ; Iduronate Sulfatase/genetics/*physiology ; Liver/ultrastructure ; Mice ; Mice, Knockout ; Microscopy, Electron ; Mucopolysaccharidosis II/blood/enzymology/physiopathology

With the development of the research on biotechnology and modern pharmacy, the application of enzyme drugs have grown rapidly and enzyme drugs have become an important branch of biopharmaceutics. In this article, some new varieties of therapeutic enzymes, enzyme targets, mechanisms and new technologies of application in therapeutic enzymes were reviewed, and the direction of development of therapeutic enzymes were discussed.
Adenosine Deaminase ; genetics ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Enzyme Replacement Therapy ; methods ; Fibrinolytic Agents ; therapeutic use ; Protein C ; genetics ; therapeutic use ; RNA, Catalytic ; genetics ; therapeutic use ; Streptokinase ; genetics ; therapeutic use ; Urokinase-Type Plasminogen Activator ; genetics ; therapeutic use

OBJECTIVES: Ovarian hormones have been shown to regulate body weight, intra-abdominal fat accumulation and plasma level of cytokines. The aim of this study was to investigate the effect of estrogen replacement therapy on visceral adipose tissue, plasma level of apelin, lipid profiles, and glucose in ovariectomized (OVX) rats. METHODS: Thirty female Wistar rats were divided into OVX (n = 20) and sham (n = 10) groups. OVX rats were subdivided into estrogen replacement therapy (OVX+est; n = 10) receiving 17 β-estradiol valerates (30 µg/kg, s.c., 5 day/week, for eight weeks), and vehicle control group receiving sesame oil same as experiment group (OVX+ses oil; n = 10). After the treatments, all groups were sacrificed and blood samples were collected, visceral fats were taken from the abdominal cavity and weighed immediately. Apelin were measured using enzyme-linked immunosorbent assay kits. Lipid profiles and glucose were measured using the enzymatic colorimetric method. Data were analyzed with one-way analysis of variance and (P < 0.05) determined as the statistical significance level. RESULTS: After eight weeks, body weight, body mass index (BMI), visceral fat, apelin and lipid profiles (P < 0.01) were increased significantly in OVX rats compared to sham group. Treatment with estrogen leads to significant reduction in body weight and BMI (P < 0.05), there was no significant change in serum apelin level in OVX+est rats compared to OVX+ses. CONCLUSIONS: These results suggest that estradiol replacement therapy successfully attenuated some of the metabolic syndrome components, and apelin does not probably stand as a mediator of these physiological functions.
Abdominal Cavity ; Animals ; Blood Glucose* ; Body Mass Index ; Body Weight ; Cytokines ; Enzyme-Linked Immunosorbent Assay ; Estradiol ; Estrogen Replacement Therapy* ; Estrogens* ; Female ; Glucose ; Humans ; Intra-Abdominal Fat* ; Methods ; Plasma ; Rats* ; Rats, Wistar ; Sesame Oil ; Valerates

OBJECTIVEGaucher disease is the most common lysosomal storage disorder. A deficiency of beta-glucocerebrosidase causes accumulation of the glucocerebroside in macrophages throughout the body. This study summarizes the effects of enzyme replacement therapy (ERT) with Imiglucerase in children with Gaucher disease.

METHODSData from 72 patients (46 were male and 26 female, age ranged from 16 months to 22 years, median 8 years and 8 months) who were treated in the hospital between May 1999 and October 2005 were collected and analyzed, 57 of the patients had type 1 Gaucher disease, 2 patients with type 2, and 13 patients with type 3. Twenty-two patients had undergone total splenectomy. Imiglucerase was given at an initial dose 60 U/kg body weight by intravenous infusion every 2 weeks. The dose was reduced to 45 U/kg when they had achieved the specified therapeutic goals after 2 years. Clinical outcome data of Imiglucerase treatment were collected using routine Gaucher clinical measures, including growth, hematology, liver and spleen 3-dimensional measurements, and skeletal assessments every 3 - 6 months.

RESULTSThree patients were lost to follow-up, 4 patients died, and 65 patients continued to receive the therapy. Hemoglobin and platelet levels of the patients with intact spleen increased most rapidly from the first 12 months of ERT (P < 0.01). Hemoglobin level of the patients who had undergone splenectomy determined at 30 months of treatment was higher than that of baseline (P < 0.01), but platelet levels were not significantly different (P > 0.05). The volumes of the liver decreased after the 6 months of ERT, decreased in average by (39 +/- 17)% at 24 months (P < 0.01). The volumes of spleen decreased after the 12 months of ERT by (59 +/- 21)% at 24 months (P < 0.01). During the first 12 month, the height and weight of the patients who were 2 - 12 years old increased (8.6 +/- 4.3) cm and (2.6 +/- 1.7) kg, respectively, and those of the patients who were 12 - 18 years old increased (5.2 +/- 3.9) cm and (4.5 +/- 3.3) kg, separately. Bone pain reported by 16 patients relieved after 3 months of treatment. But radiological evidence of bone disease did not change. The signs and symptoms of CNS involvement in patients with type 2 and type 3 disease were not improved. No serious adverse events were reported.

CONCLUSIONSERT with Imiglucerase could improve the quality of life of the patients with Gaucher disease by ameliorating the Gaucher disease-associated anemia, thrombocytopenia, organomegaly, growth retardation and bone pain.

Adolescent ; Anemia ; enzymology ; Child ; Child, Preschool ; Enzyme Replacement Therapy ; adverse effects ; methods ; Female ; Gaucher Disease ; drug therapy ; enzymology ; physiopathology ; Glucosylceramidase ; administration & dosage ; adverse effects ; deficiency ; therapeutic use ; Growth Disorders ; enzymology ; Hepatomegaly ; enzymology ; Humans ; Infant ; Male ; Recombinant Proteins ; therapeutic use ; Retrospective Studies ; Splenomegaly ; enzymology ; Thrombocytopenia ; enzymology ; Treatment Outcome ; Young Adult