Systematic gene therapy derived from an investigative study of AAV2/8 vector gene therapy for Fabry disease.

BACKGROUND: Fabry disease (FD) is a progressive multisystemic disease characterized by a lysosomal enzyme deficiency. A lack of α-galactosidase A (α-Gal A) activity results in the progressive systemic accumulation of its substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), which results in renal, cardiac, and/or cerebrovascular disease and early death. Enzyme replacement therapy (ERT) is the current standard of care for FD; however, it has important limitations, including a low half-life, limited distribution, and requirement of lifelong biweekly infusions of recombinant enzymes. METHODS: Herein, we evaluated a gene therapy approach using an episomal adeno-associated viral 2/8 (AAV2/8) vector that encodes the human GLA cDNA driven by a liver-specific expression cassette in a mouse model of FD that lacks α-Gal A activity and progressively accumulates Gb3 and Lyso-Gb3 in plasma and tissues. RESULTS: A pharmacology and toxicology study showed that administration of AAV2/8-hGLA vectors (AAV2/8-hGLA) in FD mice without immunosuppression resulted in significantly increased plasma and tissue α-Gal A activity and substantially normalized Gb3 and Lyso-Gb3 content. CONCLUSIONS: Moreover, the plasma enzymatic activity of α-Gal A continued to be stably expressed for up to 38 weeks and sometimes even longer, indicating that AAV2/8-hGLA is effective in treating FD mice, and that α-Gal A is continuously and highly expressed in the liver, secreted into plasma, and absorbed by various tissues. These findings provide a basis for the clinical development of AAV2/8-hGLA.

Development of Lanzyme as the Potential Enzyme Replacement Therapy Drug for Fabry Disease.

Fabry disease (FD) is a progressive multisystemic disease characterized by lysosomal enzyme deficiency. Enzyme replacement therapy (ERT) is one of the most significant advancements and breakthroughs in treating FD. However, limited resources and the high cost of ERT might prevent patients from receiving prompt and effective therapy, thereby resulting in severe complications. Future progress in ERT can uncover promising treatment options. In this study, we developed and validated a recombinant enzyme (Lanzyme) based on a CHO-S cell system to provide a new potential option for FD therapy. Our results indicated that Lanzyme was heavily glycosylated, and its highest activity was similar to a commercial enzyme (Fabrazyme®). Our pharmacokinetic assessment revealed that the half-life of Lanzyme was up to 11 min, which is nearly twice that of the commercial enzyme. In vivo experiments revealed that Lanzyme treatment sharply decreased the accumulation levels of Gb3 and lyso-Gb3 in various tissues of FD model mice, with superior or comparable therapeutic effects to Fabrazyme®. Based on these data, Lanzyme may represent a new and promising treatment approach for FD. Building this enzyme production system for ERT can offer additional choice, potentially with enhanced efficacy, for the benefit of patients with FD.

Adverse trends of cardiovascular risk factors among low risk populations (1983-1994)--a cohort study of workers and farmers in Guangzhou, China.

BACKGROUND: The levels and trends of cardiovascular risk factors vary greatly throughout China. We examine 10-year trends of cardiovascular risk factors (1983-1994) and the factors related to these trends among low-risk cohorts of workers and farmers in Guangzhou, China. METHODS: This is a cohort study of 3,131 workers and 3,493 farmers aged 25-64 years at baseline with 10 years of follow-up. We performed a longitudinal analysis to account for the aging of the cohorts and the repeated measures of the same individual. RESULTS: At baseline the prevalence of overweight (including obese) ranged from 1.0% to 11.8%, hypertension ranged from 3.8% to 10.5%, and mean serum total cholesterol (TC) ranged from 155.4 mg/dl to 187.2 mg/dl. Although prevalence of smoking declined, blood pressure levels and body mass index (BMI) increased significantly, and lipid profiles changed unfavorably during the 10-year follow-ups. The prevalence of hypertension increased from 5.0 percentage points (female farmers) to 12.3 percentage points (male farmers). Mean TC increased significantly (e.g., +22.8 mg/dl and +17.0 mg/dl in male and female farmers, respectively). In the longitudinal data analyses, increase in BMI was associated with increase in blood pressure levels and TC. Significant adverse trends of risk factors persisted after adjustment for aging, education, BMI, smoking, and alcohol intake. CONCLUSION: Urgent action is needed to prevent and reverse the unhealthy trends occurring among these low risk Chinese workers and farmers.

[Epidemiological survey of rheumatic heart disease in schoolchildren in Guangdong and Xinjiang].

OBJECTIVE: To investigate the prevalence of rheumatic heart disease (RHD) among schoolchildren in Guangdong Province and Xinjiang Uygur Autonomous Region. METHODS: Using a cluster sampling method, an epidemiological survey of RHD was conducted in 16 682 primary and high school students by auscultation in Guangdong Province and Xinjiang Uygur Autonomous Region from 2005 to 2006. Review of the clinical records, RHD survey in adults, and examination of the positivity rate of group A beta-hemolytic Streptococcus (GAS) by throat swab cultures in the students aged between 9 and 12 years in the sampled schools were also carried out. RESULTS: No RHD patient was found in the sampled population. In Xinjiang, the prevalence of RHD was 12.9/1000 among adults, higher than that (2.2/1000) in Guangdong Province. The GAS-positive rate in the schoolchildren in Xinjiang ranged from 9.8% to 12.6%, higher than that in Guangdong (2.3%-3.9%). CONCLUSION: The GAS-positive rate among children and incidence of RHD in adults are higher in Xinjiang than in Guangdong. The prevalence of RHD among the schoolchildren shows a reduction compared with that in 1994.