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Yang F.-Q.,Liver Disease Research Center | Yu Y.-Y.,Peking University | Wang G.-Q.,Peking University | Chen J.,Ditan Hospital | And 6 more authors.
Journal of Viral Hepatitis | Year: 2012

A DNA vaccine against the hepatitis B virus (HBV), enhanced by IL-2/IFN-Î fusion protein expression from a plasmid construct and mediated by in vivo electroporation, was evaluated in a total of 39 HBeAg-positive patients with chronic hepatitis B (CHB). The six of 39 patients with a serum alanine aminotransferase (ALT) value of 1-2 times upper limit of normal (ULN) were assigned to the open-label arm (Group01) receiving vaccine monotherapy; the remaining 33 patients with an ALT of more than two times ULN were enroled to the randomized and controlled arm (Group02) receiving lamivudine (LAM) monotherapy (LAM+placebo) or combined therapy (LAM+DNA vaccine) in 1:2 ratio. In Group01, a significant elevation of HBV-specific IFN-Î-secreting T-cell counts in comparison with baseline was observed. In Group02, the proportion of patients with HBV DNA suppression was higher with LAM+DNA vaccine than with LAM monotherapy at each visit time point after the final injection of DNA vaccine at week 36, revealing a significant difference between the two groups (P = 0.03) at week 60. The incidence of dual-site mutations of rtM204/I/S+rtL180M was significantly lower (P = 0.03) with an identified lower virological breakthrough (VBT) rate (P = 0.03) in patients receiving LAM+DNA vaccine than LAM monotherapy, accompanied with a significant higher positive T-cell response rate in patients receiving LAM+DNA vaccine (P = 0.03). In conclusion, this study provides evidence that HBV DNA vaccination is safe and immunologically effective, and that the HBV-specific T-cell responses induced by DNA vaccination under LAM chemotherapy showed a correlation with the suppression of viral replication in patients with CHB. © 2012 Blackwell Publishing Ltd. Source


Yang H.-Y.,Liver Disease Research Center | Chen G.-M.,Liver Disease Research Center | Cui Y.-M.,Peking University | Zhao X.,Peking University | And 5 more authors.
Medical Journal of Chinese People's Liberation Army | Year: 2013

Objective To evaluate the safety and immunogenicity of the therapeutic dual-plasmid HBV DNA vaccine mediated by electroporation (EP) in vivo against the hepatitis B virus in healthy adult volunteers. Methods The enrolled 30 healthy volunteers were randomly divided into three dosage groups (10 volunteers in each group), namely: high-dose (4mg), middle-dose (2mg) and low-dose (lmg) groups. Volunteers received four intramuscular injections of HBV DNA vaccine mediated by in vivo EP at the 0, 4th, 12th and 24th week. Each dose group was further divided into 2 sub-groups (5 persons/per group) with different EP frequencies, i.e. 36 and 60 volt. The changes in response was determined by physical diagnosis (ECG, chest X-ray, type-B ultrasound), lab findings (blood and urine routine, blood biochemistry, prothrombin time, thyroid function, tumor biomarkers), immunological variables (IFN- γ, ANA, anti-dsDNA Ab), serological variables pertaining to HBV (HBsAg, HBcAb, HBeAg, HBeAb, HBV DNA) and serum anti-HBs status in volunteers before and after receiving EP mediated HBV DNA vaccination. Results The dual-plasmid HBV DNA vaccination mediated by in vivo EP was well tolerated in all healthy volunteers with a stable life signs. It was found that EP-mediated immunization of the therapeutic DNA vaccine against hepatitis B virus had a specific and obvious anti-HBs humoral immune response in one volunteer (l7.22mU/ml). Four repeated intramuscular injections of the vaccine did not show any significant adverse effects in the receptors. Although mild elevation of serum ALT and enlarged spleen were found in one individual, the abnormalities disappeared spontaneously at the end of the trial. Conclusions EP-mediated dual-plasmid HBV DNA vaccine is safe and well tolerated with certain degree of humoral immunogenicity. Source


Rao G.-R.,Liver Disease Research Center | Shi Y.-F.,Liver Disease Research Center | Huang B.,Liver Disease Research Center | Zhang H.-J.,Liver Disease Research Center | And 5 more authors.
Chinese Journal of Biologicals | Year: 2015

Objective: To extract and purify the plasmid TV-BIKDD for targeted therapy of lung cancer and control its quality. Methods: Plasmid was crudely extracted from recombinant E. coli DH5α/TV-BIKDD by alkaline lysis, purified by two steps of chromatography with monolithic columns, i.e. CIM® DEAE-8 Tube monolithic column and CIM C4 HLD-8 Tube Monolithic Column, and determined for plasmid content and proportion of supercoil DNA. Three consecutive batches of solutions mainly consisting of supercoil DNA were purified by the method and subjected to control tests. Results: Most of RNA was removed from crude extract of plasmid by CIM DEAE-8 Tube monolithic column. After chromatography with CIM C4 HLD-8 Tube Monolithic Column, the proportion of supercoil DNA reached more than 95.21%, while the total recovery rate of plasmid was 78%. The results of overall control tests on three batches of final products of plasmids met the requirements of FDA of the USA and the Technical Guideline for Products for Gene Therapy in China. Conclusion: A stable procedure for purification of recombinant plasmid TV-BIKDD was developed, which laid a foundation for further development of procedure for large-scale preparation of samples for clinical use. Source


Li X.-H.,Shanghai JiaoTong University | Lu Y.,Fudan University | Ling Y.,Shanghai JiaoTong University | Fu Q.-C.,Liver Disease Research Center | And 11 more authors.
BMC Medical Genetics | Year: 2011

Background: Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China.Methods: The coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old).Results: Neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065).Conclusions: We identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China. © 2011 Li et al; licensee BioMed Central Ltd. Source

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