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Intramuscular delivery of rAAV-mediated kallikrein gene reduces hypertension and prevents cardiovascular injuries in model rats

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Acta Pharmacologica Sinica 2007年第12期28卷 1898-1906页

作者： Yao WANG~(2,3),Ling-bo HOU~(2,3),Zhen-jun LIU~2,Yan WANG~2,Chun-lian CHEN~2,Xiao XIAO~(2,4),Dao-wen WANG~(2,5)~2 Institute of Hypertension and Department of Internal Medicine,Tongji Hospital,Tongji Medical College,Huazhong University of Science andTechnology,Wuhan 430030,China ~4 Departments of Molecular Genetics and Biochentistry and Gene Therapy Center University of Pittsburgh,Pittsburgh,PA 15261,USA Institute of Hypertension and Department of Internal Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China Departments of Molecular Genetics and Biochemistry and Gene Therapy Center University of Pittsburgh Pittsburgh USA

Aim:The overexpression of the human tissue kallikrein （HK） gene can reduceblood pressure and ameliorate the secondary syndromes associated with hyper-tension in animal *** current study was designed to investigate hy-potensive effect of intramuscular delivery of HK ***:We generatedan recombinant adeno-associated virus （rAAV） vector expressing human tissuekallikrein under the control of a cytomegalovirus promoter and administered therAAV-HK vector to a spontaneously hypertensive rat model at a dose of 1×1010virons/rat through intramuscular ***:A persistent,high-level ex-pression of HK post-gene delivery was confirmed by *** systolic bloodpressure in the rats receiving rAAV-LacZ and saline increased from 171.3 mmHg to182.3 mmHg 28 weeks' post *** contrast,the delivery of the HK gene byAAV vectors attenuated the increase of the systolic blood pressure in the *** systolic blood pressure was only slightly lowered （from a level of 174mmHg to 170.5 mmHg） post-vector *** difference in blood pres-sure between the treated group and the control groups is statistically significantat 12.6 *** hypotensive effect of rAAV-HK persisted until the end of thetesting *** addition,a significant amelioration of cardiovascularhypertrophy,renal injury,and collagen depositions in the rAAV-HK-treated ani-mals were also ***:All the effects are comparable with thoseof intravenous ***,the intramuscular administration of rAAV-HKmay be used in gene therapy for hypertension.

关键词： recombinant adeno-associated virus vector human tissue kallikrein intramuscular administration hypertension gene therapy cardiovascular remodeling spontaneously hypertensive rat

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The use of miR122 and its target sequence in adeno-associated virus-mediated trichosanthin gene therapy

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Journal of Integrative Medicine 2021年第6期19卷 515-525页

作者： Gai Ran Xi-lin Feng Yi-lin Xie Qing-yun Zheng Peng-peng Guo Ming Yang Ying-lu Feng Chen Ling Li-qing Zhu Chen Zhong State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology(Ministry of Education) School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438China Division of Cellular and Molecular Therapy Department of PediatricsUniversity of FloridaGainesvilleFL 32611USA Department of Traditional Chinese Medicine Chinese People’s Liberation Army 971 HospitalQingdao 266071Shandong ProvinceChina Department of Clinical Laboratory The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina

Objective:Plant-derived cytotoxic transgene expression,such as trichosanthin(tcs),regulated by recombinant adeno-associated virus(r AAV)vector is a promising cancer gene ***,the cytotoxic transgene can hamper the vector production in the r AAV producer cell line,human embryonic kidney(HEK293)***,we explored micro RNA-122(miR122)and its target sequence to limit the expression of the cytotoxic gene in the r AAV producer ***:A miR122 target(122 T)sequence was incorporated into the 30 untranslated region of the tcs c DNA *** firefly luciferase(fluc)transgene was used as an appropriate *** line HEK293-mir122 was generated by the lentiviral vector-mediated genome integration of the mir122 gene in parental HEK293 *** effects of miR122 overexpression on cell growth,transgene expression,and r AAV production were ***:The presence of 122 T sequence significantly reduced transgene expression in the miR122-enriched Huh7 cell line(in vitro),fresh human hepatocytes(ex vivo),and mouse liver(in vivo).Also,the normal liver physiology was unaffected by delivery of 122 T sequence by r AAV *** with the parental cells,the miR122-overexpressing HEK293-mir122 cell line showed similar cell growth rate and expression of transgene without 122 T,as well as the ability to produce liver-targeting r AAV ***,the yield of r AAV vectors carrying the tcs-122 T gene was increased by 77.7-fold in HEK293-mir122 ***,the tcs-122 T-containing r AAV vectors significantly reduced the proliferation of hepatocellular carcinoma cells without affecting the normal liver ***:HEK293-mir122 cells along with the 122 T sequence provide a potential tool to attenuate the cytotoxic transgene expression,such as tcs,during r AAV vector production.

关键词： Trichosanthin miR122 target sequence recombinant adeno-associated virus vector Gene therapy Liver cancer

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Prevalence of neutralizing antibodies against liver-tropic adeno-associated virus serotype vectors in 100 healthy Chinese and its potential relation to body constitutions

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Journal of Integrative Medicine 2015年第5期13卷 341-346页

作者： Chen Ling Yuan Wang Ying-lu Feng Ya-ni Zhang Jun Li Xin-rui Hu Li-na Wang Mao-feng Zhong Xiao-feng Zhai Irene Zolotukhin Arun Srivastava Chang-quan Ling Division of Cellular and Molecular Therapy Department of Pediatrics University of Florida College of Medicine Shands Cancer Center University of Florida College of Medicine Changhai Hospital of Traditional Chinese Medicine Second Military Medical University Department of Traditional Chinese Medicine 401 Hospital of the Chinese People’s Liberation Army Shanghai University of Traditional Chinese Medicine E-Institute of TCM Internal Medicine Shanghai Municipal Education Commission

recombinant adeno-associated virus （rAAV） serotype 2, 3 and 8 vectors are the most promising liver- tropic AAV serotype vectors. Liver diseases are significant problems in China. However, to date, few studies on AAV neutralizing antibodies （Nabs） were working with the Chinese population or with the rAAV3 vectors. The present study aimed to determine the prevalence of Nabs in Chinese population against wild-type AAV2, AAV3 and AAV8 capsids as well as additional two AAV3 variants. In addition, we performed a preliminary analysis to investigate the potential influence of traditional Chinese medicine body constitutions on AAV Nabs. Our work demonstrated that the majority of healthy Chinese subjects were positive for AAV Nabs, with the order of AAV2 〉 AAV3 = AAVLK03 〉 AAV8. There was no difference between： 1）AAV3 and its variants; 2） male and female subjects; and 3） different age cohorts （〈 35, 36- 50, and 〉 51 years old）. People in the Qi-deficiency constitution had significantly increased AAV8 Nabs than people in the Gentleness constitution. Our studies may have impact on the future clinical design of AAV-based gene therapy in the Chinese population.

关键词： medicine, Chinese traditional recombinant adeno-associated virus vector neutralizing antibodies body constitutions

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Recent development and gene therapy for glycogen storage disease type Ia

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Liver Research 2017年第3期1卷 174-180页

作者： Janice Y.Chou Goo-Young Kim Jun-Ho Cho Section on Cellular Differentiation Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA

Glycogen storage disease type Ia(GSD-Ia)is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase-α(G6Pase-αor G6PC)that is expressed primarily in the liver,kidney,and intestine.G6Pase-αcatalyzes the hydrolysis of glucose-6-phosphate(G6P)to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis,and is a key enzyme for endogenous glucose *** active site of G6Pase-αis inside the endoplasmic reticulum(ER)*** catalysis,the substrate G6P must be translocated from the cytoplasm into the ER lumen by a G6P transporter(G6PT).The functional coupling of G6Pase-αand G6PT maintains interprandial glucose *** therapies for GSD-Ia are available,but cannot prevent the long-term complication of hepatocellular adenoma that may undergo malignant transformation to hepatocellular *** models of GSD-Ia are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches,including gene therapy.

关键词： Glycogen storage disease type Ia(GSD-Ia) Glucose-6-phosphatase-α(G6Pase-αor G6PC) Gene therapy Hepatocellular adenoma recombinant adeno-associated virus vector

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