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gene therapy and erectile dysfunction： the current status

Asian Journal of Andrology 2007年第1期9卷 8-15页

作者： David H. W. Lau Sashi S. Kommu Emad J. Siddiqui Cecil S. Thompson Robert J. Morgan Dimitri P. Mikhailidis Faiz H. Mumtaz Department of Urology Royal Free Hospital and University College Medical School University College London Royal Free Campus Rowland Hill Street London NW3 2QG UK Department of Clinical Biochemistry Royal Free Hospital and University College Medical School University College London Royal Free Campus Rowland Hill Street London NW3 2QG UK Department of Surgery Royal Free Hospital and University College Medical School University College London Royal Free Campus Rowland Hill Street London NW3 2QG UK Department of Urology Chase Farm Hospital The Ridgeway Enfield EN2 8JL UK Institute of Cancer Research and The Royal Marsden Hospitals NHS Foundation Trust Surrey SM2 5PT UK

Current available treatment options for erectile dysfunction （ED） are effective but not without failure and/or side effects. Although the development of phosphodiesterase type 5 （PDE5） inhibitors （i.e. sildenafil, tadalafil and vardenafil） has revolutionized the treatment of ED, these oral medications require on-demand access and are not as effective in treating ED related to diabetic, post-prostatectomy and severe veno-occlusive disease states. Improvement in the treatment of ED is dependent on understanding the regulation of human corporal smooth muscle tone and on the identification of relevant molecular targets. Future ED therapies might consider the application of molecular technologies such as gene therapy. As a potential therapeutic tool, gene therapy might provide an effective and specific means for altering intracavernous pressure ＂on demand＂ without affecting resting penile function. However, the safety of gene therapy remains a major hurdle to overcome before being accepted as a mainstream treatment for ED. gene therapy aims to cure the underlying conditions in ED, including fibrosis. Furthermore, gene therapy might help prolong the efficacy of the PDE5 inhibitors by improving penile nitric oxide bioactivity. It is feasible to apply gene therapy to the penis because of its location and accessibility, low penile circulatory flow in the flaccid state and the presence of endothelial lined （lacunar） spaces. This review provides a brief insight of the current role of gene therapy in the management of ED.

关键词： gene therapy nitric oxide synthase erectile dysfunction calcium-sensitive potassium channel vascular endothelial growth factor calcitonin gene-related peptide

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gene therapy: light is finally in the tunnel

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Protein & Cell 2011年第12期2卷 973-989页

作者： Huibi Cao Robert S.Molday Jim Hu Programme in Physiology and Experimental Medicine Hospital for Sick ChildrenDepartments of Laboratory Medicine and Pathobiologyand PaediatricsUniversity of TorontoTorontoOntario M5G1X8Canada Department of Biochemistry and Molecular Biology 2350 Health Sciences MallUniversity of British ColumbiaVancouverB.C.V6T 1Z3Canada

After two decades of ups and downs,gene therapy has recently achieved a milestone in treating patients with Leber’s congenital amaurosis(LCA).LCA is a group of inherited blinding diseases with retinal degeneration and severe vision loss in early infancy.Mutations in several genes,including RPE65,cause the disease.Using adenoassociated virus as a vector,three independent teams of investigators have recently shown that RPE65 can be delivered to retinal pigment epithelial cells of LCA patients by subretinal injections resulting in clinical benefits without side effects.However,considering the whole field of gene therapy,there are still major obstacles to clinical applications for other diseases.These obstacles include innate and immune barriers to vector delivery,toxicity of vectors and the lack of sustained therapeutic gene expression.Therefore,new strategies are needed to overcome these hurdles for achieving safe and effective gene therapy.In this article,we shall review the major advancements over the past two decades and,using lung gene therapy as an example,discuss the current obstacles and possible solutions to provide a roadmap for future gene therapy research.

关键词： gene therapy transgenes viral vector non-viral vector helper-dependent adenoviral vector adenoassociated virus lentivirus cystic fibrosis transmembrane conductance regulator(CFTR) host immune responses

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gene therapy with caspase-3 small interfering RNA-nanoparticles is neuroprotective after optic nerve damage

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Neural Regeneration Research 2021年第12期16卷 2534-2541页

作者： Mohamed Tawfik Xiwei Zhang Lisa Grigartzik Peter Heiduschka Werner Hintz Petra Henrich-Noack Berend van Wachem Bernhard A.Sabel Institute of Medical Psychology Otto von Guericke University of MagdeburgMagdeburgGermany Institute of Process Engineering Otto von Guericke University of MagdeburgMagdeburgGermany Department of Ophthalmology Münster University HospitalMünsterGermany Department of Neurology with Institute of Translational Neurology Münster University HospitalMünsterGermany Center of Behavioral Brain Sciences(CBBS) MagdeburgGermany

Apoptosis,a key mechanism of programmed cell death,is triggered by caspase-3 protein and lowering its levels with gene therapy may rescue cell death after central nervous system damage.We developed a novel,non-viral gene therapy to block caspase-3 gene expression using small interfering RNA(siRNA)delivered by polybutylcyanoacrylate nanoparticles(CaspNPs).In vitro CaspNPs significantly blocked caspase-3 protein expression in C6 cells,and when injected intraocularly in vivo,CaspNPs lowered retinal capsase-3 immunofluorescence by 57.9%in rats with optic nerve crush.Longitudinal,repeated retinal ganglion cell counts using confocal neuroimaging showed that post-traumatic cell loss after intraocular CaspNPs injection was only 36.1%versus 63.4%in lesioned controls.Because non-viral gene therapy with siRNA-nanoparticles can selectively silence caspace-3 gene expression and block apoptosis in post-mitotic neurons,siRNA delivery with nanoparticles may be promising for neuroprotection or restoration of central visual system damage and other neurological disorders.The animal study procedures were approved by the German National Act on the use of experimental animals(Ethic Committee Referat Verbraucherschutz,Veterinärangelegenheiten;Landesverwaltungsamt Sachsen-Anhalt,Halle,Germany,#IMP/G/01-1150/12 and#IMP/G/01-1469/17).

关键词： apoptosis brain caspase-3 drug delivery gene therapy in vivo confocal neuroimaging nanoparticles neurodegeneration neuroprotection retina siRNA

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gene therapy of HSV-TK Transferred by the EBV based Expression Vector on Experimental Hepatocellular Carcinoma

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2001年第2期21卷 122-125页

作者：丁庆庆吴在德陈孝平胡俊波詹永强 Department of general Surgery Tongji Hospital Tongji Medical College Huazkong University of Science and Technology Wuhan

To study the therapeutic effects of herpes simplex virus thymidine kinase gene transferred by the EBV based expression vector on experimental hepatocellular carcinoma, pDR2 TK gene was delivered into human hepatocellular carcinoma cell line SMMC 7721 by using liposome mediated transfection technique,and then gene expression was detected by RT PCR, and the killing effects were examined through MTT method. In the nude mice hepatoma model,the antitumor effects of pDR2 TK /GCV system was evaluated in terms of tumor growth. MTT results showed that the pDR2 TK /GCV had cytotoxic effect and about 70 % SMMC 7721 cells were killed when GCV was at 1000 μmol/L. In vivo experiment showed that the tumor size in nude mice with transferred pDR2 TK gene was significantly smaller than that in control group . On the 10th day the tumor in 3 mice (60 %) disappeared completely after GCV treatment. It is concluded that the pDR2 TK/GCV system has marked killing effects on the experimental hepatocellular carcinoma.

关键词： hepatocellular carcinoma gene therapy EB virus expression vector HSV TK gene

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gene therapy and genome editing for primary immunodeficiency diseases

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genes & Diseases 2020年第1期7卷 38-51页

作者： Zhi-Yong Zhang Adrian J.Thrasher Fang Zhang Molecular and Cellular Immunology Great Ormond Street Institute of Child HealthUniversity Colleage LondonUK Department of Immunology and Rheumatology Children’s Hospital of Chongqing Medical UniversityChina

In past two decades the gene therapy using genetic modified autologous hematopoietic stem cells(HSCs)transduced with the viral vector has become a promising alternative option for treating primary immunodeficiency diseases(PIDs).Despite of some pitfalls at early stage clinical trials,the field of gene therapy has advanced significantly in the last decade with improvements in viral vector safety,preparatory regime for manufacturing high quality virus,automated CD34 cell purification.Hence,the overall outcome from the clinical trials for the different PIDs has been very encouraging.In addition to the viral vector based gene therapy,the recent fast moving forward developments in genome editing using engineered nucleases in HSCs has provided a new promising platform for the treatment of PIDs.This review provides an overall outcome and progress in gene therapy clinical trials for SCID-X,ADA-SCID,WAS,X-CGD,and the recent developments in genome editing technology applied in HSCs for developing potential therapy,particular in the key studies for PIDs.

关键词： Adenosine deaminase deficient Chronic granulomatous disease gene therapy Genome editing Hematopoietic progenitor stem cells Primary immunodeficiency diseases Wiskott-Aldrich syndrome X-liked severe combined immunodeficiency

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gene therapy of Cancer:Induction of Anti-Tumor Immunity

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Cellular & Molecular Immunology 2004年第2期1卷 105-111页

作者： Jesus Prieto Division

Many malignancies lack satisfactory treatment and new therapeutic options are urgently needed.gene therapy is a new modality to treat both inherited and acquired diseases based on the transfer of genetic material to the tissues.Different gene therapy strategies against cancers have been developed.A considerable number of preclinical studies indicate that a great variety of cancers are amenable to gene therapy.Among these strategies, induction of anti-tumor immunity is the most promising approach.gene therapy with cytokines has reached unprecedented success in preclinical models of cancer.Synergistic rather than additive effects have been demonstrated by combination of gene transfer of cytokines/chemokines,costimulatory molecules or adoptive cell therapy.Recent progress in vector technology and in imaging techniques allowing in vivo assessment of gene expression will facilitate the development of clinical applications of gene therapy,a procedure which may have a notorious impact in the management of cancers lacking effective treatment.Cellular & Molecular Immunology.2004;1(2):105-111.

关键词： gene therapy anti-tumor immunity cytokines costimulatory molecules dendritic cell

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gene therapy for Parkinson’s Disease and Ethical Challenges: A Systematic Review

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Advances in Parkinson's Disease 2023年第2期12卷 9-28页

作者： Théodora M. Zohoncon Joseph Sawadogo Abdou Azaque Zoure Abdoul Karim Ouattara Marie N. L. Ouedraogo Luc Zongo Paul Ouedraogo Florencia W. Djigma Christelle W. M. Nadembèga Raphael Kabore Djénéba Ouermi Dorcas Obiri-Yeboah Jacques Simpore Pietro Annigoni Biomolecular Research Centre (CERBA) Ouagadougou Burkina Faso Faculty of Medicine University Saint Thomas d’Aquin (USTA) Ouagadougou Burkina Faso Saint Camille Hospital Ouagadougou (HOSCO) Ouagadougou Burkina Faso Molecular Biology and genetics Laboratory (LABIOgene) Joseph KI-ZERBO University Ouagadougou Burkina Faso National Center for Scientific and Technological Research (CNRST/IRSS) Ouagadougou Burkina Faso Norbert Zongo University/Manga University Centre Koudougou Burkina Faso Department of Microbiology and Immunology School of Medical Sciences University of Cape Coast Cape Coast Ghana

Background: Parkinson’s disease (PD) is a complex, multifactorial neurodegenerative disorder with a pathophysiology deriving from the synergy of abnormal aggregation of neuroinflammation, synuclein and dysfunction of lysosomes, mitochondria and synaptic transport difficulties influenced by genetic and idiopathic factors. Worldwide, PD has a prevalence of 2-3% in people over the age of 65. To date, there is no certified, effective treatment for PD. Aim: The aims of this research were: (i) to present, on the basis of recent advances in molecular genetics and epigenetics, the genomic aspects and challenges of gene therapy trials for PD;(ii) to outline the ethical principles applicable to therapeutic trials for PD. Method: A systematic literature review was carried out to identify relevant articles reporting on genomic aspects and gene therapy in PD from 2001 to October 2023. The search was conducted in French and/or English in three databases: PubMed, Google Scholar and Science Direct. PRISMA guidelines were used in this systematic review. Results: A total of thirty-three publications were selected. An inductive thematic analysis revealed that numerous genetic mutations (SNCA, Parkin, PINK1, DJ-1, LRRK2, ATP13A2, VPS35, Parkin/PRKN, PINK1, DJ1/PARK7) and epigenetic events such as the action of certain miRNAs (miR-7, miR-153, miR-133b, miR-124, miR-137) are responsible for the onset of PD, and that genetic therapy for this pathology raises ethical questions that need to be elucidated in the light of the bioethical principles of autonomy, beneficence, non-maleficence and justice. Conclusion: There is no zero risk in biotechnology. Then, it will be necessary to assess all the potential risks of Parkinson disease’s gene therapy to make the right decision. It is therefore essential to pursue research and, with the guidance of ethics, to advance treatment options and meet the challenges of brain manipulation and its impact on human identity. The golden rule of medicine remains: “Primum non nocere”.

关键词： Neurodegenerative Diseases Parkinson Disease Molecular Mechanism gene therapy gene therapy Ethics

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Ultrasound-targeted microbubble destruction in gene therapy: A new tool to cure human diseases

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genes & Diseases 2017年第2期4卷 64-74页

作者： Jun Wu Ren-Ke Li Toronto general Research Institute Division of Cardiovascular SurgeryUniversity Health NetworkTorontoOntarioCanada Division of Cardiac Surgery Department of SurgeryUniversity of TorontoTorontoOntarioCanada

Human gene therapy has made significant advances in less than two decades.Within this short period of time,gene therapy has proceeded from the conceptual stage to technology development and laboratory research,and finally to clinical trials for the treatment of a variety of deadly diseases.Cardiovascular disease,cancer,and stroke are leading causes of death worldwide.Despite advances in medical,interventional,radiation and surgical treatments,the mortality rate remains high,and the need for novel therapies is great.gene therapy provides an efficient approach to disease treatment.Notable advances in gene therapy have been made for genetic disorders,including severe combined immune deficiency,chronic granulomatus disorder,hemophilia and blindness,as well as for acquired diseases,including cancer and neurodegenerative and cardiovascular diseases.However,lack of an efficient delivery system to target cells as well as the difficulty of sustained expression of transgenes has hindered advancements in gene therapy.Ultrasound targeted microbubble destruction(UTMD)is a promising approach for target-specific gene delivery,and it has been successfully investigated for the treatment of many diseases in the past decade.In this paper,we review UTMD-mediated gene delivery for the treatment of cardiovascular diseases,cancer and stroke.

关键词： gene therapy Cardiovascular diseases Cancer Stroke UTMD

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Antitumor effect of cytosine deaminase/5-fluorocytosine suicide gene therapy system mediated by Bifidobacterium infantis on melanoma

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Acta Pharmacologica Sinica 2005年第5期26卷 629-634页

作者： Cheng YI~2,Ying HUANG~3,Zhi-ying GUO~3,Shu-ren WANG~(3,4)~2Cancer Center,West China Hospital,Sichuan University Chengdu,610041,China ~3Department of Pathophysiology,West China School ofPreclinical and Forensic Medicine,Sichuan University,Chengdu 610041,China Cancer Center West China Hospital Sichuan University Chengdu China Department of Pathophysiology West China School of Preclinical and Forensic Medicine Sichuan University Chengdu China

Aim:To construct a Bifidobacterium infantis/CD targeting gene therapy systemand observe the antitumor effect of cytosine deaminase/5-fluorocytosine(CD/5-FC)suicide gene therapy system mediated by Bifidobacterium infantis on mela-noma in vitro and in vivo.Methods:A recombinant CD/pGEX-1LamdaT plasmidwas transfected into Bifidobacterium infantis by electroporation.Bifidobac-terium infantis transfected by recombinant CD/pGEX-1LamdaT plasmid was in-cubated with 5-FC anaerobically.Then the supernatant fluid was collected andadded to melanoma B 16-F10 cells to observe the killing effect for B 16-F10 cells.Mice were inoculated with melanoma B 16-F10 cells to establish animal models.The mice were then injected with 5-FC and Bifidobacterium infantis transfectedby recombinant CD/pGEX-1LamdaT plasmid.Results:Two segments of approxi-mate 4.9 kb and 1.3 kb were extracted from the 6.2 kb recombinant plasmid,whichwere equal to the size of the pGEX-1LamdaT plasmid and CD gene,respectively.Sequencing results showed that the full length and sequence of nucleotide acid ofthe inserted gene in extracted recombinant plasmid was completely identical to theCD gene.In vitro,B16-F10 cells treated by supernatant fluid were remarkablydamaged morphologically,and the cell growth was significantly inhibited.Experi-ments on the mice melanoma model showed that after treatment with a combina-tion of transfected Bifidobacterium infantis and 5-FC,the tumor volume wassignificantly inhibited compared with controls.Conclusion:The foreign gene,CD gene,was correctly inserted into pGEX-1LambdaT plasmid and transferredinto Bifidobacterium infantis.CD/5-FC suicide gene therapy system mediated byBifidobacterium infantis demonstrated a good antitumor effect on melanoma invitro and in vivo.

关键词： Bifidobacterium infantis cytosine deaminase gene therapy

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Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy

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Cell Research 2007年第2期17卷 89-99页

作者： Qi Zhang~1 Guihua Chen~1 Xinyuan Liu~2 Qijun Qian~3 ~1Transplantation Research Institute of Sun Yat-sen University,The Third Affiliated Hospital of Sun Yat-Sen University,600 Tianhe Rd,Guangzhou 510630,China ~2Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,Shanghai 200031,China ~3Laboratory of Viral and gene therapy,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,225 Changhai Rd,Shanghai 200438,China Transplantation Research Institute of Sun Yat-sen University The Third Affiliated Hospital of Sun Yat-Sen University Guangzhou China Institute of Biochemistry and Cell Biology Chinese Academy of Sciences Shanghai China Laboratory of Viral and gene therapy Eastern Hepatobiliary Surgery Hospital Second Military Medical University Shanghai China

Antibodies as therapeutic agents are mostly used in oncology,as illustrated by their applications in lymphoma,breastcancer or colorectal cancer.This review provides a brief historical sketch of the development of monoclonal antibodiesfor cancer treatment and Summarizes the most significant clinical data for the best-established reagents to date.It alsodiscusses strategies to improve the anti-rumor efficacy of antibody therapy,including antibody gene therapy and exploi-tation of bone marrow derived primary mesenchymal stem cells as the antibody gene transporter.

关键词： monoclonal antibody cancer gene therapy

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