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Human Gene Therapy

Youn-Shen Bee, Leilei Tu, Shwu-Jiuan Sheu, Hsiu-Chen Lin, Jia-Hua Tang, Jiang-Hui Wang, Selwyn M Prea, Gregory J Dusting, Deng-Chyang Wu, Jingxiang Zhong, Bang V Bui, Ming-Hong Tai, Guei-Sheung Liu
Choroidal neovascularization (CNV) is a common pathological feature in neovascular age-related macular degeneration which is the leading cause of vision loss amongst elderly populations in developed countries. In this study, we evaluated the effect of a novel endogenous inhibitor of angiogenesis, calreticulin anti-angiogenic domain (CAD), subconjunctivally delivered by an adenoviral vector (Ad-CAD) in a rat model of laser-induced CNV. CAD was expressed in Ad-CAD infected cells and inhibited the angiogenic activity in human umbilical vein endothelial cells in vitro...
March 31, 2017: Human Gene Therapy
Megan L Cramer, Guohong Shao, Louise R Rodino-Klapac, Louis G Chicoine, Paul T Martin
Use of adeno-associated virus (AAV) to transduce genes into skeletal muscles can be associated with T-cell responses to viral capsid and/or to transgenic protein. Intramuscular mononuclear cell infiltrates primarily consisting of CD8+ T cells and also containing FOXP3+ regulatory T cells were present in rhesus macaque skeletal muscle treated with rAAVrh74.MCK.GALGT2 by vascular delivery. Administration of oral prednisone prior to AAV gene delivery and throughout the study reduced such infiltrates by 60% at 24 weeks post AAV delivery compared with AAV-treated animals not receiving prednisone, regardless of the presence of pre-existing AAV serum antibodies at the time of treatment...
March 23, 2017: Human Gene Therapy
Jesse D Riordan
N/A *Note: There is no option for manuscript type "Letter to the Editor". I selected "Review" as the type, but this submission is a Letter to the Editor.
March 23, 2017: Human Gene Therapy
Sarah Wassmer, Brian Leonard, Stuart Coupland, Adam Baker, John Hamilton, William W Hauswirth, Catherine Tsilfidis
Retinal detachment is an acute disorder in humans that is caused by trauma or disease, and it can often lead to permanent visual deficits that result from the death of photoreceptors in the retina. The final pathway for photoreceptor cell death is apoptosis and necroptosis. The X-linked inhibitor of apoptosis (XIAP) has been shown to block both of these cell death pathways. We tested the effects of XIAP on photoreceptor survival in a feline model of retinal detachment. The study was performed in 12 cats, divided into 2 experimental groups...
March 23, 2017: Human Gene Therapy
William F Penny, H Kirk Hammond
Despite improvements in drug and device therapy for heart failure, hospitalization rates and mortality have changed little in the past decade. Randomized clinical trials using gene transfer to improve function of the failing heart are the focus of this review. Four randomized clinical trials of gene transfer in heart failure with reduced ejection fraction (HFrEF) have been published. Each enrolled patients with stable symptomatic HFrEF and used either intracoronary delivery of a virus vector or endocardial injection of a plasmid...
March 16, 2017: Human Gene Therapy
Colin L Sweeney, Uimook Choi, Chengyu Liu, Sherry Koontz, Seung-Kwon Ha, Harry L Malech
Chronic granulomatous disease (CGD) is characterized by defects in the production of microbicidal reactive oxygen species (ROS) by phagocytes. Testing of gene and cell therapies for the treatment of CGD in human hematopoietic cells requires preclinical transplant models. The use of the lymphocyte-deficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl/)SzJ (NSG) mouse strain for human hematopoietic cell xenografts to test CGD therapies is complicated by the presence of functional mouse granulocytes capable of producing ROS for subsequent bacterial and fungal killing...
March 6, 2017: Human Gene Therapy
Rodrigo Esaki Tamura, Aline Hunger, Denise C Fernandes, Francisco R Laurindo, Eugenia Costanzi-Strauss, Bryan E Strauss
Previously, the authors developed an adenoviral vector, Ad-PG, where transgene expression is regulated by a p53-responsive promoter. When used to transfer the p53 cDNA, a positive feedback mechanism is established. In the present study, a critical comparison is performed between Ad-PGp53 and AdRGD-PGp53, where the RGD motif was incorporated in the adenoviral fiber protein. AdRGD-PGp53 provided superior transgene expression levels and resulted in the killing of prostate carcinoma cell lines DU145 and PC3. In vitro, this effect was associated with increased production of cytoplasmic and mitochondrial oxidants, DNA damage as revealed by detection of phosphorylated H2AX, as well as cell death consistent with apoptosis...
February 6, 2017: Human Gene Therapy
QingQing Hao, XueFei Dong, Xu Chen, Feng Yan, Xiaoyu Wang, Haishui Shi, Bo Dong
Recent study have demonstrated that ACE2 plays an important role in the pathogenesis of abdominal Aortic Aneurysm (AAA). But, little study was reported about the direct effect of ACE2 overexpression on the aneurysm. In this study, we hypothesize that overexpression of ACE2 may prevent the pathogenesis of aneurysm by decreasing RAS activation. Thirty-nine Mice were assigned to 3 groups randomly (n=13 in each group), ACE2 group, Ad.EGFP group and Control group. After 8-week treatment, abdominal aortas with AAA were obtained for HE staining, VVG, immunohistochemistry and Western blotting...
January 31, 2017: Human Gene Therapy
Xiao-Mei Zhang, Yu-Jing Zhang, Wei Wang, Yu-Quan Wei, Hongxin Deng
Crohn's disease which mainly affects the gastrointestinal tract and impairs patient's quality of life, is a refractory inflammatory disease with clinical manifestations of abdominal pain, fever, bowel obstruction and diarrhoea with blood or mucus. Besides the common complication of intestinal obstruction, the formation of fistulas should also be concerned about and anorectal fistula is the most typical. The disease is difficult to radical cure and easy to relapse, which urges people to find other effective treatment in addition to surgery...
January 28, 2017: Human Gene Therapy
Terence R Flotte, Guangping Gao
No abstract text is available yet for this article.
April 2017: Human Gene Therapy
Robert M Kotin, Richard O Snyder
Recombinant adeno-associated virus (rAAV) vectors are proving to be a reliable gene transfer system for several clinical applications, with an increasing body of evidence supporting safety and efficacy. Realizing the clinical and commercial potential of rAAV depends on a reliable source of high-quality, well-characterized rAAV lots. This requirement has been very challenging to achieve due to limits of manufacturing platforms, lot-to-lot variability, or differences in the rigor applied to quality-control assays...
April 2017: Human Gene Therapy
Kenneth I Berns, Nicholas Muzyczka
AAV has been studied for 55 years and has been developed as a vector for about 35 years. By now, there is a fairly good idea of the dimensions of what would be useful to know to employ AAV optimally as a vector, but there are still many unanswered questions within the system. As with all biological systems, each good experiment raises further questions to answer. This article provides an overview of those areas in which unknown information can be identified and of those questions that have not yet been recognized...
April 2017: Human Gene Therapy
Gwladys Gernoux, James M Wilson, Christian Mueller
Recombinant adeno-associated viruses (AAVs) are quickly becoming the preferred viral vector for viral gene delivery for the treatment of a wide variety of genetic disorders. However, since their use in a clinical trial targeting hemophilia B patients 10 years ago, immune responses to the AAV capsid appear to have hampered some of the early clinical gene transfer efficacy. Indeed, AAV-based gene transfer has been shown to reactivate capsid-specific memory T cells, which have correlated with a decline in AAV-transduced tissue in some patients...
April 2017: Human Gene Therapy
Randy J Chandler, Mark S Sands, Charles P Venditti
Currently, clinical gene therapy is experiencing a renaissance, with new products for clinical use approved in Europe and clinical trials for multiple diseases reporting positive results, especially those using recombinant adeno-associated viral (rAAV) vectors. Amid this new success, it is prudent to recall that the field of gene therapy experienced tragic setbacks in 1999 and 2002 because of the serious adverse events related to retroviral and adenoviral gene delivery in two clinical trials that resulted in the death of two patients...
April 2017: Human Gene Therapy
Paul N Valdmanis, Mark A Kay
The use of recombinant adeno-associated viruses (rAAVs) ushered in a new millennium of gene transfer for therapeutic treatment of a number of conditions, including congenital blindness, hemophilia, and spinal muscular atrophy. rAAV vectors have remarkable staying power from a therapeutic standpoint, withstanding several ebbs and flows. As new technologies such as clustered regularly interspaced short palindromic repeat genome editing emerge, it is now the delivery tool-the AAV vector-that is the stalwart. The long-standing safety of this vector in a multitude of clinical settings makes rAAV a selling point in the advancement of approaches for gene replacement, gene knockdown, gene editing, and genome modification/engineering...
April 2017: Human Gene Therapy
Hildegund C J Ertl, Katherine A High
Recombinant adenovirus-associated (rAAV) vectors due to their ease of construction, wide tissue tropism, and lack of pathogenicity remain at the forefront for long-term gene replacement therapy. In spite of very encouraging preclinical results, clinical trials were initially unsuccessful; expression of the rAAV vector-delivered therapeutic protein was transient. Loss of expression was linked to an expansion of AAV capsid-specific T-cell responses, leading to the hypothesis that rAAV vectors recall pre-existing memory T cells that had been induced by natural infections with AAV together with a helper virus...
April 2017: Human Gene Therapy
Arun Srivastava, Barrie J Carter
There are conflicting reports that integration of the wild-type adeno-associated virus 2 (AAV2) genome is associated with induction of hepatocellular carcinoma (HCC) in a small subset of patients. However, there are several lines of evidence that contradict this assertion: (i) AAV2 has long been known to be a non-pathogenic virus, although ∼90% of the human population is seropositive for AAV2 antibodies; (ii) AAV2 has been shown to possess anticancer activity; (iii) epidemiological evidence suggests that AAV2 infection plays a protective role against cervical carcinoma; and (iv) five different AAV serotype vectors (AAV1, AAV2, AAV5, AAV8, and AAV9) have been or are currently being used in 162 Phase I/II clinical trials and one Phase III clinical trial in humans to date, and no cancer of any type has ever been observed or reported...
April 2017: Human Gene Therapy
Alisha M Gruntman, Lin Su, Terence R Flotte
In order to pursue a clinical gene therapy for a human neurologic disease, it is often necessary to perform proof-of-concept trials in mouse models of that disease. In order to demonstrate a potential clinical efficacy, one must be able to select an appropriate vector and route of delivery for the appropriate age group in the disease model. Since many diseases require correction early in life, investigators often need to deliver recombinant adeno-associated viral (rAAV) vectors to neonatal mice. Herein, general central nervous system expression patterns of nuclear GFP following delivery of rAAV by three different routes are reported...
March 2017: Human Gene Therapy
Terence R Flotte
No abstract text is available yet for this article.
March 2017: Human Gene Therapy
Christiane Dinsart, Kalliopi Pervolaraki, Alexandra Stroh-Dege, Muriel Lavie, Isabelle Ronsse, Jean Rommelaere, Jo Van Damme, Katrien Van Raemdonck, Sofie Struyf
Application of oncolytic viruses is a valuable option to broaden the armament of anticancer therapies, as these combine specific cytotoxic effects and immune-stimulating properties. The self-replicating H-1 parvovirus (H-1PV) is a prototypical oncolytic virus that, besides targeting tumor cells, also infects endothelial cells, thus combining oncolytic and angiostatic traits. To increase its therapeutic value, H-1PV can be armed with cytokines or chemokines to enhance the immunological response. Some chemokines-more specifically, the CXCR3 ligands CXCL4L1 and CXCL10-combine immune-stimulating properties with angiostatic activity...
March 2017: Human Gene Therapy
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