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Human Gene Therapy

Ziying Yan, Wei Zou, Zehua Feng, Weiran Shen, Soo-Yeun Park, Xuefeng Deng, Jianming Qiu, John F Engelhardt
The genome of recombinant adeno-associated virus 2 (rAAV2) remains a promising candidate for gene therapy for cystic fibrosis (CF) lung disease, but due to limitations in the packaging capacity and the tropism of this virus with respect to the airways, strategies have evolved for packaging an rAAV2 genome (up to 5.8kb) into the capsid of human bocavirus 1 (HBoV1) to produce a chimeric rAAV2/HBoV1 vector. Although a replication-incompetent HBoV1 genome has been established as a trans helper for capsid complementation, this system remains suboptimal with respect to virion yield...
November 6, 2018: Human Gene Therapy
Michelle E McClements, Alun R Barnard, Mandeep S Singh, Peter Charbel Issa, Zhichun Jiang, Roxana A Radu, Robert E MacLaren
The recent approval in the US of the first adeno-associated viral (AAV) vector for the treatment of an inherited retinal degeneration validates this approach for the treatment of many other diseases. A major limiting factor continues to be the size restriction of the AAV transgene at under 5kb. Stargardt disease is the most prevalent form of recessively inherited blindness and is caused by mutations in ABCA4, which has a coding sequence length of 6.8kb. Dual vector approaches increase the capacity of AAV gene therapy but at the cost of substantially reduced levels of target protein, which may be insufficient to achieve a therapeutic effect...
November 1, 2018: Human Gene Therapy
Yingxi Xu, Saisai Li, Ying Wang, Jia Liu, Xinhe Mao, Haiyan Xing, Zheng Tian, Kejing Tang, Xiaolong Liao, Qing Rao, Dongsheng Xiong, Min Wang, Jianxiang Wang
CD20 is an effective immunotherapy target for CD20+ B-cell malignant cells. Monoclonal antibody, especially Rituximab, has been a conventional strategy in the treatment of B-cell malignancies such as non-Hodgkin's lymphoma (NHL). However, treatment with monoclonal antibodies has not been enough to overcome the refractory/relapsed problems. Chimeric antigen receptor engineered T (CAR-T) cells have revealed excellent therapeutic effect on lymphocytic leukemia in recent years. In this study, a CD20 specific CAR was constructed and the cytotoxic efficacy of CD20 CAR-T cells on B-cell malignant cells was evaluated by CD107a degranulation, pro-inflammation cytokine production and true lytic ability in vitro and in vivo...
November 1, 2018: Human Gene Therapy
Shuaishuai Huang, Yu Ren, Xue Wang, Lissy Lazar, Suya Ma, Guobin Weng, Jinshun Zhao
Chronic renal disease or acute renal injury could result in end-stage renal disease or renal failure. Sonoporation, induced by ultrasound-targeted microbubble destruction (UTMD), has evolved as a new technology for gene delivery. It increases the transfection efficiency of the genes into target kidney tissues. Moreover, UTMD-mediated gene delivery can directly repair the damaged tissues or improve the recruitment and homing of stem cells in the recovery of injured tissues, which has the potential to act as a non-viral and effective method to current gene therapy...
October 31, 2018: Human Gene Therapy
Hanen Khabou, Chloé Cordeau, Laure Pacot, Sylvain Fisson, Deniz Dalkara
Today, there are >500 published studies and 40 clinical trials to treat retinal disorders using gene therapy. The great majority of them rely on the use of adeno-associated virus vectors (AAV) for therapeutic gene delivery. Thus far, AAVs have an excellent safety profile in the clinic. Nevertheless, it is known that AAV-mediated gene delivery leads to toxicity at higher input doses in experimental gene therapy. This study reveals the factors that contribute to retinal toxicity after subretinal administration of AAV vectors in wild-type mice...
October 31, 2018: Human Gene Therapy
Yimin Xiao, Yanxia Zhang, Yueqiu Chen, Jingjing Li, Zihan Zhang, Yimin Sun, Han Shen, Zhenao Zhao, Zan Huang, Wencheng Zhang, Weiqian Chen, Zhenya Shen
Follistatin-like 1 (Fstl1) protects cardiomyocytes from a broad spectrum of pathologic injuries including myocardial infarction (MI). It is worthy of note that although cardiac Fstl1 is elevated in post-MI microenvironment, its cardioprotective role is still restricted to a limited extent considering the frequency and severity of adverse cardiac remodeling following MI. We therefore propose that intrinsic Fstl1-suppressing microRNA (miRNA) may exist in the heart and its neutralization may further facilitate post-MI recovery...
October 31, 2018: Human Gene Therapy
Liangfeng Jiang, Zhiming Wu, Xingcheng Meng, Xiufeng Chu, Hongjun Huang, Chaoyang Xu
Long non-coding RNA HOXA-AS2 has been found to be an oncogene in several types of human malignant tumors. However, the role HOXA-AS2 in regulating the occurrence and development of papillary thyroid cancer (PTC) is still unclear. This study focused on investigating the function and mechanism of HOXA-AS2 in PTC progression. Using qRT-PCR analysis, we found that HOXA-AS2 was differentially expressed in PTC tissues and cell lines. The result of Kaplan Meier analysis indicated that the overall survival rate of patients with higher level of HOXA-AS2 was lower than those with relative lower level of HOXA-AS2...
October 30, 2018: Human Gene Therapy
Yi Gong, Anna Berenson, Fiza Laheji, Guangping Gao, Dan Wang, Carrie Ng, Adrienn Volak, Rene Kok, Vasileios Kreouzis, Inge Dijkstra, Stephan Kemp, Casey A Maguire, Florian Eichler
Mutations in the gene encoding the peroxisomal ATP binding cassette transporter (ABCD1) cause elevations in very long chain fatty acids (VLCFA) and the neurodegenerative disease adrenoleukodystrophy (ALD). In most adults, this manifests as the spinal cord axonopathy, adrenomyeloneuropathy (AMN). A challenge in virus-based gene therapy in AMN is how to achieve functional gene correction to the entire spinal cord while minimizing leakage into the systemic circulation, which could contribute to toxicity. In the present study, we used an osmotic pump to deliver adeno-associated virus (AAV) vector into the lumbar CSF space in mice...
October 25, 2018: Human Gene Therapy
K Tyler McCullough, Sanford L Boye, Diego Fajardo, Kaitlyn R Calabro, James J Peterson, Christianne E Strang, Dibyendu Chakraborty, Sebastian Gloskowski, Scott Haskett, Steven Samuelsson, Haiyan Jiang, Clark Douglas Witherspoon, Paul D Gamlin, Morgan L Maeder, Shannon Boye
Mutations in GUCY2D, the gene encoding retinal guanylate cyclase-1 (retGC1), are the leading cause of autosomal dominant cone-rod dystrophy (CORD6). Significant progress towards clinical application of gene replacement therapy for Leber congenital amaurosis (LCA) due to recessive mutations in GUCY2D (LCA1) has been made, but a different approach is needed to treat CORD6 where gain of function mutations cause dysfunction and dystrophy. The CRISPR/Cas9 gene editing system efficiently disrupts genes at desired loci, enabling complete gene knockout or homology directed repair...
October 25, 2018: Human Gene Therapy
Eliza Tsitoura, Dorothea Kazazi, Devrim Öz-Arslan, Elif Arik Sever, Shirin Khalili, Niki Vassilaki, Elina Aslanoglou, Nicolas Dérian, Adrien Six, Osman Ugur Sezerman, David Klatzmann, Penelope Mavromara
Antigen delivery platforms based on engineered viruses or virus like particles (VLPs) are currently developed as vaccines against infectious diseases. As the interaction of vaccines with dendritic cells (DCs) shapes the immunological response, we compared the interaction of a range of virus-based vectors and VLPs with DCs in a murine model of systemic administration and transcriptome analyses of splenic DC. The transcriptome profiles of DCs separated the vaccine vectors in two distinct groups characterised by high and low magnitude of differential gene expression, which strongly correlated with (i) the surface expression of co-stimulatory molecules CD40, CD83 and CD86 on DCs and (ii) antigen-specific T cell responses (Derian, N...
October 23, 2018: Human Gene Therapy
Adrianne Stone, Matthew W Grol, Merry Z C Ruan, Brian Dawson, Yuqing Chen, Ming-Ming Jiang, I-Wen Song, Prathap Jayaram, Racel Cela, Francis Gannon, Brendan H L Lee
Osteoarthritis (OA) is a degenerative disease of synovial joints characterized by progressive loss of articular cartilage, subchondral bone remodeling, and intra-articular inflammation with synovitis that results in chronic pain and motor impairment. Despite the economic and health impacts, current medical therapies are targeted at symptomatic relief of OA and fail to alter its progression. Given the complexity of OA pathogenesis, we hypothesized that a combinatorial gene therapy approach, designed to inhibit inflammation with interleukin-1 receptor antagonist (IL-1Ra) while promoting chondroprotection using lubricin (PRG4), would improve preservation of the joint compared to monotherapy alone...
October 17, 2018: Human Gene Therapy
Ekati Drakopoulou, Maria Georgomanoli, Carsten Werner Lederer, Marina Kleanthous, Caroline Costa, Ornellie Bernadin, François-Loic Cosset, Ersi Voskaridou, Els Verhoeyen, Eleni Papanikolaou, Nicholas P Anagnou
We have previously demonstrated that the self-inactivating γ-globin lentiviral vector GGHI can significantly increase HbF in erythroid cells from thalassemia patients and thus improve the disease phenotype in vitro. In the present study, we further improved the GGHI vector by incorporating novel enhancer elements and pseudotyping it also with the baboon endogenous virus envelope glycoprotein BaEVRless, which efficiently and specifically targets human CD34+ cells. We evaluated the hypothesis that the newly constructed vector designated as GGHI-mB-3D, would increase hCD34+ cell tropism and thus the transduction efficiency at low multiplicity of infection, leading to increased transgene expression...
October 16, 2018: Human Gene Therapy
Sichen Du, Huayuan Ou, Renjie Cui, Nan Jiang, Meiqin Zhang, Xiaorong Li, Jing Ma, Jin Zhang, Duan Ma
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA gene. Enzyme replacement treatment is the most effective therapy available for type 1 GD patients, but it is very expensive and does not improve neurologic outcomes in type 2 and 3 GD patients. This study evaluated the effectiveness of an adeno-associated virus 9 (AAV9) vector expressing the Gba gene delivered systemically in GD mouse models. To detect the therapeutic effects of the AAV9-mediated Gba transfer on the systemic symptoms of GD, an inducible whole-body Gba knockout mouse was developed in which tamoxifen effectively induced whole-body Gba gene deletion, and the mice displayed systemic symptoms of GD...
October 16, 2018: Human Gene Therapy
Smriti Agrawal Zaneveld, Aiden Eblimit, Qingnan Liang, Renae Bertrand, Nathaniel Wu, Hehe Liu, Quynh Nguyen, Jacques Zaneveld, Keqing Wang, Yumei Li, Rui Chen
Hereditary retinal dystrophy is clinically defined as a broad group of chronic and progressive disorders that affect visual function by causing photoreceptor degeneration. Previously, we identified mutations in the gene encoding receptor expression-enhancing protein 6 (REEP6), in individuals with autosomal recessive retinitis pigmentosa (RP), the most common form of inherited retinal dystrophy. One individual was molecularly diagnosed with biallelic REEP6 mutations, a missense mutation over a frameshift mutation...
October 16, 2018: Human Gene Therapy
Wei Wei, Jianhui Luo
Cell therapy has emerged as a promising new treatment in medicine, which is expected to be able to cure diseases by repairing, replacing, and regenerating tissues, as well as immune-modulation. However, challenges remain in ensuring consistent quality, clinical efficacy and safety profiles because of the diversity of cell types and clinical indications for cell therapy products (CTPs), as well as different and complex manufacturing process. Therefore, scientific consensus and regulatory measurements are urgently warranted to promote the translation of the latest scientific advances and innovative manufacturing technologies into clinical application...
October 12, 2018: Human Gene Therapy
Ya-Shan Chen, Tse-Hung Huang, Chao-Lin Liu, Hui-Shan Chen, Meng-Hua Lee, Hsin-Wei Chen, Chia-Rui Shen
Interleukin (IL)-17 and the cells that produce it within the tumor microenvironment appear to promote tumor development and are associated with survival in cancer patients. Here we investigated the role of the IL-17/IL-17 receptor A (IL-17RA) axis in regulating melanoma progression and evaluated the therapeutic potential of blocking the IL-17/IL-17RA pathway. First, recombinant mouse IL-17 (γmIL-17) treatment significantly increased proliferation of mouse B16F10 cells and human A375 and A2058 cells. Silencing IL-17RA by small hairpin RNA (shRNA) in B16F10 cells reduced the γmIL-17-elicited cell proliferation, migration, and invasion, and significantly reduced vascular endothelial growth factor and matrix metalloproteinase production...
October 3, 2018: Human Gene Therapy
Silveli Suzuki-Hatano, Madhurima Saha, Skylar A Rizzo, Rachael L Witko, Bennett J Gosiker, Manashwi Ramanathan, Meghan S Soustek, Michael D Jones, Peter B Kang, Barry J Byrne, W Todd Cade, Christina A Pacak
Barth syndrome (BTHS) is a rare mitochondrial disease that affects heart and skeletal muscle and has no curative treatment. It is caused by recessive mutations in the X-linked gene TAZ, which encodes tafazzin. To develop a clinically relevant gene therapy to restore tafazzin function and treat BTHS, three different adeno-associated virus serotype 9 vectors were tested and compared to identify the optimal promoter-cytomegalovirus (CMV), desmin (Des), or a native tafazzin promoter (Taz)-for TAZ expression following intravenous administration of 1 × 1013 vector genomes/kilogram to a mouse model of BTHS as either neonates (1-2 days of age) or adults (3 months of age)...
October 3, 2018: Human Gene Therapy
Tristan McCaughey, David M Budden, Paul G Sanfilippo, George E C Gooden, Li Fan, Eva Fenwick, Gwyneth Rees, Casimir MacGregor, Lei Si, Christine Chen, Helena Hai Liang, Alice Pébay, Timothy Baldwin, Alex W Hewitt
The CRISPR/Cas system could provide an efficient and reliable means of editing the human genome and has the potential to revolutionize modern medicine; however, rapid developments are raising complex ethical issues. There has been significant scientific debate regarding the acceptability of some applications of CRISPR/Cas, with leaders in the field highlighting the need for the lay public's views to shape expert discussion. As such, we sought to determine the factors that influence public opinion on gene editing...
October 3, 2018: Human Gene Therapy
Alexis Stamatikos, Nagadhara Dronadula, Philip Ng, Donna Palmer, Ethan Knight, Bradley K Wacker, Chongren Tang, Francis Kim, David A Dichek
Atherosclerosis, a disease of blood vessels, is driven by cholesterol accumulation and inflammation. Gene therapy that removes cholesterol from blood vessels and decreases inflammation is a promising approach for prevention and treatment of atherosclerosis. In previous work, we reported that helper-dependent adenoviral (HDAd) overexpression of apolipoprotein A-I (apoAI) in endothelial cells (ECs) increases cholesterol efflux in vitro and reduces atherosclerosis in vivo. However, the effect of HDAdApoAI on atherosclerosis is partial...
October 2, 2018: Human Gene Therapy
Elizabeth M Simpson, Andrea J Korecki, Oriol Fornes, Trevor J McGill, Jorge Luis Cueva-Vargas, Jessica Agostinone, Rachelle A Farkas, Jack W Hickmott, Siu Ling Lam, Anthony Mathelier, Lauren M Renner, Jonathan Stoddard, Michelle Zhou, Adriana Di Polo, Martha Neuringer, Wyeth W Wasserman
Retinal gene therapy is leading the neurological gene therapy field, with 32 ongoing clinical trials of recombinant adeno-associated virus (rAAV)-based therapies. Importantly, over 50% of those trials are using restricted promoters from human genes. Promoters that restrict expression have demonstrated increased efficacy and can limit the therapeutic to the target cells thereby reducing unwanted off-target effects. Retinal ganglion cells are a critical target in ocular gene therapy; they are involved in common diseases such as glaucoma, rare diseases such as Leber's hereditary optic neuropathy, and in revolutionary optogenetic treatments...
October 2, 2018: Human Gene Therapy
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