Gene therapy for ADA ‐SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products
Gene and cell therapy research recently reached a fundamental milestone toward the goal to deliver new medicines for orphan diseases. In 2016, the European Commission granted market approval to GlaxoSmithKline (GSK) for ex vivo hematopoietic stem cell (HSC) gene therapy for the treatment of adenosine deaminase (ADA)‐deficient severe combined immunodeficiency (SCID), a very rare congenital disorder of the immune system. The new medicine, named Strimvelis™, is an advanced therapy medicinal product (ATMP) (Salmikangas et al, ) originally developed by the San Raffaele Telethon Institute for Gene Therapy (SR‐Tiget), a ...
Source: EMBO Molecular Medicine - April 10, 2017 Category: Molecular Biology Authors: Alessandro Aiuti, Maria Grazia Roncarolo, Luigi Naldini Tags: Commentary Source Type: research
A clinical and mechanistic study of topical borneol ‐induced analgesia
We examined the analgesic efficacy of topical borneol in a randomized, double‐blind, placebo‐controlled clinical study involving 122 patients with postoperative pain. Topical application of borneol led to significantly greater pain relief than placebo did. Using mouse models of pain, we identified the TRPM8 channel as a molecular target of borneol and showed that topical borneol‐induced analgesia was almost exclusively mediated by TRPM8, and involved a downstream glutamatergic mechanism in the spinal cord. Investigation of the actions of topical borneol and menthol revealed mechanistic differences between borneol‐ ...
Source: EMBO Molecular Medicine - April 10, 2017 Category: Molecular Biology Authors: Shu Wang, Dan Zhang, Jinsheng Hu, Qi Jia, Wei Xu, Deyuan Su, Hualing Song, Zhichun Xu, Jianmin Cui, Ming Zhou, Jian Yang, Jianru Xiao Tags: Research Article Source Type: research
Ferrochelatase is a therapeutic target for ocular neovascularization
Abstract
Ocular neovascularization underlies major blinding eye diseases such as “wet” age‐related macular degeneration (AMD). Despite the successes of treatments targeting the vascular endothelial growth factor (VEGF) pathway, resistant and refractory patient populations necessitate discovery of new therapeutic targets. Using a forward chemical genetic approach, we identified the heme synthesis enzyme ferrochelatase (FECH) as necessary for angiogenesis in vitro and in vivo. FECH is overexpressed in wet AMD eyes and murine choroidal neovascularization; siRNA knockdown of Fech or partial loss of enzymatic function i...
Source: EMBO Molecular Medicine - April 4, 2017 Category: Molecular Biology Authors: Halesha D Basavarajappa, Rania S Sulaiman, Xiaoping Qi, Trupti Shetty, Sardar Sheik Pran Babu, Kamakshi L Sishtla, Bit Lee, Judith Quigley, Sameerah Alkhairy, Christian M Briggs, Kamna Gupta, Buyun Tang, Mehdi Shadmand, Maria B Grant, Michael E Boulton, S Tags: Research Article Source Type: research
Administration of RANKL boosts thymic regeneration upon bone marrow transplantation
This study thus indicates that RANKL may be clinically useful to improve T‐cell function recovery after BMT by controlling multiple facets of thymic regeneration.
Ex vivo RANKL administration boosts thymic epithelial cell regeneration and ameliorates T‐cell reconstitution by enhancing thymus homing upon bone marrow transplant (BMT). These effects are beneficial to both young and aged individuals and mediated by LTα expression in lymphoid tissue inducer (LTi) cells. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - April 1, 2017 Category: Molecular Biology Authors: Noella Lopes, Hortense Vachon, Julien Marie, Magali Irla Tags: Research Article Source Type: research
VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis
Abstract
Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF‐A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin–Tie2 system in the thyroid gland. Our genetic depletion experiments revealed that VEGFR2, but not VEGF...
Source: EMBO Molecular Medicine - April 1, 2017 Category: Molecular Biology Authors: Jeon Yeob Jang, Sung Yong Choi, Intae Park, Do Young Park, Kibaek Choe, Pilhan Kim, Young Keum Kim, Byung ‐Joo Lee, Masanori Hirashima, Yoshiaki Kubota, Jeong‐Won Park, Sheue‐Yann Cheng, Andras Nagy, Young Joo Park, Kari Alitalo, Minho Shong, Gou Yo Tags: Research Article Source Type: research
Poly ‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD
Abstract
The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non‐conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain‐of‐function mechanism. Here, we established a poly‐GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly‐GP levels were already detectable in asymptomatic C9orf72 mutation carriers compare...
Source: EMBO Molecular Medicine - April 1, 2017 Category: Molecular Biology Authors: Carina Lehmer, Patrick Oeckl, Jochen H Weishaupt, Alexander E Volk, Janine Diehl ‐Schmid, Matthias L Schroeter, Martin Lauer, Johannes Kornhuber, Johannes Levin, Klaus Fassbender, Bernhard Landwehrmeyer, , Martin H Schludi, Thomas Arzberger, Elisabeth K Tags: Report Source Type: research
Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice
Abstract
PIKfyve is an evolutionarily conserved lipid kinase that regulates pleiotropic cellular functions. Here, we identify PIKfyve as a key regulator of cardiometabolic status and mitochondrial integrity in chronic diet‐induced obesity. In vitro, we show that PIKfyve is critical for the control of mitochondrial fragmentation and hypertrophic and apoptotic responses to stress. We also provide evidence that inactivation of PIKfyve by the selective inhibitor STA suppresses excessive mitochondrial ROS production and apoptosis through a SIRT3‐dependent pathway in cardiomyoblasts. In addition, we report that chronic STA t...
Source: EMBO Molecular Medicine - April 1, 2017 Category: Molecular Biology Authors: Helene Tronchere, Mathieu Cinato, Andrei Timotin, Laurie Guitou, Camille Villedieu, Helene Thibault, Delphine Baetz, Bernard Payrastre, Philippe Valet, Angelo Parini, Oksana Kunduzova, Frederic Boal Tags: Research Article Source Type: research
RIG ‐I antiviral signaling drives interleukin‐23 production and psoriasis‐like skin disease
Abstract
Retinoic acid inducible‐gene I (RIG‐I) functions as one of the major sensors of RNA viruses. DDX58, which encodes the RIG‐I protein, has been newly identified as a susceptibility gene in psoriasis. Here, we show that the activation of RIG‐I by 5′ppp‐dsRNA, its synthetic ligand, directly causes the production of IL‐23 and triggers psoriasis‐like skin disease in mice. Repeated injections of IL‐23 to the ears failed to induce IL‐23 production and a full psoriasis‐like skin phenotype, in either germ‐free or RIG‐I‐deficient mice. RIG‐I is also critical for a full development of skin inflam...
Source: EMBO Molecular Medicine - April 1, 2017 Category: Molecular Biology Authors: Huiyuan Zhu, Fangzhou Lou, Qianqian Yin, Yuanyuan Gao, Yang Sun, Jing Bai, Zhenyao Xu, Zhaoyuan Liu, Wei Cai, Fang Ke, Lingyun Zhang, Hong Zhou, Hong Wang, Gang Wang, Xiang Chen, Hongxin Zhang, Zhugang Wang, Florent Ginhoux, Chuanjian Lu, Bing Su, Honglin Tags: Research Article Source Type: research
Hepatic stellate cells limit hepatocellular carcinoma progression through the orphan receptor endosialin
Abstract
Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. A major contributor to HCC progression is the cross talk between tumor cells and the surrounding stroma including activated hepatic stellate cells (HSC). Activation of HSC during liver damage leads to upregulation of the orphan receptor endosialin (CD248), which contributes to regulating the balance of liver regeneration and fibrosis. Based on the established role of endosialin in regulating HSC/hepatocyte cross talk, we hypothesized that HSC‐expressed endosialin might similarly affect cell proliferation during hepatocarcino...
Source: EMBO Molecular Medicine - April 1, 2017 Category: Molecular Biology Authors: Carolin Mogler, Courtney K önig, Matthias Wieland, Anja Runge, Eva Besemfelder, Dorde Komljenovic, Thomas Longerich, Peter Schirmacher, Hellmut G Augustin Tags: Report Source Type: research
Seeding and transgenic overexpression of alpha ‐synuclein triggers dendritic spine pathology in the neocortex
Abstract
Although misfolded and aggregated α‐synuclein (α‐syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how α‐synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long‐term in vivo imaging of apical dendrites was performed in mice overexpressing wild‐type human α‐synuclein. Additionally, intracranial injection of preformed α‐synuclein fibrils was performed to induce cortical α‐syn pathology. We ...
Source: EMBO Molecular Medicine - March 28, 2017 Category: Molecular Biology Authors: Sonja Blumenstock, Eva F Rodrigues, Finn Peters, Lidia Blazquez ‐Llorca, Felix Schmidt, Armin Giese, Jochen Herms Tags: Research Article Source Type: research
Culturing human intestinal stem cells for regenerative applications in the treatment of inflammatory bowel disease
Abstract
Both the incidence and prevalence of inflammatory bowel disease (IBD) is increasing globally; in the industrialized world up to 0.5% of the population are affected and around 4.2 million individuals suffer from IBD in Europe and North America combined. Successful engraftment in experimental colitis models suggests that intestinal stem cell transplantation could constitute a novel treatment strategy to re‐establish mucosal barrier function in patients with severe disease. Intestinal stem cells can be grown in vitro in organoid structures, though only a fraction of the cells contained are stem cells with regener...
Source: EMBO Molecular Medicine - March 9, 2017 Category: Molecular Biology Authors: Fredrik EO Holmberg, Jakob B Seidelin, Xiaolei Yin, Benjamin E Mead, Zhixiang Tong, Yuan Li, Jeffrey M Karp, Ole H Nielsen Tags: Review Source Type: research
Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations
Abstract
Heterozygous inactivating mutations in ribosomal protein genes (RPGs) are associated with hematopoietic and developmental abnormalities, activation of p53, and altered risk of cancer in humans and model organisms. Here we performed a large‐scale analysis of cancer genome data to examine the frequency and selective pressure of RPG lesions across human cancers. We found that hemizygous RPG deletions are common, occurring in about 43% of 10,744 cancer specimens and cell lines. Consistent with p53‐dependent negative selection, such lesions are underrepresented in TP53‐intact tumors (P ≪ 10−10), and shRNA...
Source: EMBO Molecular Medicine - March 5, 2017 Category: Molecular Biology Authors: Ram Ajore, David Raiser, Marie McConkey, Magnus J öud, Bernd Boidol, Brenton Mar, Gordon Saksena, David M Weinstock, Scott Armstrong, Steven R Ellis, Benjamin L Ebert, Björn Nilsson Tags: Research Article Source Type: research
Transcriptional response to hepatitis C virus infection and interferon ‐alpha treatment in the human liver
Abstract
Hepatitis C virus (HCV) is widely used to investigate host–virus interactions. Cellular responses to HCV infection have been extensively studied in vitro. However, in human liver, interferon (IFN)‐stimulated gene expression can mask direct transcriptional responses to infection. To better characterize the direct effects of HCV infection in vivo, we analyze the transcriptomes of HCV‐infected patients lacking an activated endogenous IFN system. We show that expression changes observed in these patients predominantly reflect immune cell infiltrates rather than cell‐intrinsic pathways. We also investigate th...
Source: EMBO Molecular Medicine - March 1, 2017 Category: Molecular Biology Authors: Tujana Boldanova, Aleksei Suslov, Markus H Heim, Anamaria Necsulea Tags: Research Article Source Type: research
An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti‐amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed pep...
Source: EMBO Molecular Medicine - March 1, 2017 Category: Molecular Biology Authors: Yu ‐Sung Cheng, Zih‐ten Chen, Tai‐Yan Liao, Chen Lin, Howard C‐H Shen, Ya‐Han Wang, Chi‐Wei Chang, Ren‐Shyan Liu, Rita P‐Y Chen, Pang‐hsien Tu Tags: Research Article Source Type: research
Antibodies inhibit transmission and aggregation of C9orf72 poly ‐GA dipeptide repeat proteins
Abstract
Cell‐to‐cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat‐associated non‐ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly‐GA, poly‐GP, and poly‐PA are tran...
Source: EMBO Molecular Medicine - March 1, 2017 Category: Molecular Biology Authors: Qihui Zhou, Carina Lehmer, Meike Michaelsen, Kohji Mori, Dominik Alterauge, Dirk Baumjohann, Martin H Schludi, Johanna Greiling, Daniel Farny, Andrew Flatley, Regina Feederle, Stephanie May, Franziska Schreiber, Thomas Arzberger, Christoph Kuhm, Thomas Kl Tags: Research Article Source Type: research
