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https://www.readbyqxmd.com/read/29160746/nucleic-acid-therapies-for-cystic-fibrosis
#1
Shruti Sasaki, Shuling Guo
Nucleic acid therapeutics are an established class of drugs that enable specific targeting of a gene of interest. This diverse family of drugs includes antisense oligonucleotides, siRNAs, and mRNA replacement therapies, which can elicit both gene repression and activation, primarily at the RNA level. Recent advances in medicinal chemistry have increased drug potency and enhanced delivery and distribution to a broad array of tissue and cell types. A key advantage of nucleic acid therapeutics is in their application to monogenic diseases...
November 21, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/29160106/display-of-the-albumin-binding-domain-in-the-envelope-improves-lentiviral-vector-bioavailability
#2
Antonio Rodriguez, Guillermo Garaulet, Juan José Lazcano, Hernán Alarcón, Sergio de Frutos, Jorge Luis Martínez-Torrecuadrada
Vesicular stomatitis virus G glycoprotein (VSVg) is extensively used for retroviral and lentiviral vector (LV) pseudotyping. However, VSVg pseudotyped vectors are serum inactivated, blocking the in vivo gene delivery. Several strategies have been employed to prevent complement inactivation, including chemical and genetic envelope modifications. Here we have employed the streptococcal Albumin Binding Domain (ABD) to generate a construct to express ABD as a GPI-anchored protein. LV particles bearing ABD are able to bind bovine and human serum albumin in vitro...
November 21, 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/29160103/integration-site-analysis-in-gene-therapy-patients-expectations-and-reality
#3
Luca Biasco
Integration site analysis is one of the major tools for addressing the safety of gene therapy clinical protocols based on the use of integrating vectors. Over the past years, the study of viral insertions in gene therapy treated patients has allowed identifying insertional mutagenesis events, evaluating the safety of new viral vector platforms and tracking the in vivo clonal dynamics of genetically engineered cell products. While gene therapy is progressively expanding its impact on a broader area of clinical applications, increasingly more accessible, faster and more reliable safety readouts are required from integration site analysis...
November 21, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29160033/discordant-fetal-phenotype-of-hypophosphatasia-in-two-siblings
#4
Satoru Ikenoue, Kei Miyakoshi, Tomohiro Ishii, Yu Sato, Toshimitsu Otani, Yohei Akiba, Yoshifumi Kasuga, Daigo Ochiai, Tadashi Matsumoto, Yosuke Ichihashi, Yohei Matsuzaki, Kanako Tachikawa, Toshimi Michigami, Gen Nishimura, Kazushige Ikeda, Tomonobu Hasegawa, Mamoru Tanaka
Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton...
November 21, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29159826/pharmacological-and-molecular-approaches-for-the-treatment-of-%C3%AE-hemoglobin-disorders
#5
REVIEW
Neelam Lohani, Nupur Bhargava, Anjana Munshi, Sivaprakash Ramalingam
β-hemoglobin disorders, such as β-thalassemia and sickle cell anemia are among the most prevalent inherited genetic disorders worldwide. These disorders are caused by mutations in the gene encoding hemoglobin-β (HBB), a vital protein found in red blood cells (RBCs) that carries oxygen from lungs to all parts of the human body. As a consequence, there has been an enduring interest in this field in formulating therapeutic strategies for the treatment of these diseases. Currently, there is no cure available for hemoglobin disorders, although, some patients have been treated with bone marrow transplantation, whose scope is limited because of the difficulty in finding a histocompatible donor and also due to transplant-associated clinical complications that can arise during the treatment...
November 20, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29159775/toxic-effects-of-phytol-and-retinol-on-human-glioblastoma-cells-are-associated-with-modulation-of-cholesterol-and-fatty-acid-biosynthetic-pathways
#6
Gustavo Facchini, Raffaela Silvestre Ignarro, Erika Rodrigues-Silva, André Schwambach Vieira, Iscia Lopes-Cendes, Roger Frigério Castilho, Fabio Rogerio
Glioblastoma (GBM) is the most common primary brain tumor. Genetic mutations may reprogram the metabolism of neoplastic cells. Particularly, alterations in cholesterol and fatty acid biosynthetic pathways may favor biomass synthesis and resistance to therapy. Therefore, compounds that interfere with those pathways, such as phytol (PHY) and retinol (RET), may be appropriate for cytotoxic approaches. We tested the effect of PHY or RET on the viability of human GBM cell lines (U87MG, A172 and T98G). Since the compounds showed a dose-dependent cytotoxic effect, additional analyses were performed with IC50 values...
November 20, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29159718/genetics-and-epigenetics-in-the-pathogenesis-of-primary-biliary-cholangitis
#7
REVIEW
Satoru Joshita, Takeji Umemura, Eiji Tanaka, Masao Ota
Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. Fortunately, ursodeoxycholic acid therapy has improved the outcome of the vast majority of PBC cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades...
November 20, 2017: Clinical Journal of Gastroenterology
https://www.readbyqxmd.com/read/29159549/-diagnostics-of-wilson-s-disease
#8
REVIEW
W Hermann, D Huster
Wilson's disease is a rare genetic but treatable metabolic disorder which has a favorable prognosis when diagnosed early and treated adequately. Therefore, knowledge of this rare clinical condition and a reliable diagnosis are indispensable. The diagnostic work-up is initiated in cases of unexplained acute or chronic liver disease and/or an extrapyramidal motor disturbance occurring mostly between the 5th and 45th years of life. Manifestations with initial symptoms have occasionally been observed at an age younger than 1 year and later than 70 years...
November 20, 2017: Der Nervenarzt
https://www.readbyqxmd.com/read/29159201/interactions-between-retroviruses-and-the-host-cell-genome
#9
REVIEW
Valentina Poletti, Fulvio Mavilio
Replication-defective retroviral vectors have been used for more than 25 years as a tool for efficient and stable insertion of therapeutic transgenes in human cells. Patients suffering from severe genetic diseases have been successfully treated by transplantation of autologous hematopoietic stem-progenitor cells (HSPCs) transduced with retroviral vectors, and the first of this class of therapies, Strimvelis, has recently received market authorization in Europe. Some clinical trials, however, resulted in severe adverse events caused by vector-induced proto-oncogene activation, which showed that retroviral vectors may retain a genotoxic potential associated to proviral integration in the human genome...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29159192/sex-differences-in-lrrk2-g2019s-and-idiopathic-parkinson-s-disease
#10
Marta San Luciano, Cuiling Wang, Roberto A Ortega, Nir Giladi, Karen Marder, Susan Bressman, Rachel Saunders-Pullman
Objective: To evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD). Methods: 530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women...
November 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29158685/invasive-aspergillus-terreus-morphological-transitions-and-immunoadaptations-mediating-antifungal-resistance
#11
Louis Bengyella, Elsie Laban Yekwa, Muhammad Nasir Subhani, Ernest Tambo, Kiran Nawaz, Bakoena Ashton Hetsa, Sehrish Iftikhar, Sayanika Devi Waikhom, Pranab Roy
Background and aims: Aspergillus terreus Thom is a pathogen of public health and agricultural importance for its seamless abilities to expand its ecological niche. The aim of this study was holistically to investigate A. terreus morphological and immunoadaptations and their implication in antifungal resistance and proliferation during infection. Materials and methods: In-depth unstructured mining of relevant peer-reviewed literature was performed for A. terreus morphological, immune, resistance, and genetic diversity based on the sequenced calmodulin-like gene...
2017: Infection and Drug Resistance
https://www.readbyqxmd.com/read/29158558/protein-arginine-methyltransferase-5-prmt5-has-prognostic-relevance-and-is-a-druggable-target-in-multiple-myeloma
#12
A Gullà, T Hideshima, G Bianchi, M Fulciniti, M K Samur, J Qi, Y-T Tai, T Harada, E Morelli, N Amodio, R Carrasco, P Tagliaferri, N C Munshi, P Tassone, K C Anderson
Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased PFS and OS...
November 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29158367/safety-pharmacokinetics-pharmacodynamics-and-antitumor-activity-of-necuparanib-combined-with-nab-paclitaxel-and-gemcitabine-in-patients-with-metastatic-pancreatic-cancer-phase-i-results
#13
Eileen M O'Reilly, James Roach, Paul Miller, Kenneth H Yu, Catherine Tjan, Molly Rosano, Silva Krause, William Avery, Julie Wolf, Keith Flaherty, Darrell Nix, David P Ryan
LESSONS LEARNED: Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing.Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low-level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling...
November 20, 2017: Oncologist
https://www.readbyqxmd.com/read/29158268/car-t-cell-therapies-in-glioblastoma-a-first-look
#14
Denis Migliorini, Pierre-Yves Dietrich, Roger Stupp, Gerald P Linette, Avery D Posey, Carl H June
Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, immunosuppressive microenvironment and partially permissive anatomical blood brain barrier (BBB)...
November 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29158016/genetic-hemochromatosis-pathophysiology-diagnostic-and-therapeutic-management
#15
Pierre Brissot, Thibault Cavey, Martine Ropert, Pascal Guggenbuhl, Olivier Loréal
The term hemochromatosis (HC) corresponds to several diseases characterized by systemic iron overload of genetic origin and affecting both the quality of life and life expectancy. Major improvement in the knowledge of iron metabolism permits to divide these diseases into two main pathophysiological categories. For most HC forms (types 1, 2, 3 and 4B HC) iron overload is related to cellular hepcidin deprivation which causes an increase of plasma iron concentration and the appearance of plasma non-transferrin bound iron...
November 17, 2017: La Presse Médicale
https://www.readbyqxmd.com/read/29157988/de-novo-thrombotic-microangiopathy-after-kidney-transplantation
#16
REVIEW
Neetika Garg, Helmut G Rennke, Martha Pavlakis, Kambiz Zandi-Nejad
Thrombotic microangiopathy (TMA) is a serious complication of transplantation that adversely affects kidney transplant recipient and allograft survival. Post-transplant TMA is usually classified into two categories: 1) recurrent TMA and 2) de novo TMA. Atypical hemolytic uremic syndrome (aHUS) resulting from dysregulation and over-activation of the alternate complement pathway is a rare disease but the most common diagnosis associated with recurrence in the allografts. De novo TMA, on the other hand, represents an overwhelming majority of the cases of post-transplant TMA and is a substantially more heterogeneous entity than recurrent aHUS...
November 4, 2017: Transplantation Reviews
https://www.readbyqxmd.com/read/29157973/when-the-good-go-bad-mutant-npm1-in-acute-myeloid-leukemia
#17
REVIEW
Preethi Kunchala, Sudhakiranmayi Kuravi, Roy Jensen, Joseph McGuirk, Ramesh Balusu
Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein that performs diverse biological functions including molecular chaperoning, ribosome biogenesis, DNA repair, and genome stability. Acute myeloid leukemia (AML) is a heterogeneous disease, more than half of the AML cases exhibit normal karyotype (NK). Approximately 50-60 percent of patients with NK-AML carry NPM1 mutations which are characterized by cytoplasmic dislocation of the NPM1 protein. In AML, mutant NPM1 (NPM1c+) acts in a dominant negative fashion and also blocks the differentiation of myeloid cells through gain-of-function for the AML phenotype...
November 4, 2017: Blood Reviews
https://www.readbyqxmd.com/read/29157486/nouveaut%C3%A3-s-dans-l%C3%A2-hyperplasie-cong%C3%A3-nitale-des-surr%C3%A3-nales-new-insights-in-congenital-adrenal-hyperplasia
#18
L Dumeige, C Bouvattier, M Lombès
Congenital adrenal hyperplasia is an autosomal recessive disease due to functional abnormalities of adrenal steroid enzymes. The most common form of the disease is due to a 21-hydroxylase deficiency. The classical forms (most severe) are characterized by a deficiency in cortisol and sometimes in aldosterone, which may compromise the vital prognosis of neonates, and by an increase in androgen synthesis, leading to the virilization of girls' external genitalia at birth, followed by clinical signs of hyperandrogenism during childhood and adolescence...
October 2017: Annales D'endocrinologie
https://www.readbyqxmd.com/read/29157484/actualisation-sur-l%C3%A2-hypoparathyro%C3%A3-die-un-peu-de-th%C3%A3-orie-beaucoup-de-pratique-update-on-hypoparathyroidism-a-little-theory-a-lot-of-practice
#19
S Espiard, M-C Vantyghem, R Desailloud
Parathormone (PTH), produced by parathyroid glands, is the main regulator of calcium homeostasis. Hypoparathyroidism (hypoPT), due to decrease of PTH production, is a rare disease. Symptoms are multiple, altering function of several organs and leading to a decrease of quality of life. Acquired etiologies, including thyroïdectomy, the main cause of hypoPT, can be distinguished from congenital etiologies, including genetic defects. HypoPT, which is classically treated by supplementation by calcium and active vitamin D, can now be treated by recombinant injection in certain indications as a poor control under classical therapy...
October 2017: Annales D'endocrinologie
https://www.readbyqxmd.com/read/29157399/the-dynamics-of-the-gut-microbiome-in-multiple-sclerosis-in-relation-to-disease
#20
REVIEW
Ellen M Mowry, Justin D Glenn
Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease of unknown etiology, although genetic components and environmental triggers are thought to collude to commence pathogenesis. Numerous investigations are now demonstrating the role of the gut microbiota in neuroinflammation and how alterations in its content may be associated with MS disease. This article explores the studies using MS rodent models to determine the roles of gut bacteria in neuroinflammatory disease, evaluate the evidence linking gut bacterial dysbiosis and MS, and give insight into potential MS therapies targeting the gut microbiota currently under investigation...
February 2018: Neurologic Clinics
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