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Human Gene Therapy. Clinical Development

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https://www.readbyqxmd.com/read/29869533/the-current-state-of-advanced-therapy-medicinal-products-in-the-czech-republic
#1
Zuzana Kočí, Tomáš Boráň, Petr Krůpa, Šárka Kubinová
Advanced therapy medicinal products (ATMPs) represent a new generation of biopharmaceuticals that comprise gene therapy medicinal products (GTMPs), somatic cell therapy products (CTMPs), tissue engineered products (TEPs), and combined advanced therapy medicinal products (cATMPs). The joint effort of the academia-industry-regulatory triangle translated scientific progress into ten authorized ATMPs in the European Community. This notion holds promise for the whole field of ATMP therapies that have been increasingly evaluated in a number of clinical studies, also in the Czech Republic (CR)...
July 13, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29869540/gene-therapy-for-osteoarthritis-pharmacokinetics-of-intra-articular-self-complementary-adeno-associated-virus-interleukin-1-receptor-antagonist-delivery-in-an-equine-model
#2
Rachael S Watson Levings, Ted A Broome, Andrew D Smith, Brett L Rice, Eric P Gibbs, David A Myara, E Viktoria Hyddmark, Elham Nasri, Ali Zarezadeh, Padraic P Levings, Yuan Lu, Margaret E White, E Anthony Dacanay, Gregory B Foremny, Christopher H Evans, Alison J Morton, Mathew Winter, Michael J Dark, David M Nickerson, Patrick T Colahan, Steven C Ghivizzani
Toward the treatment of osteoarthritis (OA), the authors have been investigating self-complementary adeno-associated virus (scAAV) for intra-articular delivery of therapeutic gene products. As OA frequently affects weight-bearing joints, pharmacokinetic studies of scAAV gene delivery were performed in the joints of the equine forelimb to identify parameters relevant to clinical translation in humans. Using interleukin-1 receptor antagonist (IL-1Ra) as a secreted therapeutic reporter, scAAV vector plasmids containing codon-optimized cDNA for equine IL-1Ra (eqIL-1Ra) were generated, which produced eqIL-1Ra at levels 30- to 50-fold higher than the native sequence...
June 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29869535/self-complementary-adeno-associated-virus-mediated-interleukin-1-receptor-antagonist-gene-delivery-for-the-treatment-of-osteoarthritis-test-of-efficacy-in-an-equine-model
#3
Rachael S Watson Levings, Andrew D Smith, Ted A Broome, Brett L Rice, Eric P Gibbs, David A Myara, E Viktoria Hyddmark, Elham Nasri, Ali Zarezadeh, Padraic P Levings, Yuan Lu, Margaret E White, E Anthony Dacanay, Gregory B Foremny, Christopher H Evans, Alison J Morton, Mathew Winter, Michael J Dark, David M Nickerson, Patrick T Colahan, Steven C Ghivizzani
The authors are investigating self-complementary adeno-associated virus (scAAV) as a vector for intra-articular gene-delivery of interleukin-1 receptor antagonist (IL-1Ra), and its therapeutic capacity in the treatment of osteoarthritis (OA). To model gene transfer on a scale proportional to the human knee, a frequent site of OA incidence, studies were focused on the joints of the equine forelimb. Using AAV2.5 capsid and equine IL-1Ra as a homologous transgene, a functional ceiling dose of ∼5 × 1012 viral genomes was previously identified, which elevated the steady state levels of eqIL-1Ra in synovial fluids by >40-fold over endogenous production for at least 6 months...
June 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29664709/non-clinical-efficacy-and-safety-studies-on-g1xcgd-a-lentiviral-vector-for-ex-vivo-gene-therapy-of-x-linked-chronic-granulomatous-disease
#4
Christian Brendel, Michael Rothe, Giorgia Santilli, Sabine Charrier, Stefan Stein, Hana Kunkel, Daniela Abriss, Uta Müller-Kuller, Bobby Gaspar, Ute Modlich, Anne Galy, Axel Schambach, Adrian J Thrasher, Manuel Grez
Chronic granulomatous disease (CGD) is a debilitating primary immunodeficiency affecting phagocyte function due to the absence of nicotinamide dinucleotide phosphate (NADPH) oxidase activity. The vast majority of CGD patients in the Western world have mutations within the X-linked CYBB gene encoding for gp91phox (NOX2), the redox center of the NADPH oxidase complex (XCGD). Current treatments of XCGD are not entirely satisfactory, and prior attempts at autologous gene therapy using gammaretrovirus vectors did not provide long-term curative effects...
April 17, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29624465/practical-implications-of-factor-ix-gene-transfer-for-individuals-with-hemophilia-b-a-clinical-perspective
#5
Wolfgang Miesbach, Eileen K Sawyer
Gene therapy for severe hemophilia is on the cusp of entering clinical practice. However, there is limited clinical experience in this area given that gene transfer is a relatively recent technology. Therefore, this clinical perspective article will review the evidence supporting gene therapy in this field, examine ways to open a dialogue about gene therapy with patients in the clinic setting, and present a case of a participant in a recent clinical trial of gene therapy for hemophilia. Clinical trials in hemophilia using adeno-associated virus (AAV) vectors to transfer functional factor IX (FIX) have reported increases in FIX activity to functional levels, reduced bleed frequency, and a lessening or abrogation of the need for costly FIX replacement...
April 6, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29641281/a-multicenter-double-blind-phase-iii-clinical-trial-to-evaluate-the-efficacy-and-safety-of-a-cell-and-gene-therapy-in-knee-osteoarthritis-patients
#6
Myung-Ku Kim, Chul-Won Ha, Yong In, Sung-Do Cho, Eui-Sung Choi, Jeong-Ku Ha, Ju-Hong Lee, Jae-Doo Yoo, Seong-Il Bin, Choong-Hyeok Choi, Hee-Soo Kyung, Myung-Chul Lee
The aim of this study was to test the clinical efficacy of TissueGene-C (TG-C), a cell and gene therapeutic for osteoarthritis consisting of non-transformed and transduced chondrocytes (3:1) retrovirally transduced to overexpress transforming growth factor-β1. A total of 163 Kellgren-Lawrence grade 3 patients with knee osteoarthritis were randomly assigned to receive intra-articular TG-C or placebo. Primary efficacy measures included criteria for subjective assessment by International Knee Documentation Committee (IKDC) and pain severity by Visual Analog Scale (VAS) for 52 weeks...
March 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29641280/gene-therapy-briefs
#7
Alex Philippidis
No abstract text is available yet for this article.
March 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29641279/interview-with-jean-bennett-md-phd
#8
James M Wilson
No abstract text is available yet for this article.
March 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29624457/low-seroprevalence-of-neutralizing-antibodies-targeting-two-clade-f-aav-in-humans
#9
Jeff L Ellsworth, Michael O'Callaghan, Hillard Rubin, Albert Seymour
To assess the therapeutic utility of AAVHSC15 and AAVHSC17, two recently described Clade F adeno-associated viruses (AAVs), the seroprevalence of neutralizing antibodies (NAbs) to these AAVs was assessed in a representative human population and compared to that of AAV9. NAb levels were measured in 100 unique human sera of different races (34, Black, 33 Caucasian, and 33 Hispanic) and sex (49% female, 51% male) collected within the United States. Fifty-six sera were tested in Huh7 cells and 44 sera were tested in 2V6...
March 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29409358/aavrh-10-mediated-apoe2-central-nervous-system-gene-therapy-for-apoe4-associated-alzheimer-s-disease
#10
Jonathan B Rosenberg, Michael G Kaplitt, Bishnu P De, Alvin Chen, Thomas Flagiello, Christiana Salami, Eduard Pey, Lingzhi Zhao, Rodolfo J Ricart Arbona, Sebastien Monette, Jonathan P Dyke, Douglas J Ballon, Stephen M Kaminsky, Dolan Sondhi, Gregory A Petsko, Steven M Paul, Ronald G Crystal
Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage...
March 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29228803/in-vitro-human-placental-studies-to-support-adenovirus-mediated-vegf-d-%C3%AE-n%C3%AE-c-maternal-gene-therapy-for-the-treatment-of-severe-early-onset-fetal-growth-restriction
#11
Michelle Desforges, Alexandra Rogue, Nick Pearson, Carlo Rossi, Elena Olearo, Roy Forster, Mark Lees, Neil J Sebire, Susan L Greenwood, Colin P Sibley, Anna L David, Paul Brownbill
Severe fetal growth restriction (FGR) affects 1 in 500 pregnancies, is untreatable, and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) is one cause. Transduction of uterine arteries in normal and FGR animal models using an adenovirus (Ad) encoding VEGF isoforms increases UBF and improves fetal growth in utero. Understanding potential adverse consequences of this therapy before first-in-woman clinical application is essential. The aims of this study were to determine whether Ad...
March 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29486610/a-multicenter-double-blind-phase-iii-clinical-trial-to-evaluate-the-efficacy-and-safety-of-a-cell-and-gene-therapy-in-knee-osteoarthritis-patients
#12
Myung-Ku Kim, Chul-Won Ha, Yong In, Sung-Do Cho, Eui-Sung Choi, Jeong-Ku Ha, Ju-Hong Lee, Jae-Doo Yoo, Seong-Il Bin, Choong-Hyeok Choi, Hee-Soo Kyung, Myung-Chul Lee
OBJECTIVE: To test the clinical efficacy of TissueGene-C (TG-C), a cell and gene therapeutic for osteoarthritis consisting of non-transformed and transduced chondrocytes (3:1), retrovirally transduced to overexpress TGF-β1. DESIGN: We randomly assigned 163 with knee osteoarthritis to receive intra-articular TG-C or placebo in Kellgren-Lawrence grade 3 patients for clinical trial. Primary efficacy measures included criteria for subjective assessment by International Knee Documentation Committee (IKDC) and pain severity by Visual Analog Scale (VAS) for 52 weeks...
February 27, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29486604/low-seroprevalence-of-neutralizing-antibodies-targeting-two-clade-f-aav-in-humans
#13
Jeff L Ellsworth, Michael OCallaghan, Hillard Rubin, Albert Seymour
To assess the therapeutic utility of AAVHSC15 and AAVHSC17, two recently described Clade F adeno-associated viruses, the seroprevalence of neutralizing antibodies to these AAVs was assessed in a representative human population and compared to that of AAV9. Neutralizing antibody levels were measured in 100 unique human sera of different races (34:33:33, Black:Caucasian:Hispanic) and sex (49% Female, 51% Male) collected within the United States. Fifty-six sera were tested in HuH7 cells and 44 sera were tested in 2V6...
February 27, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29243984/gene-therapy-briefs
#14
Alex Philippidis
No abstract text is available yet for this article.
December 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29243983/2017-is-the-year-we-have-been-waiting-for
#15
James M Wilson
No abstract text is available yet for this article.
December 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29160099/safety-of-intradiaphragmatic-delivery-of-adeno-associated-virus-mediated-alpha-glucosidase-raav1-cmv-hgaa-gene-therapy-in-children-affected-by-pompe-disease
#16
Manuela Corti, Cristina Liberati, Barbara K Smith, Lee Ann Lawson, Ibrahim S Tuna, Thomas J Conlon, Kirsten E Coleman, Saleem Islam, Roland W Herzog, David D Fuller, Shelley W Collins, Barry J Byrne
A first-in-human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory and neural dysfunction in early-onset Pompe disease was conducted. The primary objective of this study was to assess the safety of rAAV1-CMV-hGAA vector delivered to the diaphragm muscle of Pompe disease subjects with ventilatory insufficiency. Safety was assessed by measurement of change in serum chemistries and hematology, urinalysis, and immune response to GAA and AAV, as well as change in level of health. The data demonstrate that the AAV treatment was safe and there were no adverse events related to the study agent...
December 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29131688/carl-june-speaks-of-his-pioneering-efforts-that-led-to-the-first-food-and-drug-administration-approved-gene-therapy-product
#17
James M Wilson
No abstract text is available yet for this article.
December 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29130351/the-gene-therapy-resource-program-a-decade-of-dedication-to-translational-research-by-the-national-heart-lung-and-blood-institute
#18
Terence R Flotte, Eric Daniels, Janet Benson, Jeneé M Bevett-Rose, Kenneth Cornetta, Margaret Diggins, Julie Johnston, Susan Sepelak, Johannes C M van der Loo, James M Wilson, Cheryl L McDonald
Over a 10-year period, the Gene Therapy Resource Program (GTRP) of the National Heart Lung and Blood Institute has provided a set of core services to investigators to facilitate the clinical translation of gene therapy. These services have included a preclinical (research-grade) vector production core; current Good Manufacturing Practice clinical-grade vector cores for recombinant adeno-associated virus and lentivirus vectors; a pharmacology and toxicology core; and a coordinating center to manage program logistics and to provide regulatory and financial support to early-phase clinical trials...
December 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29064732/differential-prevalence-of-antibodies-against-adeno-associated-virus-in-healthy-children-and-patients-with-mucopolysaccharidosis-iii-perspective-for-aav-mediated-gene-therapy
#19
Haiyan Fu, Aaron S Meadows, Ricardo J Pineda, Krista L Kunkler, Kristen V Truxal, Kim L McBride, Kevin M Flanigan, Douglas M McCarty
Recombinant adeno-associated virus (AAV) vectors are promising gene therapy tools. However, pre-existing antibodies (Abs) to many useful AAV serotypes pose a critical challenge for the translation of gene therapies. As part of AAV gene therapy program for treating mucopolysaccharidosis (MPS) III patients, the seroprevalence profiles of AAV1-9 and rh74 were investigated in MPS IIIA/IIIB patients and in healthy children. Using enzyme-linked immunosorbent assay for αAAV-IgG, significantly higher seroprevalence was observed for AAV1 and AAVrh74 in 2- to 7-year-old MPS III patients than in healthy controls...
December 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29020838/safety-and-efficacy-of-aav5-vectors-expressing-human-or-canine-cngb3-in-cngb3-mutant-dogs
#20
Guo-Jie Ye, András M Komáromy, Caroline Zeiss, Roberto Calcedo, Christine D Harman, Kristin L Koehl, Gabriel A Stewart, Simone Iwabe, Vince A Chiodo, William W Hauswirth, Gustavo D Aguirre, Jeffrey D Chulay
Achromatopsia is an inherited retinal disorder of cone photoreceptors characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. Approximately 50% of cases are caused by mutations in the cone photoreceptor-specific cyclic nucleotide gated channel beta subunit (CNGB3) gene. Studies in CNGB3-mutant dogs showed that subretinal injection of an AAV vector expressing human CNGB3, which has 76% amino acid identity with canine CNGB3, driven by a 2.1 kb human red cone opsin promoter (PR2...
October 11, 2017: Human Gene Therapy. Clinical Development
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