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Gene Therapy

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https://www.readbyqxmd.com/read/28644430/the-clinical-landscape-for-sma-in-a-new-therapeutic-era
#1
REVIEW
K Talbot, E F Tizzano
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy...
June 23, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28639617/gene-therapy-for-spinomuscular-atrophy-a-biomedical-advance-a-missed-opportunity-for-more-equitable-drug-pricing
#2
T Friedmann
An experimental approach for gene therapy of spinomuscular atrophy has been reported to prevent development of the neuromuscular features of this lethal and previously untreatable disorder. The approach involves treatment of patients suffering from SMN1-associated infantile form of the disease with a splice-switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the nearly identical SMN2 gene to allow the generation of functional SMN protein, thereby mitigating the development of the disease...
June 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28622288/optimization-of-design-and-production-strategies-for-novel-adeno-associated-viral-display-peptide-libraries
#3
J Körbelin, A Hunger, M Alawi, T Sieber, M Binder, M Trepel
Libraries displaying random peptides on the surface of adeno-associated virus (AAV) are powerful tools for the generation of target-specific gene therapy vectors. However, for unknown reasons the success rate of AAV library screenings is variable and the influence of the production procedure has not been thoroughly evaluated. During library screenings, the capsid variants with the most favorable tropism are enriched over several selection rounds on a target of choice and identified by subsequent sequencing of the encapsidated viral genomes encoding the library capsids with targeting peptide insertions...
June 16, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28617420/mirna-mediated-post-transcriptional-silencing-of-transgenes-leads-to-increased-adeno-associated-viral-vector-yield-and-targeting-specificity
#4
C A Reid, S L Boye, W W Hauswirth, D M Lipinski
The production of high titer recombinant adeno-associated virus (rAAV) vector is essential for treatment of genetic diseases affecting the retina and choroid, where anatomical constraints may limit injectable volumes. Problematically, cytotoxicity arising from over-expression of the transgene during vector production frequently leads to a reduction in vector yield. Herein, we evaluate the use of micro-RNA (miRNA) mediated silencing to limit over-expression of cytotoxic transgenes during packaging as a method of increasing vector yield...
June 15, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28561814/the-sma-trust-the-role-of-a-disease-focused-research-charity-in-developing-treatments-for-sma
#5
REVIEW
V Christie-Brown, J Mitchell, K Talbot
SMA is a rare hereditary neuromuscular disease that causes weakness and muscle wasting as a result of the loss of spinal motor neurons. In its most severe form, SMA is the commonest genetic cause of death in infants, and children with less severe forms of SMA face the prospect of lifelong disability from progressive muscle wasting, loss of mobility and limb weakness. The initial discovery of the defective gene has been followed by major advances in our understanding of the genetic, cellular and molecular basis of SMA, providing the foundation for a range of approaches to treatment including gene therapy, antisense oligonucleotide treatments and more traditional drug-based approaches to slow or halt disease progression...
May 31, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28561813/therapeutic-approaches-for-spinal-muscular-atrophy-sma
#6
REVIEW
M Scoto, R S Finkel, E Mercuri, F Muntoni
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by progressive muscle wasting and loss of muscle function due to severe motor neuron dysfunction, secondary to mutations in the survival motor neuron 1 (SMN1) gene. A second neighboring centromeric gene, SMN2, is intact in all patients but contains a C-to-T variation in exon 7 that affects a splice enhancer and determines exclusion of exon 7 in the majority of its transcript, leading to an unstable protein that cannot substitute for mutant SMN1...
May 31, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28556834/developmental-regulation-of-smn-expression-pathophysiological-implications-and-perspectives-for-therapy-development-in-spinal-muscular-atrophy
#7
REVIEW
S Jablonka, M Sendtner
Spinal muscular atrophy (SMA), the predominant form of motoneuron diease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction...
May 30, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28553929/silencing-of-hiv-1-by-agoshrna-molecules
#8
E Herrera-Carrillo, A Harwig, B Berkhout
RNA interference (RNAi) is a sequence-specific gene silencing mechanism that is triggered by the expression of a short hairpin RNA (shRNA). shRNA molecules enter the RNAi pathway at the Dicer processing step. Recent studies indicated that the cellular microRNA (miRNA) miR-451 is not recognized by Dicer, but that is processed instead by the Argonaute 2 (Ago2) protein. Subsequently, Dicer-independent shRNAs were described that rely on Ago2 for processing as well as the subsequent silencing step. We called these AgoshRNA molecules because they depend on Ago2 both for maturation and activation...
May 29, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28553928/synergistic-effects-of-deleting-multiple-nonessential-elements-in-nonreplicative-hsv-1-bac-genomic-vectors-play-a-critical-role-in-their-viability
#9
M Ventosa, A Ortiz-Temprano, H Khalique, F Lim
Nonreplicative Herpes simplex virus type-1 (HSV-1) genomic vectors have already entered into clinical trials for neurological gene therapy thanks to their scalable growth in permissive cells. However, the small transgene capacity of this type of HSV-1 vectors currently used in the clinic represents an important limiting factor as a gene delivery system. To develop high capacity nonreplicative genomic HSV-1 vectors, in this study we have characterized a series of multiply deleted mutants which we have constructed in bacterial artificial chromosomes (BACs), removing up to 24 kb of unstable or dispensable genomic sequences to allow insertion of transgenes up to this size...
May 29, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28530652/cd34-cells-from-dental-pulp-stem-cells-with-a-zfn-mediated-and-homology-driven-repair-mediated-locus-specific-knock-in-of-an-artificial-%C3%AE-globin-gene
#10
S Chattong, O Ruangwattanasuk, W Yindeedej, A Setpakdee, K Manotham
In humans, mutations in the β-globin gene (HBB) have two important clinical manifestations: β-thalassemia and sickle cell disease. The progress in genome editing and stem cell research may be relevant to the treatment of β-globin-related diseases. In this work, we employed zinc-finger nuclease (ZFN)-mediated gene integration of synthetic β-globin cDNA into HBB loci, thus correcting almost all β-globin mutations. The integration was achieved in both HEK 293 cells and isolated dental pulp stem cell (DPSCs)...
May 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28504658/cure-sma-and-our-patient-community-celebrate-the-first-approved-drug-for-sma
#11
REVIEW
J Glascock, M Lenz, K Hobby, J Jarecki
Cure SMA is dedicated to the treatment and cure of spinal muscular atrophy (SMA), the number one genetic cause of death for infants. We fund groundbreaking research and provide families the support they need for today. Today, we have more than 115 000 members and supporters, with 35 volunteer chapters throughout the United States. In the last year, Cure SMA provided direct services to several thousand families. Since 1984, we've led and invested in the research that has made today's breakthroughs possible. With deep connections and expertise in both the patient and research communities, we have been uniquely positioned to direct funds to where they can make the greatest difference as quickly as possible...
May 15, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28504657/engineering-liposomal-nanoparticles-for-targeted-gene-therapy
#12
REVIEW
C Zylberberg, K Gaskill, S Pasley, S Matosevic
Recent mechanistic studies have attempted to deepen our understanding of the process by which liposome-mediated delivery of genetic material occurs. Understanding the interactions between lipid nanoparticles and cells is still largely elusive. Liposome-mediated delivery of genetic material faces systemic obstacles alongside entry into the cell, endosomal escape, lysosomal degradation and nuclear uptake. Rational design approaches for targeted delivery have been developed to reduce off-target effects and enhance transfection...
May 15, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28504656/effect-of-il-1%C3%AE-tnf-%C3%AE-and-igf-1-on-trans-endothelial-passage-of-synthetic-vectors-through-an-in-vitro-vascular-endothelial-barrier-of-striated-muscle
#13
J-P Gomez, C Gonçalves, C Pichon, P Midoux
When administrated in the blood circulation, plasmid DNA (pDNA) complexed with synthetic vectors must pass through a vascular endothelium to transfect underlying tissues. Under inflammatory condition, cytokines effects can modify the endothelium integrity. Here, the trans-endothelial passage (TEP) of DNA complexes including polyplexes, lipoplexes and lipopolyplexes was investigated in the presence of TNF-α-, IL-1β or IGF-1. The experiments were performed by using an in vitro model comprising a monolayer of mouse cardiac endothelial cells (MCEC) seeded on a trans-well insert and the transfection of C2C12 myoblasts cultured on the lower chamber as read out of TEP...
May 15, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28492521/coinjection-of-il2-dna-enhances-e7-specific-antitumor-immunity-elicited-by-intravaginal-therapeutic-hpv-dna-vaccination-with-electroporation
#14
Y Sun, S Peng, A Yang, E Farmer, T-C Wu, Chien-Fu Hung
The generation and use of therapeutic human papillomavirus (HPV) DNA vaccines represent an appealing treatment method against HPV-associated cervical cancer due to their safety and durability. Previously, we created a therapeutic HPV DNA vaccine candidate by linking the HPV16-E7 DNA sequence to calreticulin (CRT/E7), which we showed could generate significant E7-specific cytotoxic T lymphocyte (CTL)-mediated anti-tumor immune responses against HPV16 oncogenes expressing murine tumor model TC-1. Here we assess the therapeutic efficacy of intravaginal immunization with pcDNA3-CRT/E7 followed by electroporation...
May 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28467403/building-the-patient-community
#15
REVIEW
F Raffai, O Timmis
There are many challenges in conducting rare disease research. The conditions are often poorly understood, small patient populations are dispersed around the world, and there are limited funding opportunities. Patient groups can serve as a key partner in overcoming these challenges, as they understand the impact of rare conditions on patients' lives. This gives patient groups valuable scientific insights into the disease. This can be used to create research strategies, address research bottlenecks and directly fund research that appropriately addresses patient needs...
May 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28467402/new-treatments-for-serious-conditions-ethical-implications
#16
REVIEW
N M P King, C E Bishop
Approval of Spinraza (nusinersen) for treatment of spinal muscular atrophy prompts consideration of a number of ethical issues that arise whenever a new treatment is proposed for a serious condition, especially one that is rare and can devastatingly affect children. Patients, families, clinicians, researchers, institutions and policymakers all must take account of the ways that newly available treatments affect informed and shared decision-making about therapeutic and research options. The issues to consider include: addressing what is still uncertain and unknown; the possibility that potential benefits will be exaggerated and potential harms underemphasized in the media, by advocacy organizations, and in consent forms and processes; the high cost of many novel drugs and biologics; the effects of including conditions of variable phenotype in state-mandated newborn screening panels; and how new treatments can change the standard of care, altering what is and is not known about a disorder and posing challenges for decision-making at both individual and policy levels...
May 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28485723/developing-gene-and-cell-therapies-for-rare-diseases-an-opportunity-for-synergy-between-academia-and-industry
#17
REVIEW
F Mavilio
For the last twenty years, academic research has been the major, and often only, driving force behind the spectacular development of gene transfer technology for the therapy of rare genetic diseases. Investors and industry became eventually interested in gene and cell therapy, due to the success of a series of pioneering clinical trials that proved efficacy and safety of last-generation technology, and to favorable orphan drug legislation in both Europe and the United States. Developing this forms of therapy is however complex and requires skills and knowledge not necessary available to the industry, which is better placed to develop processes and products and put them on the market...
May 9, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28485722/how-the-discovery-of-iss-n1-led-to-the-first-medical-therapy-for-spinal-muscular-atrophy
#18
REVIEW
N N Singh, M D Howell, E J Androphy, R N Singh
Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School...
May 9, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28485721/sost-silencing-promotes-proliferation-and-invasion-and-reduces-apoptosis-of-retinoblastoma-cells-by-activating-wnt-%C3%AE-catenin-signaling-pathway
#19
T Wu, L-N Wang, D-R Tang, F-Y Sun
This study aimed to investigate the effects of SOST and the Wnt/β-catenin signaling pathway on the proliferation, migration, invasion, and apoptosis of human retinoblastoma cells. Fifty-five retinoblastoma and 21 normal retinal tissue samples were collected as the case group and control group, respectively. HXO-RB44 and SO-RB50 cells were selected and assigned into blank, negative control (NC), siRNA1, siRNA2, siRNA3, IWR-1-endo 1, IWR-1-endo 2, and IWR-1-endo 3 groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to detect the expression of SOST, Wnt1, and β-catenin in the collected tissue samples...
May 9, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28485720/herpesvirus-micrornas-for-use-in-gene-therapy-immune-evasion-strategies
#20
REVIEW
S T F Bots, R C Hoeben
Transplantation of allogeneic cells as well as of genetically corrected autologous cells are potent approaches to restore cellular functions in patients suffering from genetic diseases. The recipient's immune responses against non-self-antigens may compromise the survival of the grafted cells. Recipients of the graft may therefore require life-long treatment with immunosuppressive drugs. An alternative approach to reduce graft rejection could involve the use of immune-evasion molecules. Expression of such molecules in cells of the graft may subvert recognition by the host's immune system...
May 9, 2017: Gene Therapy
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