A5019388295- CRISPR and Genetic Engineering
- Virus-based gene therapy research
- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Chromosomal and Genetic Variations
- T-cell and Retrovirus Studies
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Animal Disease Management and Epidemiology
- Animal Genetics and Reproduction
- Cancer Genomics and Diagnostics
- Pluripotent Stem Cells Research
- Molecular Biology Techniques and Applications
- Advanced biosensing and bioanalysis techniques
- RNA Research and Splicing
- Bacteriophages and microbial interactions
- Viral gastroenteritis research and epidemiology
- Biochemical and Molecular Research
- Renal Diseases and Glomerulopathies
- Viral Infectious Diseases and Gene Expression in Insects
- Renal Transplantation Outcomes and Treatments
- HIV/AIDS Research and Interventions
- CAR-T cell therapy research
- Genomics and Phylogenetic Studies
- Mitochondrial Function and Pathology
Invitae (United States)
2023
Detection Limit (United States)
2020
Thrive
2020
Genos (Croatia)
2020
University of Pennsylvania
2008-2016
Rutgers, The State University of New Jersey
2014
Université Paris Cité
2011
Assistance Publique – Hôpitaux de Paris
2011
University of California, San Diego
2011
Inserm
2011
A real-time trial of a cancer blood test Cancers diagnosed early are often more responsive to treatment. Blood tests that detect molecular markers have successfully identified individuals already known the disease. Lennon et al. conducted an exploratory study closely reflects way in which such would be used future. They evaluated feasibility and safety incorporating multicancer into routine clinical care 10,000 women with no history cancer. Over 12-month period, detected 26 cancers different...
In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted vector-induced through enhancer-mediated mutagenesis 25% of patients. We assessed the efficacy and safety self-inactivating retrovirus for treatment SCID-X1.
<h3>Importance</h3> Wiskott-Aldrich syndrome is a rare primary immunodeficiency associated with severe microthrombocytopenia. Partially HLA antigen–matched allogeneic hematopoietic stem cell (HSC) transplantation often curative but significant comorbidity. <h3>Objective</h3> To assess the outcomes and safety of autologous HSC gene therapy in syndrome. <h3>Design, Setting, Participants</h3> Gene-corrected HSCs were infused 7 consecutive patients lacking related or unrelated donors (age range,...
Significance DNA transposons that translocate by excision from a donor site and insertion into target are often used for genome engineering insertional mutagenesis transgenesis. The piggyBac element is especially useful because it can excise precisely an site, restoring the to its pretransposon state. Precise particularly when transient transgenesis needed, example, in introduction of transcription factors induced pluripotent stem cell production. We have generate Excision + Integration −...
Abstract Gene transfer using adeno-associated virus (AAV) vectors has great potential for treating human disease. Recently, questions have arisen about the safety of AAV vectors, specifically, whether integration vector DNA in transduced cell genomes promotes tumor formation. This study addresses these with high-dose liver-directed AAV-mediated gene adult mouse as a model (80 AAV-injected mice and 52 controls). After 18 months follow-up, did not show significantly higher rate hepatocellular...
Genome-wide siRNA screens have identified host cell factors important for efficient HIV infection, among which are nuclear pore proteins such as RanBP2/Nup358 and the karyopherin Transportin-3/TNPO3. Analysis of roles these in replication cycle suggested that correct trafficking through may facilitate subsequent integration step. Here we present data coupling between steps by demonstrating depletion Transportin-3 or RanBP2 altered terminal step early replication, selection chromosomal sites...
The selection of chromosomal targets for retroviral integration varies markedly, tracking with the genus retrovirus, suggestive targeting by binding to cellular factors. γ-Retroviral murine leukemia virus (MLV) DNA into host genome is favored at transcription start sites, but underlying mechanism this preference unknown. Here, we have identified bromodomain and extraterminal domain (BET) proteins (Brd2, -3, -4) as cellular-binding partners MLV integrase. We show that purified recombinant...
A hallmark of retroviral replication is integration the viral genome into host cell DNA. This characteristic makes retrovirus-based vectors attractive delivery vehicles for gene therapy. However, adverse events in therapeutic trials, caused by activation proto-oncogenes due to murine leukemia virus (MLV)-derived vector integration, hamper their application. Here, we show that bromodomain and extraterminal (BET) proteins (BRD2, BRD3, BRD4) MLV integrase specifically interact colocalize within...
Lentiviral vector-based gene therapy has been used to target the human immunodeficiency virus (HIV) using an antisense env payload. We have analyzed lentiviral-vector integration sites from three treated individuals. compared ex vivo vector-transduced CD4+ cell products cells recovered at several times after infusion. Integration were 454 pyrosequencing, yielding a total of 7,782 unique product and 237 Integrated vector copies in both data sets found be strongly enriched within active genes...
The goal of this study was to investigate whether the location HIV integration differs in resting versus activated T cells, a feature that could contribute formation latent viral reservoirs via effects on targeting.Primary or CD4 cells were infected with purified X4-tropic presence and absence nucleoside triphosphates genomic locations integrated provirus determined.We sequenced analyzed total 2661 sites using linker-mediated PCR 454 sequencing. Integration site data sets then compared each...
The quinoline-based allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are promising candidates for clinically useful antiviral agents. Studies using these compounds have highlighted the role of IN in both early and late stages virus replication. However, dissecting exact mechanism action ALLINIs has been complicated by multifunctional nature because they inhibit binding with its cofactor LEDGF/p75 promote aberrant multimerization similar potencies vitro. Here we report design small...
HIV infection can be treated effectively with antiretroviral agents, but the persistence of a latent reservoir integrated proviruses prevents eradication from infected individuals. The chromosomal environment has been proposed to influence latency, determinants transcriptional repression have not fully clarified, and it is unclear whether same molecular mechanisms drive latency in different cell culture models. Here we compare data five vitro models based on primary human T cells or line....
Integration of new DNA into cellular genomes mediates replication retroviruses and transposons; integration reactions have also been adapted for use in human gene therapy. Tracking the distributions sites is important to characterize populations transduced cells monitor potential outgrow pathogenic cell clones. Here, we describe a pipeline quantitative analysis site named INSPIIRED (integration paired-end reads). We optimized biochemical steps isolation using Illumina sequencing, including...
At least 8% of the human genome was formed by integration retroviral DNA sequences. Here we analyze forces directing accumulation endogenous retroviruses (HERVs) comparing de novo HERV targeting with distribution fixed elements in genome. All known genomic HERVs are inactive due to mutation, but were able study using a reconstituted consensus HERV-K (designated Con ). We found that integrated preferentially transcription units, gene-rich regions, and near features associated active units...
The Bunyaviridae comprise a large family of RNA viruses with worldwide distribution and includes the pathogenic New World hantavirus, Andes virus (ANDV). Host factors needed for hantavirus entry remain largely enigmatic therapeutics are unavailable. To identify cellular requirements ANDV infection, we performed two parallel genetic screens. Analysis library insertionally mutagenized human haploid cells siRNA genomic screen converged on components (SREBP-2, SCAP, S1P S2P) sterol regulatory...
Analysis of sites newly integrated DNA in cellular genomes is important to several fields, but methods for analyzing and visualizing these datasets are still under development. Here, we describe tools data analysis visualization that take as input integration site from our INSPIIRED pipeline. Paired-end sequencing allows inference the numbers transduced cells well distributions target genomes. We present interactive heatmaps allow comparison genomic features support numerous user-defined...
We report alterations to the murine leukemia virus (MLV) integrase (IN) protein that successfully result in decreasing its integration frequency at transcription start sites and CpG islands, thereby reducing potential for insertional activation. The host bromo extraterminal (BET) proteins Brd2, 3 4 interact with MLV IN primarily through BET ET domain. Using solution NMR, interaction studies, next generation sequencing, we show C-terminal tail peptide region of is important disruption this...
Recently evolved alleles of Apolipoprotein L-1 ( APOL1 ) provide increased protection against African trypanosome parasites while also significantly increasing the risk developing kidney disease in humans. protects infections by forming ion channels within parasite, causing lysis. While correlation to is robust, there little consensus concerning underlying mechanism. We show human cells that renal variants have a population active at plasma membrane, which results an influx both Na + and Ca...