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Therapeutic monoclonal antibodies (mAbs) are currently being developed for the treatment of cancer and other diseases. Despite clinical success, widespread application of mAb therapies may be limited by manufacturing capabilities. In this paper, we describe a mAb delivery system that allows continuous production of a full-length antibody at high-concentrations in vivo after gene transfer. The mAb is expressed from a single open reading frame by linking the heavy and light chains with a 2A self-processing peptide derived from the foot-and-mouth disease virus. Using this expression system, we generated a recombinant adeno-associated virus vector encoding the VEGFR2-neutralizing mAb DC101 (rAAV8-DC101). A single dose of rAAV8-DC101 resulted in long-term expression of>1,000µg/ml of DC101 in mice, demonstrating significant anti-tumor efficacy. This report describes the first feasible gene therapy approach for stable delivery of mAbs at therapeutic levels, which may serve as an attractive alternative to direct injection of mAbs. [ABSTRACT FROM AUTHOR]

In this article, the author discusses the reorganization of the research and development (R&D) operations of the pharmaceutical company Merck by setting up the four new innovation hubs in several parts of the world. Topics discussed include sales of internal compounds including external therapies against glaucoma, psychiatric disorders and male infertility, identification of papers of translational interest published in several journals, and limited pool of academic investigators.

The article presents abstracts on biotechnology which include gene therapy on children with X-linked adrenoleukodystrophy, mapping drug promiscuity and DNA-binding specificity of transcription activator-like (TAL) effectors.

Focuses on the construction of influenza A virus from cloned cDNA segments. Difficulties faced in the in vitro alteration of the virus; Key features of the approach applied by researchers to study the pathogen; Cautions of a senior writer on the research paper on genetic engineering of influenza; Potential use of influenza for vaccines and gene therapy.

The article presents data related to biotechnology research papers in the U.S. The US remains the most productive country in terms of biotech-related papers. But numbers of papers from the European Union surpassed the US last year (with Germany and the UK ahead of most EU countries); elsewhere, Korea, China and Japan also publish frequently. Some of the top cited papers, published in different journals, by field are: RNAi--Systematic functional analysis of the Caenorhabditis elegans genome using RNAi; Gene therapy--LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X2 and Nuclear transfer--Derivation of oocytes from mouse embryonic stem cells.

The author comments on the paper presented on a clinical trial, in which an anti-HIV-1 gene is transferred and expressed using a lentiviral vector. The author suggests that the trial demonstrated safe gene delivery to patients' T-cells and that lentiviral vectors can be effectively used in treating various disorders. The author gives details related to lentiviral vectors and concludes that the vectors play a vital role in advancing gene therapy applications in different conditions.

The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the 'gold standard' for modeling human influenza virus infection and transmission. Here we describe the 2.41 Gb draft genome assembly of the domestic ferret, constituting 2.28 Gb of sequence plus gaps. We annotated 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues. We characterized the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time-course data and showed distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis disease progression, we showed that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with cystic fibrosis disease. [ABSTRACT FROM AUTHOR]

The development of high-throughput sequencing technologies has advanced our understanding of cancer. However, characterizing somatic structural variants in tumor genomes is still challenging because current strategies depend on the initial alignment of reads to a reference genome. Here, we describe SMUFIN (somatic mutation finder), a single program that directly compares sequence reads from normal and tumor genomes to accurately identify and characterize a range of somatic sequence variation, from single-nucleotide variants (SNV) to large structural variants at base pair resolution. Performance tests on modeled tumor genomes showed average sensitivity of 92% and 74% for SNVs and structural variants, with specificities of 95% and 91%, respectively. Analyses of aggressive forms of solid and hematological tumors revealed that SMUFIN identifies breakpoints associated with chromothripsis and chromoplexy with high specificity. SMUFIN provides an integrated solution for the accurate, fast and comprehensive characterization of somatic sequence variation in cancer. [ABSTRACT FROM AUTHOR]

The article focuses on research topics related to science and technology performed by several healthcare companies including XO1, Solstice Biologics and Arvinas. Topics discussed include protein homeostasis in drug discovery, development of disease resistance traits through plant microbiome and the use of RNA interference based drug. Also mentions the gene therapy of eye.

Current viral vectors for gene therapy are associated with serious safety concerns, including leukemogenesis, and nonviral vectors are limited by low gene transfer efficiency. Here we investigate the therapeutic utility of chemically modified mRNA as an alternative to DNA-based gene therapy. A combination of nucleotide modifications abrogates mRNA interaction with Toll-like receptor (TLR)3, TLR7, TLR8 and retinoid-inducible gene I (RIG-I), resulting in low immunogenicity and higher stability in mice. A single intramuscular injection of modified murine erythropoietin mRNA raises the average hematocrit in mice from 51.5% to 64.2% after 28 days. In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP-B expression, and treated mice survived until the predetermined end of the study after 28 days. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA), the most common autosomal recessive neurodegenerative disease affecting children, results in impaired motor neuron function. Despite knowledge of the pathogenic role of decreased survival motor neuron (SMN) protein levels, efforts to increase SMN have not resulted in a treatment for patients. We recently demonstrated that self-complementary adeno-associated virus 9 (scAAV9) can infect ∼60% of motor neurons when injected intravenously into neonatal mice. Here we use scAAV9-mediated postnatal day 1 vascular gene delivery to replace SMN in SMA pups and rescue motor function, neuromuscular physiology and life span. Treatment on postnatal day 5 results in partial correction, whereas postnatal day 10 treatment has little effect, suggesting a developmental period in which scAAV9 therapy has maximal benefit. Notably, we also show extensive scAAV9-mediated motor neuron transduction after injection into a newborn cynomolgus macaque. This demonstration that scAAV9 traverses the blood-brain barrier in a nonhuman primate emphasizes the clinical potential of scAAV9 gene therapy for SMA. [ABSTRACT FROM AUTHOR]

Delivery of genes to the brain and spinal cord across the blood-brain barrier (BBB) has not yet been achieved. Here we show that adeno-associated virus (AAV) 9 injected intravenously bypasses the BBB and efficiently targets cells of the central nervous system (CNS). Injection of AAV9-GFP into neonatal mice through the facial vein results in extensive transduction of dorsal root ganglia and motor neurons throughout the spinal cord and widespread transduction of neurons throughout the brain, including the neocortex, hippocampus and cerebellum. In adult mice, tail vein injection of AAV9-GFP leads to robust transduction of astrocytes throughout the entire CNS, with limited neuronal transduction. This approach may enable the development of gene therapies for a range of neurodegenerative diseases, such as spinal muscular atrophy, through targeting of motor neurons, and amyotrophic lateral sclerosis, through targeting of astrocytes. It may also be useful for rapid postnatal genetic manipulations in basic neuroscience studies. [ABSTRACT FROM AUTHOR]

Transferring multiple genes into the same cell allows for the combination of genetic correction, marking, selection and conditional elimination of transduced cells or the reconstitution of multisubunit components and synergistic pathways. However, this cannot be reliably accomplished by current gene transfer technologies. Based on the finding that some cellular promoters intrinsically promote divergent transcription, we have developed synthetic bidirectional promoters that mediate coordinate transcription of two mRNAs in a ubiquitous or a tissue-specific manner. Lentiviral vectors incorporating the new promoters enabled efficient dual gene transfer in several tissues in vivo after direct delivery or transgenesis, and in a human gene therapy model. Because divergent gene pairs, likely transcribed from shared promoters, are common in the genome, the synthetic promoters that we developed may mimic a well-represented feature of transcription. Vectors incorporating these promoters should increase the power of gene function studies and expand the reach and safety of gene therapy. [ABSTRACT FROM AUTHOR]

The article focuses on the health biotechnology sector in China. China is focusing on several aspects of health biotechnology, including therapeutic antibodies, severe acquired respiratory syndrome research, gene therapy, functional genomics and stem cells. In addition to work in the field of genome sequencing, the country is pioneering research on adult stem cells from blood and umbilical cord. In 2003, the Chinese firm Shenzhen SiBono GenTech was the first firm in the world to obtain a drug license for a recombinant gene therapy. It's participation as the only developing country in the Human Genome Project showcased its capability in genomics.

Successful cancer gene therapy requires a vector that systemically and specifically targets tumor cells throughout the body. Although several vectors have been developed to express cytotoxic genes via tumor-specific promoters or to seclectively replicate in tumor cells, most are taken up and expressed by just a few targeted tumor cells. By contrast, we show here that blood-borne Sindbis viral vectors systemically and specifically infect tumor cells. A single intraperitoneal treatment allows the vectors to target most tumor cells, as demonstrated by immunohistochemistry, without infecting normal cells. Further, Sindbis infection is sufficient to induce complete tumor regression. We demonstrate systemic vector targeting of tumors growing subcutaneously, intrapancreatically, intraperitoneally and in the lungs. The vectors can also target syngeneic and spontaneous tumors in immune-competent mice. We document the anti-tumor specificity of a vector that systemically targets and eradicates tumor cells throughout the body without adverse effects. [ABSTRACT FROM AUTHOR]

The ability to safely and efficiently transfer foreign DNA into cells is a fundamental goal in biotechnology. Toward this end, rapid advances have recently been made in our understanding of mechanisms for DNA stability and transport within cells. Current synthetic DNA delivery systems are versatile and safe, but substantially less efficient than viruses. Indeed, most current systems address only one of the obstacles to DNA delivery by enhancing DNA uptake. In fact, the effectiveness of gene expression is also dependent on several additional factors, including the release of intracellular DNA, stability of DNA in the cytoplasm, unpackaging of the DNA-vector complex, and the targeting of DNA to the nucleus. Delivery systems of the future must fully accommodate all these processes to effectively shepherd DNA across the plasma membrane, through the hostile intracellular environment, and into the nucleus. [ABSTRACT FROM AUTHOR]

The article discusses development in gene therapies such as gene therapy Glybera (alipogene tiparvovec) and mentions the need to define therapies prices on the basis of similar patient benefits to control it high prices. Topics discussed include the need to the pricing and reimbursement (P&R) approaches in gene therapies; high prices of artificial organs in the U.S.; and the role of a gene therapy to restore vision in patients with retinal degeneration diseases.

Focuses on the importance of tissue selectivity of adenovirus for gene therapy. Requirements for the development of tissue selective adenovirus; Ways to overcome hurdles of growing CAR-ablated vectors; Success in the creation of adenovirus vectors that lack native receptor binding.

The article focuses on financing and underwriting issues related to gene therapy. Topics discussed include challenge of how to encourage appropriate investment for the potentially lifesaving therapy, pricing strategies for commercialization of the gene therapy and future aspects one-time payment policy for gene therapy in the U.S. to develop vaccines for rare diseases.

The article discusses research on adeno-associated virus serotype 9 (AAV9), a viral vector that crosses the blood-brain barrier and targets the central nervous system. The vector, which is administered intravenously, effectively transduces brain cells located throughout the central nervous system in both neonatal and adult mice. If this technology can be translated to humans, it may allow for significant developments in gene therapy of diseases that target large parts of the brain, such as Parkinson's disease, Alzheimer's disease, and motorneuron diseases.

This article discusses research into the use of microRNA (miRNA) to silence the genetic mutations in messenger RNA (mRNA) caused by cancer viruses. Research into the modification of tumoricidal viruses such as Coxsackievirus A21so that its miRNA was less pathologically prolific with mRNA in muscle tissue is cited as an example of miRNA modification in the development of anticarcinogenic biological pharmaceuticals. The risk of genetic mutations introducing complications into these therapies is considered. The possibility that these therapies will permit the development of personalized medicine in the treatment of cancer is considered.

The article focuses on the advances in efficiency and safety of gene therapy using DNA replicator sequences. Experimental evidence showed that human replicators placed near a marker gene in an expression cassette can prevent gene silencing at two chromosomal locations. Such condition paved the way for further studies on DNA replicators as tools for improving the safety and efficiency of gene therapy.

Focuses on steps taken by the U.S. Food and Drug Administration and the National Institutes of Health to deal with the widespread concerns regarding gene therapy. Meeting held to review the safety findings preclinical testing and gene therapy clinical trials; Reasons for the complications in the assessment of the safety of gene-therapy procedures; Complications in the clinical use of adenovirus-based gene vectors.

Discusses the use of gene therapy and tissue engineering in various treatments of human diseases. Description of both these techniques; Limitations associated with the use of these techniques; Role of DNA-material hybrid systems in improving forms of gene therapy; Use of matrix materials in gene therapy.

Discusses antiangiogenesis gene therapy using endostatin. Benefits of the use of endostatin in gene therapy; Potential advantages of gene therapy over protein therapy; Advantages of the genome revolution in generating vast numbers of pharmaceutical agents.

Editorial. Discusses the mistakes related to the gene therapy administered to a patient afflicted with X-linked severe combined immune deficiency. Clinical trial performed by the Alain Fischer and colleagues at the Necker Hospital in Paris, France; Failure and success rates of the clinical trial performed; Uncertain risk of insertional mutagenesis.

Reports on the plans of the U.S. Recombinant DNA Advisory Committee (RAC) of the U.S. National Institute of Health regarding the gene therapy clinical trials. Proposal given by RAC.

Discusses that researchers at the Memorial Sloan Kettering Cancer Center in New York city and the University of California in San Francisco, California have used a lentivirus vector to introduce functional β-globin genes into hematopoietic stem cells. Significance of HIV-1 and related lentivirus for gene therapy in humans.

Addresses the problem associated with delivery of human gene therapy by recombinant adeno-associated virus (rAAV) vectors. Limitations of small packaging capacity of the rAAV; Injection of the vectors into mouse portal veins; Reconstitution of the complete expression cassette; Assessment of the hepatocyte transduction efficiency.

Focuses on the use of mycoplasmas in gene therapy to deliver therapeutic gene at the cell surface. Description of mycoplasamas; Benefit of the behavior of mycoplasmas as commensal organisms; Absence of endotoxic substances and antigens found on the cell wall of Gram negative bacteria in mycoplasmas.