#Researchers Develop Innovative Gene Transfer-based Treatment Approach University of North carolina (UNC) School of medicine researchers have developed an innovative,
experimental gene transfer-based treatment for children with giant axonal neuropathy (GAN). Researchers led by Steven J. Gray, Ph d,
. assistant professor in the Department of Ophthalmology and a researcher in UNC Gene therapy Center and Carolina Institute for Developmental Disabilities, developed the experimental treatment in studies conducted at UNC.
Gray work in this area was funded almost entirely by Hannah Hope Fund, a charity founded by the parents of Hannah Sames, an 11-year-old girl with giant axonal neuropathy (GAN),
to support the development of a treatment and cure. This extremely rare genetic disorder causes children to gradually lose the ability to balance themselves,
move their muscles and to feel certain sensations. Most children born with GAN do not survive beyond their early 20s because of progressive impairment of their ability to breath.
The treatment approach developed at UNC uses a genetically modified virus called AAV to deliver a missing gene, the gigaxonin gene (scaav9/Jet-GAN), into the cerebrospinal fluid of children with GAN.
The therapeutic viral vector to be used in each of these injections is prepared at the UNC Vector Core Human Applications Laboratory.
and is expected to pave the way to developing treatments for many other related diseases. Gray chose to focus his career on this rare genetic condition after meeting Hannah,
Our goal has always been to bring hope to the families affected by this devastating disease,
This trial is the first in history to deliver gene therapy through the spinal fluid to test the potential to achieve broad treatment of the spinal cord and brain (central nervous system or CNS.
and wee already seeing clear application of this approach to treat other diseases studied in my lab. ray serves as an associate investigator on the trial as does R. Jude Samulski, Ph d.,director of the UNC Gene therapy Center."
it is very rewarding to finally see these approaches being tested for some of the unmet clinical needs caused by these terminal genetic disorders,
"This specific study represents a culmination of years of basic research from the UNC Gene therapy Center
if we could'help save her child',to last week gene therapy administration; a remarkable and humbling journey that I privileged to be a part of."
"This first intrathecal (into the spinal fluid) delivery of a viral gene therapy vector in a human patient is a fundamental step towards developing a causal treatment for giant axonal neuropathy (GAN), a devastating progressive neurogenetic
including spinal muscular atrophy. Bringing such path-breaking treatments to children affected by neurogenetic disorders is really the core mission of our team here at the NINDS
so we are excited very to be helping to move this approach to a clinical trial.
which will be given by a single injection by spinal tap into their cerebrospinal fluid, which flows around the brain and spinal cord.
University of North carolina at Chapel Hil r
#Microarray for Research into Haematological and Solid Cancers Oxford Gene Technology (OGT) released a new microarray designed to improve the accuracy and efficiency of cancer research.
The Cytosure Cancer+SNP array (4x180k) combines long oligo array comparative genomic hybridisation (acgh) probes with fully validated single nucleotide polymorphism (SNP) content
, providing the detection of both copy number variations (CNVS) and loss of heterozygosity (LOH) on a single chip.
The array has been optimized in collaboration with Professor Jacqueline Schoumans from the Lausanne University Hospital in Switzerland, an expert in both acgh and cancer genomics.
Unique to the proprietary Cytosure Cancer+SNP array any reference sample can be used for analysis without changes to the standard acgh protocol and, thanks to novel SNP probe chemistry,
no restriction digest is required. The capacity to use matched samples is a particular advantage for research into genetic aberrations in cancer,
enabling any constitutional abnormalities to be filtered out. The 60-mer oligonucleotide probes utilized in the array provide a high signal-to-noise ratio and highly sensitive detection;
this makes them ideal for research into complex malignant tissues. OGT Cytosure Interpret Software is used for data analysis,
including updated features, such as the B-allele frequency plot, that have been optimized for the identification of biologically relevant genomic variants in tumor samples s
#New Technique Maps Elusive Chemical Markers on Proteins Unveiling how the 20,000 or so proteins in the human body worknd malfunctions the key to understanding much of health and disease.
Now, Salk researchers developed a new technique that allows scientists to better understand an elusive step critical in protein formation.
2015 in the journal Cell, allows researchers to map critical chemical tagsalled phosphateshat bond to amino acids (the building blocks of proteins) in the final stages of creating a protein.
because theye so hard to study, said Tony Hunter, American Cancer Society Professor, holder of the Dulbecco Chair in the Salk Molecular and Cell biology Laboratory and senior author of the new paper.
they would have to use a trick to make a stronger bond between phosphate and histidine.
Then, they developed antibodies that specifically recognize these stable phosphohistidine analogues, but also detect authentic phosphohistidine in proteins.
the team added their phosphohistidine antibodies to a collection of different mammalian cells grown on slides
and observed where in the cell the antibodies bound, which indicates parts of cells that have high levels of proteins with phosphohistidines. he thing that surprised us most is that
when we stained the cells with the new antibodies, we saw discrete areas within the cells that had high levels of histidine phosphorylation,
The team expects these antibody tools to be useful to other labs aiming to determine
The work and the researchers involved were supported by the National institutes of health, a Salk Institute Innovation Grant and the Helmsley Center for Genomic medicine o
#Scientists Use Nanoparticles to Shut down Mechanism that Drives Cancer Growth When scientists develop cancer therapies,
they target the features that make the disease deadly: tumor growth, metastasis, recurrence and drug resistance.
In epithelial cancers cancers of the breast, ovaries, prostate, skin and bladder, which begin in the organslining these processes are controlled by a genetic program called epithelialesenchymal transition.
Epithelialesenchymal transition is regulated by a protein called Twist, which means that Twist directly influences the development of cancer, its spread to other organs and its return after remission.
In a major step toward developing a novel therapy that targets epithelialesenchymal transition, scientists from UCLA and City of Hope have become the first to inhibit the mechanism of Twist using nanoparticles to deliver a nucleic acid called small interfering RNA,
or sirna, into tumor cells. In mouse models, delivering sirna into cancer cells inhibited the expression of Twist,
which in turn reduced epithelial-mesenchymal transition and dramatically reduced the size of tumors. The study,
which was published online in the journal Nanomedicine: Nanotechnology, Biology and Medicine, was led by Jeffrey Zink and Fuyu Tamanoi, both members of the California Nanosystems Institute and Jonsson Comprehensive Cancer Center at UCLA,
and Carlotta Glackin of City of Hope Cancer Center. e were surprised truly by the dramatic effect of delivering Twist sirna,
said Tamanoi, who also is a professor of microbiology, immunology and molecular genetics and a director of the signal transduction and therapeutics program at the Jonsson Cancer Center. his demonstrates the effectiveness of our treatment
and encourages us to explore further what is happening to the tumor. In previous studies
sirna has been shown to effectively shut down gene expression in tumor cells grown in the laboratory. But the technique had not been effective in living organisms
because enzymes in the blood called nucleases degrade sirna before it can reach tumor cells.
To circumvent that problem, the UCLA and City of Hope researchers attached sirna to the outside of a particular type of nanoparticle developed by Zink called mesoporous silica nanoparticles.
In the study, the nanoparticles were coated with a substance called polyethyleneimine, which acted to bind
and protect the sirna when they were injected into the blood. As a result the nanoparticles could accumulate in the tumor cells
and the sirna could go to work inhibiting the cellsexpression of Twist. The study found that giving mice sirna-loaded nanoparticles once a week for six weeks inhibited tumor growth,
and that it shut down not only Twist but also other genes under the control of the epithelialesenchymal transition process. his result confirms the critical importance of Twist and the epithelialesenchymal transition process,
which promotes tumor invasion and metastasis in many cancers, said Glackin, an associate professor at the City of Hope who has been studying the function of Twist for 20 years.
Twist is reactivated in a number of metastatic cancers including triple-negative breast cancer melanoma and ovarian cancer.
By shutting down the epithelialesenchymal transition process, Zink and Tamanoi may develop new therapy options for these cancers.
Another important finding was that shutting down Twist expression enabled cancer cells to overcome their resistance to cancer drugs.
The researchers now are working to design a next-generation nanoparticle that will enable delivery of Twist sirna
and cancer drug molecules in the same nanoparticle a potential one-two punch that would inhibit epithelialesenchymal transition and kill cancer cells.
Zink said the advance would be possible because of the structure of the specific type of nanoparticles the researchers are using. esoporous silica nanoparticles contain thousands of pores
which allows storage and delivery of anticancer drugs by the same nanoparticles that have attached sirna to their outsides,
said Zink, who also is distinguished a UCLA professor of chemistry and biochemistry and a pioneer in the design and synthesis of multifunctional mesoporous silica nanoparticles u
#Optical og Nosedeveloped to Detect Cancer, Other Diseases Researchers at the University of Adelaide in Australia are using optical spectroscopy to develop a quick,
noninvasive reath testthey believe will have the potential to screen for a variety of diseases, including diabetes, infections and cancers.
The research team, led by Dr. James Anstie, Australian Research Council (ARC) Research Fellow with the University Institute for Photonics and Advanced Sensing (IPAS), compared the instrument to an ptical dog nosewhich uses a special laser to measure the molecular content
of a sample of gas. ur device will use broadband cavity-enhanced frequency-comb spectroscopy to achieve sensitivities to molecular concentrations in the low parts-per-million,
high parts-per-billion levels which is need where you to be to start reliably detecting the molecular content of breath,
Anstie told Bioscience Technology. ather than sniffing out a variety of smells as a dog would,
the laser system uses light to ensethe range of molecules that are present in the sample,
Anstie said in a university press release. hose molecules are by-products of metabolic processes in the body
and their levels change when things go wrong. There have been undertaken good studies around the world which show that diseases like lung and oesophageal cancer,
asthma and diabetes can be detected in this way, even before external symptoms are showing. owever, Anstie told Bioscience Technology, ther conditions,
although they have a clear molecular signature in the breath may be masked by the general complexity involved in getting a good repeatable sample.
That means Anstie team will need to work with medical researchers to improve sampling techniques, and improve the analysis of data coming out of the device,
he said. Although there is much research needed in breath analysis, the team believes a working prototype could be ready in two to three years,
with a commercial product available within five years. Antsie said the team must show they can accurately determine molecular concentrations in simulated breath samples,
before extending into actual breath samples in about a year. Up next the team plans to extend the optical range of the device
and thus the number of molecules they can look at. e also need to improve the sensitivity of the device by sampling inside a Fabry Perot cavity.
The research, published in the journal Optics Express, was funded through the ARC, the Priemeir Research and Industry Fund and a South Australian Government Catalyst Research Grant. s
#Bacterial Computing The riendlybacteria inside our digestive systems are being given an upgrade, which may one day allow them to be programmed to detect and ultimately treat diseases such as colon cancer and immune disorders.
In a paper published today in the journal Cell Systems, researchers at MIT unveil a series of sensors, memory switches,
and circuits that can be encoded in the common human gut bacterium Bacteroides thetaiotaomicron. These basic computing elements will allow the bacteria to sense,
memorize, and respond to signals in the gut, with future applications that might include the early detection and treatment of inflammatory bowel disease or colon cancer.
Researchers have built previously genetic circuits inside model organisms such as E coli. However such strains are only found at low levels within the human gut, according to Timothy Lu, an associate professor of biological engineering and of electrical engineering and computer science,
who led the research alongside Christopher Voigt, a professor of biological engineering at MIT. e wanted to work with strains like B. thetaiotaomicron that are present in many people in abundant levels,
and can stably colonize the gut for long periods of time, Lu said. The team developed a series of genetic parts that can be used to precisely program gene expression within the bacteria. sing these parts
we built four sensors that can be encoded in the bacterium DNA that respond to a signal to switch genes on and off inside B. thetaiotaomicron,
Voigt said. These can be food additives, including sugars, which allow the bacteria to be controlled by the food that is eaten by the host,
Voigt adds. Bacterial emory To sense and report on pathologies in the gut, including signs of bleeding or inflammation,
the bacteria will need to remember this information and report it externally. To enable them to do this, the researchers equipped B. thetaiotaomicron with a form of genetic memory.
They used a class of proteins known as recombinases which can record information into BACTERIAL DNA by recognizing specific DNA addresses
and inverting their direction. The researchers also implemented a technology known as CRISPR interference, which can be used to control which genes are turned on or off in the bacterium.
The researchers used it to modulate the ability of B. thetaiotaomicron to consume a specific nutrient
and respond to signs of disease could also be used elsewhere in the body, he adds.
In addition, more advanced genetic computing circuits could be built upon this genetic toolkit in Bacteroides to enhance their performance as noninvasive diagnostics and therapeutics. or example,
and specificity when diagnosing disease with engineered bacteria, Lu said. o achieve this, we could engineer bacteria to detect multiple biomarkers,
and only trigger a response when they are all present. Tom Ellis, group leader of the Centre for Synthetic biology at Imperial College London, who was involved not in the research,
said the paper takes many of the best tools that have been developed for synthetic biology applications with E coli
and moves them over to use with a common class of gut bacteria. hereas others have developed tools and applications for engineering genetic circuits,
or biosensors, in bacteria that are placed then in the gut, this paper stands out from the crowd by first engineering a member of the Bacteroides genus,
or even in-situ synthesis of therapeutic molecules as and when they are needed. e
#Ultrasound Accelerates Skin Healing Especially for Diabetics and the Elderly Researchers from the University of Sheffield Department of Biomedical science discovered the ultrasound transmits a vibration through the skin
and wakes up cells in wounds helping to stimulate and accelerate the healing process. More than 200,000 patients in the UK suffer with chronic wounds every year at a cost of over £3. 1 billion to the NHS.
The ultrasound treatment, which also reduces the chance of wounds getting infected, is particularly effective
when treating diabetics and the elderly. There are 11 million over-65s, three million diabetics and 10 million smokers in the UK all of whom are likely to suffer problems with healing wounds.
A quarter of diabetics suffer from skin ulcers, particularly foot ulcers, due to the loss of sensation and circulation in the legs.
Lead author of the study Dr Mark Bass, from the University Centre for Membrane Interactions and Dynamics (CMIAD), said:
kin ulcers are excruciatingly painful for patients and in many cases can only be resolved by amputation of the limb. sing ultrasound wakes up the cells
and stimulates a normal healing process. Because it is just speeding up the normal processes,
the treatment doesn carry the risk of side effects that are associated often with drug treatments. he pioneering study,
which is published in The Journal of Investigative Dermatology, was carried out in collaboration with the School of Biochemistry at the University of Bristol, the Wound Biology Group at the Cardiff Institute of Tissue Engineering and Repair,
and the orthopaedic company, Bioventus LLC. Dr Bass added: ow that we have proven the effectiveness of ultrasound we need to explore the signal further.
We have found that the ultrasound signal we currently use is effective, but it is possible that by refining the treatment we could improve the effects even further. ecause ultrasound is relatively risk free we could expect to see it in broad clinical use within three or four years. ource:
The University of Sheffiel u
#Stem Cells Create Early Human Heart Development Model UC Berkeley researchers, in collaboration with scientists at the Gladstone Institutes, have developed a template for growing beating cardiac tissue from stem cells,
creating a system that could serve as a model for early heart development and as a drug-screening tool to make pregnancies safer.
In experiments published in the journal Nature Communications, the researchers used biochemical and biophysical cues to prompt stem cells to differentiate
and self-organize into micron-scale cardiac tissue, including microchambers. e believe it is the first example illustrating the process of a developing human heart chamber in vitro,
said Kevin Healy, a UC Berkeley professor of bioengineering, who is co-senior author of the study with Dr. Bruce Conklin,
a senior investigator at the Gladstone Institute of Cardiovascular disease and a professor of medical genetics and cellular and molecular pharmacology at UC San francisco. his technology could help us quickly screen for drugs likely to generate cardiac birth defects,
and guide decisions about which drugs are dangerous during pregnancy. Screening for drug toxicity To test the potential of the system as a drug-screening tool,
the researchers exposed the differentiating cells to thalidomide, a drug known to cause severe birth defects.
They found that at normal therapeutic doses the drug led to abnormal development of microchambers, including decreased size,
problems with muscle contraction and lower beat rates compared with heart tissue that had not been exposed to thalidomide. e chose drug cardiac developmental toxicity screening to demonstrate a clinically relevant application of the cardiac microchambers,
said Conklin. ach year, as many as 280,000 pregnant women are exposed to drugs with evidence of potential fetal risk.
The most commonly reported birth defects involve the heart, and the potential for generating cardiac defects is of utmost concern in determining drug safety during pregnancy.
The new milestone comes nearly four months after Healy and other UC Berkeley researchers publicly debuted a system of beating human heart cells on a chip that could be used to screen for drug toxicity.
However, that heart-on-a-chip device used pre-differentiated cardiac cells to mimic adult-like tissue structure.
In this new study, the scientists mimicked human tissue formation by starting with stem cells genetically reprogrammed from adult skin tissue to form small chambers with beating human heart cells.
location, location By the end of two weeks, the cells that began on a two-dimensional surface environment started taking on a 3d structure as a pulsating microchamber.
cells along the edge experienced greater mechanical stress and tension, and appeared more like fibroblasts,
which are critical to the development of heart tissue. his spatial differentiation happens in biology naturally,
a UC Berkeley postdoctoral researcher in bioengineering. he confined geometric pattern provided biochemical and biophysical cues that directed cardiac differentiation and the formation of a beating microchamber.
and how that process can go wrong. he fact that we used patient-derived human pluripotent stem cells in our work represents a sea change in the field,
which is an imperfect model for human disease. The researchers pointed out that while this study focused on heart tissue,
said Warren Ruder, an assistant professor of biological systems engineering in both the College of Agriculture and Life sciences and the College of Engineering."
For future experiments, Ruder is building real-world robots that will have the ability to read bacterial gene expression levels in E coli using miniature fluorescent microscopes.
understanding the biochemical sensing between organisms could have far reaching implications in ecology, biology, and robotics.
In agriculture, bacteria-robot model systems could enable robust studies that explore the interactions between soil bacteria and livestock.
engineered gene circuits in E coli, microfluid bioreactors, and robot movement. The bacteria in the mathematical experiment exhibited their genetic circuitry by either turning green or red, according to
In the mathematical model, the theoretical robot was equipped with sensors and a miniature microscope to measure the color of bacteria telling it where
and how fast to go depending upon the pigment and intensity of color. The model also revealed higher order functions in a surprising way.
The Air force Office of Scientific research funded the mathematical modeling of gene circuitry in E coli, and the Virginia Tech Student Engineerscouncil has provided funding to move these models and resulting mobile robots into the classroom as teaching tools.
Ruder conducted his research in collaboration with biomedical engineering doctoral student Keith Heyde, of Wilton, Connecticut, who studies phyto-engineering for biofuel synthesis. e hope to help democratize the field of synthetic biology for students and researchers all over the world with this model,
said Ruder. n the future, rudimentary robots and E coli that are used already commonly separately in classrooms could be linked with this model to teach students from elementary school through the Ph d.-level about bacterial relationships with other organisms. ource:
Virginia Tec s
#Immunotherapy Show Promise In fighting Blood Cancer In recent years, immunotherapy has emerged as a promising treatment for certain cancers.
Now this strategy, which uses patientsown immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable.
The results appeared in a study published online in Nature Medicine. Patients received an infusion of altered immune cells known as T-cells roughly 2. 4 billion of them after undergoing a stem cell transplantation of their own stem cells.
In 16 of 20 patients with advanced disease there was a significant clinical response. The scientists found that the T-cell therapy was tolerated generally well
and that modified immune cells traveled to the bone marrow, where myeloma tumors typically are showed found,
and a long-term ability to fight the tumors. Relapse was associated generally with a loss of the engineered T-cells. his study suggests that treatment with engineered T-cells is not only safe
but of potential clinical benefit to patients with certain types of aggressive multiple myeloma, says first author Aaron P. Rapoport, M d,
. the Gary Jobson Professor in Medical Oncology at the University of Maryland School of medicine. ur findings provide a strong foundation for further research in the field of cellular immunotherapy for myeloma to help achieve even better
results for our patients. he trial is published the first use of genetically modified T-cells for treating patients with multiple myeloma.
The approach has been used to treat leukemia as well as lymphoma, according to Dr. Rapoport, who is the Director of the Blood and Marrow Transplant Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.
More than 77,000 people in the United states have multiple myeloma, with about 24,000 new cases diagnosed each year.
Patients are treated with chemotherapy and in many cases an autologous stem cell transplant but long-term response rates are low,
and median survival is three to five years. he majority of patients who participated in this trial had a meaningful degree of clinical benefit,
Dr. Rapoport notes. ven patients who later relapsed after achieving a complete response to treatment
or didn have a complete response had periods of disease control that I believe they would not have experienced otherwise.
Some patients are still in remission after nearly three years. he research is a collaboration between the University of Maryland School of medicine, the Perelman School of medicine at the University of Pennsylvania and Adaptimmune
a clinical stage biopharmaceutical company which owns the core T-cell receptor technology and funded the study.
Dr. Rapoport and co-authors Edward A. Stadtmauer, M d.,of the University of Pennsylvania Abramson Cancer Center,
In the clinical study, patientst-cells were engineered to express an affinity-enhanced T-cell receptor (TCR) specific for a type of tumor antigen,
or protein, known as a cancer-testis antigen (CT antigen). The target CT antigens were NY-ESO-1
and LAGE-1. Up to 60 percent of advanced myelomas have been reported to express NY-ESO-1 and/or LAGE-1,
which correlates to tumor proliferation and poorer outcomes. According to Adaptimmune, the trial is published the first study of lentiviral vector mediated TCR gene expression in humans.
Of the 20 patients treated, 14 (70 percent) had a near complete or complete response three months after treatment.
Median progression-free survival was 19.1 months and overall survival was 32.1 months. Two patients had a very good partial response three months post treatment.
Half the patients were treated at the University of Maryland Greenebaum Cancer Center and half at the University of Pennsylvania Abramson Cancer Center.
Researchers note that the response rate was better than would be expected for a standard autologous stem cell transplant.
which have been associated with another type of genetically engineered T-cells (chimeric antigen receptors, or CARS) used to treat other cancers.
The study was developed originally by Carl H. June, M d.,of the University of Pennsylvania Abramson Cancer Center,
and Dr. Rapoport, who have been research collaborators for 18 years. ultiple myeloma is a treatable but largely incurable cancer.
This study reveals the promise that immunotherapy with genetically engineered T-cells holds for boosting the body ability to attack the cancer
and provide patients with better treatments and control of their disease, said E. Albert Reece, M d..,Ph d.,MBA,
vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of medicine. his trial is also an excellent example of significant
scientific advances that result from collaborations between academic medical institutions and private industry. ource: University of Marylan n
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