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Archives for May 2013

NextBio Announces Translational Medicine Partnership with Sanofi

NextBio recently announced a multi-year collaboration with Sanofi (NYSE:SNY) aimed at using NextBio Clinical to incorporate patient omics and clinical data into Sanofi’s drug research and development, as part of Sanofi’s Translational Medicine for Patients (TM4P) program.

Penn Research Makes Advance in Nanotech Gene Sequencing Technique

The allure of personalized medicine has made new, more efficient ways of sequencing genes a top research priority. One promising technique involves reading DNA bases using changes in electrical current as they are threaded through a nanoscopic hole. Now, a team led by University of Pennsylvania physicists has used solid-state nanopores to differentiate single-stranded DNA molecules containing sequences of a single repeating base.

The study was led by Marija Drndić, an associate professor in the Department of Physics and Astronomy in the School of Arts and Sciences, along with graduate students Kimberly Venta and Matthew Puster and post-doctoral researchers Gabriel Shemer, Julio A. Rodriguez-Manzo and Adrian Balan. They collaborated with assistant professor Jacob K. Rosenstein of Brown University and professor Kenneth L. Shepard of Columbia University. Their results were published in the journal ACS Nano.

In this technique, known as DNA translocation measurements, strands of DNA in a salt solution are driven through an opening in a membrane by an applied electric field. As each base of the strand passes through the pore, it blocks some ions from passing through at the same time; amplifiers attached to the nanopore chip can register the resulting drop in electrical current. Because each base has a different size, researchers hope to use this data to infer the order of the bases as the strand passes through. The differences in base sizes are so small, however, that the proportions of both the nanopores and membranes need to be close those of the DNA strands themselves — a major challenge.

The nanopore devices closest to being a commercially viable option for sequencing are made out of protein pores and lipid bilayers. Such protein pores have desirable proportions, but the lipid bilayer membranes in which they are inserted are akin to a film of soap, which leaves much to be desired in terms of durability and robustness.

Solid-state nanopore devices, which are made of thin solid-state membranes, offer advantages over their biological counterparts — they can be more easily shipped and integrated with other electronics — but the basic demonstrations of proof-of-principle sensitivity to different DNA bases have been slower.

“While biological nanopores have shown the ability to resolve single nucleotides, solid-state alternatives have lagged due to two challenges of actually manufacturing the right-sized pores and achieving high-signal, low-noise and high-bandwidth measurements,” Drndić said. “We’re attacking those two challenges here.”

Because the mechanism by which the nanopore differentiate between one type of base and another is by the amount of the pore’s aperture that is blocked, the smaller a pore’s diameter, the more accurate it is. For the nanopore to be effective at determining a sequence of bases, its diameter must approach the diameter of the DNA and its thickness must approach that of the space between one base and the next, or about 0.3 nanometers.

To get solid-state nanopores and membranes in these tiny proportions, researchers, including Drndić’s group, are investigating cutting-edge materials, such as graphene. A single layer of carbon atoms in a hexagonal lattice, graphene membranes can be made a little as about 0.5 nanometers thick but have their own disadvantages to be addressed. For example, the material itself is hydrophobic, making it more difficult to pass strands of DNA through them.

In this experiment, Drndić and her colleagues worked with a different material — silicon nitride — rather than attempting to craft single-atom-thick graphene membranes for nanopores. Treated silicon nitride is hydrophilic and has readily allowed DNA translocations, as measured by many other researchers during the last decade. And while their membrane is thicker, about 5 nanometers, silicon nitride pores can also approach graphene in terms of thinness due to the way they are manufactured.

“The way we make the nanopores in silicon nitride makes them taper off, so that the effective thickness is about a third of the rest of the membrane,” Drndić said.

Drndić and her colleagues tested their silicon nitride nanopore on homopolymers, or single strands of DNA with sequences that consist of only one base repeated several times. The researchers were able to make distinct measurements for three of the four bases: adenine, cytosine and thymine. They did not attempt to measure guanine as homopolymers made with that base bind back on themselves, making it more difficult to pass them through the nanopores.

“We show that these small pores are sensitive to the base content,” Drndić said, “and we saw these results in pores with diameters between 1 and 2 nanometers, which is actually encouraging because it suggests some manufacturing variability may be okay.”

Study: Differentiation of Short, Single-Stranded DNA Homopolymers in Solid-State Nanopores

Source: University of Pennsylvania

Major Advance Provides Human Embryonic Stem Cells for Personalized Medicine

Somatic cell nuclear transfer (SCNT) is a technique in which the nucleus of a donor cell is transferred to an egg cell whose nucleus has been removed, generating embryos that are almost an identical genetic match to the donor individual. For the first time, a team of scientists has used SCNT to produce human embryonic stem cells (hESCs). This milestone, published by Cell Press May 15th in the journal Cell, opens up new avenues for using stem cells to understand patient-specific causes of disease and for developing personalized therapies.

“Our finding offers new ways of generating stem cells for patients with dysfunctional or damaged tissues and organs,” says senior study author Shoukhrat Mitalipov of Oregon Health & Science University. “Such stem cells can regenerate and replace those damaged cells and tissues and alleviate diseases that affect millions of people.”

Another technique that has been used to generate patient-specific stem cells to model diseases is called induced pluripotent stem cells (iPS) cells, which are generated directly from the patient’s somatic cells by adding a cocktail of cellular factors to stimulate regression to a stem cell state. However, concerns that this technique may generate unexpected mutations in the stem cells means that researchers are still keen to find ways to generate hESCs by other means.

In the past, researchers have used SCNT to generate only mouse and monkey embryonic stem cells—immature cells that can develop into different types of specialized cells, from neurons to heart muscle cells. Most previous attempts failed to produce human SCNT embryos that could progress beyond the 8-cell stage, falling far short of the 150-cell blastocyst stage that could provide hESCs for clinical purposes. Until now, it was not clear which factors and protocols are important for promoting SCNT embryonic development.

To overcome these hurdles, Mitalipov and his team started in familiar territory, refining methods for producing monkey SCNT embryos. Using these optimized protocols, they transferred nuclei from human skin cells into the cytoplasm of human egg cells, generating blastocysts that gave rise to hESC colonies. The resulting hESCs resembled those derived from fertilized embryos, had no chromosomal abnormalities, showed normal gene activity, and were capable of turning into more specialized cell types that could be used for replacing damaged tissues.

Surprisingly, the best outcomes came from donors who produced a low number of high-quality egg cells. “It was thought that, to make human SCNT work, many thousands of human eggs would be needed,” Mitalipov says. “We were able to produce one ESC line using just two human eggs, which would make this approach practical for widespread therapeutic use.”

Study: Human embryonic stem cells derived by somatic cell nuclear transfer

Source: EurekAlert!

New Analyses Identify Predictive Biomarkers For Vectibix® (Panitumumab) In Patients With Metastatic Colorectal Cancer

Amgen (NASDAQ: AMGN) recently announced results from three analyses of Vectibix® (panitumumab) in combination with FOLFOX, an oxaliplatin-based chemotherapy regimen, as a first-line treatment for metastatic colorectal cancer (mCRC). These analyses include the description of new predictive biomarkers of clinical response to Vectibix, activating mutations in KRAS (beyond exon 2) and mutations in NRAS, collectively referred to as RAS.

“Amgen helped establish KRAS gene mutation as a biomarker for lack of response to anti-EGFR treatment,” said Sean E. Harper , M.D., executive vice president of Research and Development at Amgen. “The identification of new biomarkers may further help to identify appropriate patients with this incurable disease for such treatment.”

The RAS biomarkers were identified in a predefined retrospective subset analysis of the PRIME trial, where RAS was defined as exons 2, 3 and 4 of KRAS and NRAS. Mutational status of tumors was determined by Sanger sequencing in parallel with WAVE®-based SURVEYOR® Scan Kits (CRC RAScan™) from Transgenomic, Inc. (TBIO). In this exploratory analysis, patients with wild-type RAS mCRC who were administered Vectibix in combination with FOLFOX demonstrated an improvement in median overall survival (OS) of 26.0 months compared to 20.2 months for patients treated with FOLFOX alone (HR = 0.78, 95 percent CI, 0.62-0.99).

Patients with mutant RAS tumor status had inferior progression-free survival (PFS) (HR = 1.34, 95 percent CI, 1.07-1.60) and OS (HR = 1.25, 95 percent CI, 1.02-1.55) when administered Vectibix in combination with FOLFOX chemotherapy versus FOLFOX alone. These results suggest that RAS mutation status beyond KRAS may be predictive of negative outcomes in patients receiving Vectibix plus FOLFOX in mCRC. Amgen is working to inform investigators and physicians of this important new safety information, as well as working with regulatory agencies regarding appropriate communication of the outcomes of this analysis.

Results of this study will be presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting on Tuesday, June 4, 8:00 a.m. – 12:00 p.m. CDT, S405 (Abstract No. 3511; Poster Discussion).

In a separate and updated exploratory analysis of longer follow-up of OS of the PRIME trial (primary endpoint of PFS), an improvement in OS was observed in patients with wild-type KRAS exon 2 mCRC treated with Vectibix in combination with FOLFOX. Median OS was 23.8 months compared to 19.4 months for patients treated with FOLFOX alone (HR = 0.83, 95 percent CI, 0.70-0.98). In both PRIME analyses, the most commonly reported adverse events for the Vectibix treatment arms included rash, hypomagnesemia and diarrhea. The adverse event profiles for the wild-type tumor and mutant tumor populations were similar.

Updated results of the study will be presented at the 2013 ASCO Annual Meeting on Sunday, June 2, 8:00 a.m. – 11:45 a.m. CDT, S Hall A2 (Abstract No. 3620; Poster).
In a separate predefined secondary objective subset analysis of the PEAK study, patients with wild-type RAS mCRC treated with Vectibix in combination with FOLFOX had a median PFS of 13.1 months compared to 9.5 months (HR = 0.63, 95 percent CI, 0.43-0.94) for patients treated with bevacizumab in combination with FOLFOX. Median OS was not reached in the Vectibix arm, but the OS HR favored the Vectibix arm (HR = 0.55, 95 percent CI, 0.33-1.01). The most commonly reported adverse events for the Vectibix treatment arm included rash, hypomagnesemia and dehydration. The adverse event profiles for the wild-type tumor and mutant tumor populations were similar. No new toxicities were identified for Vectibix.

Updated results of the study will be presented at the 2013 ASCO Annual Meeting on Sunday, June 2, 8:00 a.m. – 11:45 a.m. CDT, S Hall A2 (Abstract No. 3631; Poster).

Source: PR Newswire

Entelos and ISB Announce Collaborative Gene Expression Breakthrough

Entelos Holding Corp. (“Entelos” or “the Company”), a premier provider of physiologicalsystemmodeling and services, and Seattle-based Institute for System Biology (ISB), the nonprofit pioneers of the systems approach to study the molecular causes of diseases, today announced the successful integration of gene expression data into quantitative physiological simulations. This proprietary capability improves understanding of the gene expression and disease outcomes to radically improve the predictive discernment of the complex nature of disease, yielding insights into novel therapeutic targets, biomarkers, and patient selection that should support a new era of precision medicine.

Entelos and ISB worked together to define a scientifically sound and scalable methodology to provide breakthrough capabilities for both the modeling and systems pharmacology communities. It addresses business-critical problems in both pharmaceutical research and healthcare. “This workflow is transformative for understanding the role of molecular interactions and their impact on pharmaceutical R&D and healthcare decision making,” stated Entelos Founder and CTO, Tom Paterson. “By utilizing our computer models, we are able to use all identified correlations across gene network studies to decipher genetic influence on the disruptions identified as disease. As an example, the new capabilities were able to help us clearly define from a pool of 51 potential biomarkers, and which biomarkers identified non-responders and responders for anti-IL1 therapies for rheumatoid arthritis.”

“The mapping and application of clinical gene expression data sets a new standard and role for quantitative physiological modeling within the drug discovery and development process,” stated Entelos President and CEO, Shawn O’Connor. “It’s only due to the unique depth and breadth of the Entelos quantitative physiological models that these sorts of mappings and analyses can be carried out across the entire pathophysiology of a disease. This is the beginning of truly understanding and leveraging the human genome for therapeutic success”

“As the interconnected features of the disease space become increasingly more visible, we are continuing to look for new ways to decipher the elaborate data that hides therapeutic success“ said Dr. Lee Hood, co-founder and president of Institute for Systems Biology and recipient of the National Medal of Science. “This approach represents a breakthrough capability for deriving insights from those data sets.”

This demonstrated convergence of top-down functional systems biology and bottom-up molecular systems biology provides an approach for using clinical gene expression data to investigate a wide diversity of diseases, to decipher disease complexity, and to understand variability and reduce uncertainty in populations and sub populations. Entelos and ISB are now seeking commercial partners to advance additional existing disease models (Atherosclerosis, Type 2 Diabetes, Hypertension, Rheumatoid Arthritis, etc.) and generate new in silico applications.

Source: Entelos