Techniques

Scientists at the Massachusetts Institute of Technology (MIT) and the University of  Vienna have developed a light-field laser imaging system that generates 3D movies of entire brains at a millisecond timescale to create a complete “living” brain map.  The research thereby offers a more complete picture of nervous system activity than has been previously possible.   The technique is envisioned to elucidate how entire neural circuits operate to generate behavior, thereby empowering new therapeutic strategies for neurological and psychiatric disorders.  To date the system has been used to simultaneously image the activity of every neuron in the worm Caenorhabditis elegans as well as the entire brain of a zebrafish larva.  Such an approach could help researchers learn more about the biological basis of brain disorders and monitor the reactions of the nervous system to drugs and other substances in the body.  The researchers believe that the “ability to survey activity throughout a nervous system may help pinpoint the cells or networks that are involved with a brain disorder, leading to new ideas for therapies.”  In addition, this technique may be useful for mechanistic toxicology to help determine the relevance of adverse events for human safety.

Source:  Drug Development News

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Linguamatics, the leader in natural language processing (NLP)-based text mining, announced that the Federal Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) has licensed its 12E text mining platform as a discovery and decision support tool to supplement laboratory research efforts on drug safety.  The FDA will use the platform to review published literature and drug product labels to address key biomedical issues, including mechanisms of drug toxicity and disease processes.  In addition to document retrieval, the 12E platform can identify, extract, synthesize, and analyze relevant facts and relationships (e.g., between genes and diseases, drugs and side effects).  Customers include top tier commercial, academic, and governmental organizations, including 9 of the top 10 global pharmaceutical companies.  The 12E platform is available both as an in-house or cloud-based system.

Typical applications in pharmaceutical, biotechnology, and healthcare include:
•    Mapping gene-disease relationships and identifying potentially novel therapeutic targets
•    Biomarker discovery
•    Drug repurposing
•    Drug safety
•    Patent analysis
•    Clinical trial site selection and study design
•    Mining electronic medical records to improve prediction of health outcomes
•    Translational medicine
•    Competitive intelligence
•    Social media mining
•    Subjective data mining (sentiment analysis, key opinion mining)

SourcesBioSpace and Business Weekly

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Assessing Safety Earlier in Drug Development

Posted by cdavenport on Wednesday Aug 1, 2012 Under Biomarker, Drug Safety, Preclinical, Risk Management

The objective of a recent survey by Cambridge Health Associates was to identify trends in safety biomarkers and their utilization in drug development.  Regardless of company size, recurrent themes for assessing drug safety in early preclinical development were noted.

  • Greater knowledge of safety biomarkers improved mechanistic understanding and helped to determine the relevance of nonclinical findings for clinical risk assessment.
  • Preclinical inclusion of systems or pathway modeling was deemed important for the selection and interpretation of biomarkers of organ toxicity.
  • Physical chemical prediction software or other forms of genetic or developmental and reproductive toxicity (DART) prediction software (e.g., DEREK, M-CASE, Leadscope) were being incorporated into early preclinical development by most companies.  All 3 software companies have Cooperative Research and Development Agreements (CRADA) with the FDA.
  • For cellular parameter screens, most companies are using image-based multi-parametric approaches of cellular analysis and cytotoxicity at the single-cell and subcellular level (via High Content Analysis [HCA])
  • Off-target screening (usually a CEREP panel) was performed by most companies early in preclinical development.

As might be expected to “slow the burn,” smaller companies ran fewer preclinical screens to predict drug safety and  performed these screens later in the drug development process.  Given that larger companies expect to have this information sooner than later, companies wanting to partner and/or be acquired may consider including more screens for drug safety earlier in their preclinical development programs.

 

SourceDSEC Drug Safety Executive Blog

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New Procedure Cage Reduces Primate stress

Posted by cdavenport on Monday Jul 23, 2012 Under Caging, Techniques, Toxicology

An innovative Procedure Cage invented by Dr. Ryoichi Nagata, SNBL USA chairman, is at the center of a comprehensive program designed to significantly raise standards for non-human primate (NHP) care and thereby improve the quality of preclinical data collected.

The Procedure Cage attaches directly to an animal’s home cage allowing animals to enter on their own.  This innovation significantly reduces animal stress by eliminating the need for capture-by-hand or use of other restraints, creating a calmer handling environment.  In addition, the use of this separate cage for study-related procedures allows the animal to always view their home cage as a “safe place.”

The Procedure Cage is currently being tested at six beta test sites including key pharmaceutical industry, government, and university locations.  The results will be presented at the American Association for Laboratory Animal Science (AALAS) National Meeting in Minneapolis on November 4-8, 2012.  The Procedure Cage is available exclusively through SNBL USA.

Procedure Cage Demo:  Click here

Source:  SNBL USA newsletter (18 July 2012)

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Transgenic and genetically modified animal models are increasingly being used in the study of disease and for the safety assessment of new compounds.  Use of these models enhances understanding of the role that specific genes play in biological pathways.   The primary uses of transgenic mouse models in toxicology have mainly been to screen for genotoxicity and carcinogenicity and to understand the mechanisms of toxicity.   These mouse models can reliably predict the carcinogenic potential of compounds and significantly reduce the number of false positives.  When applied as single assays, however, transgenic models are unable to identify all known human carcinogens.  Use of a short-term transgenic mouse assay in combination with a two-year rat chronic study could eliminate the occurrence of false negatives and increase the overall accuracy of detecting carcinogens and non-carcinogens.  Additional bonuses for use of transgenic assays include reduced duration, conservative use of animals, and decreased cost relative to a traditional two-year rodent chronic toxicity study.

Source:  Life Science Leader

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The increased requirement for combined chronic toxicity and fertility assessment of biologics has led to greater use of sexually mature non-human primates.  Older animals have different needs compared to the younger, adolescent animals with which we are used to working.  In addition, the establishment of sexual maturity requires additional parameter measurements, such as assessment of menstrual cycling, hormone analyses, and seminology.  Changes in caging are required to reflect the social hierarchy inherent with the interaction of older primates, especially since subordinate animals mature later than their dominant peers.  Provision of complex environmental stimuli also becomes a greater necessity.  Due to the increased size and weight of older primates, handling becomes more of a potential source of stress and injury, to both animals and their handlers.  Differential criteria for assessment of sexual maturity in primates are discussed.

Source:  Developments in Life Sciences

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Potential Academic Contributions to Drug Development

Posted by cdavenport on Monday May 14, 2012 Under Drug Safety, FDA, Techniques

Dr. Janet Woodcock (CDER, FDA) stated that for every 10 drugs that enter Phase I clinical trials, only 1 drug is approved.  The cost of bringing an innovative drug to market often requires a decade and a billion dollars of investment.  The paradigm where pharmaceutical companies invest heavily in research and development yet garner few drug approvals is unsustainable.

Woodcock suggests that academic researchers can contribute better methods and technologies to enable faster/better preclinical and clinical decisions to be made during drug development.  Recommendations given include:

  • Development of biomarkers that help identify not only safety risks but also identify patients most likely to benefit from a new, targeted therapy
  • Greater emphasis on applied science (e.g., drug manufacturing and scale-up enhancements)
  • Identification of biochemical pathways causal to disease states
  • Identification of proof-of-concept/surrogate endpoints
  • Enhanced understanding of how the body handles a drug
  • Take a lead on developing orphan drugs, which have historically not been a priority for pharmaceutical companies
  • Develop and implement new ways to conduct clinical trials (e.g., use of early biomarker identification to guide patient selection) with the goal of developing faster, better, smaller clinical studies to gain critical information more quickly ( e.g., work being done at Stanford University)
  • To extend clinical trials into the community and region surrounding academic medical centers to facilitate patient access, recruitment, and to enhance compliance

The public has a decreased tolerance for risk, as evidenced by increased regulatory requirements for premarket evaluation of drug safety and efficacy.  The hope is that academic researchers can drive changes in the required testing paradigms (nonclinical and clinical) to enable faster, better, and cheaper drug approvals.

Sources:  Lecture by Dr. Janet Woodcock at the California Institute for Quantitative Biosciences (qb3), UCSF and HealthCanal.com.

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Nonclinical Cardiotoxicity Testing: Stem Cell Use

Posted by cdavenport on Thursday Oct 13, 2011 Under Cardiovascular, Drug Safety, Techniques

Prospective identification and potential amelioration of cardiotoxicity is a critical component of contemporary drug development, particularly for targeted therapies (e.g., tyrosine kinases) in oncology that are designed to inhibit critical signaling pathways shared by both the tumor cell and the cardiac myocyte (e.g., HER2 and C-Abl).  Current preclinical approaches to cardiac safety, which often focus primarily on ion channel testing (e.g., hERG), need to broaden the in vitro test menu to assess other cellular functions that are critical to cardiac cell health.  Accordingly, effective nonclinical cardiotoxicity screening programs need to be implemented earlier in the development process.

Stem-cell technologies offer induced pluripotent stem-cell-derived (iPSC) cardiac myocytes that are pure, functionally relevant (exhibit electrical profiles in culture and are amenable to patch-clamp-like studies that monitor electrical potentials and voltage-gated ion channel function), and are human in origin.  The following would comprise an effective preclinical cardiac safety testing program utilizing  iPSC-derived cardiac myocytes:

  • Determining influences on key cardiac metabolic pathways focusing on AMPK;
  • Evaluating changes in fatty acid beta-oxidation;
  • Measuring changes in mitochondrial health , reactive oxygen species production, and ATP levels;
  • Assessing drug-induced apoptosis;
  • Survey potential off-target effects using a comprehensive kinase profiling platform.

In addition to the above, the preclinical program should identify compounds that demonstrate cardio-protective effects with regard to mitochondrial health and energy homeostasis.

Glossary

ABL1 = a proto-oncogene which encodes a cytoplasmic (C-ABl) and nuclear protein tyrosine kinase.  Implicated in processes of cell differentiation, cell division, cell adhesion, and stress response.

AMPK = a metabolic sensor of cellular ATP.  Controls fatty acid oxidation and glucose uptake in skeletal muscle, heart, and liver.

ATP = adenosine-5′-triphosphate, a multifunctional nucleoside triphosphate used in cells as a coenzyme.  Responsible for intracellular energy transfer.

HER2 = “Human Epidermal growth factor Receptor 2,” a receptor required for healthy heart function.

hERG = the human Ether-à-go-go Related Gene.  Codes for a potassium ion channel protein.

 

SourceDrug Discovery and Development

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Zebrafish: Preclinical Screening and Toxicity Assessment

Posted by cdavenport on Saturday Sep 3, 2011 Under Drug Safety, Techniques, Toxicology

Zebrafish offer a nonclinical model for the high-throughput screening of drug compounds, including toxicity assessment, with resolution at the cellular level in living vertebrate organisms.  These small, freshwater, tropical fish share genetic and biochemical similarity to humans, in addition to similar organ system development.  Vertebrate disease models (e.g., Parkinson’s, epilepsy, wound repair) are available , as are 3-D image resolution and data analysis capabilities.  Live-imaging options, unparalleled in other vertebrate organisms, are possible using the transparent larvae.  Furthermore, live-cell microscopy can provide views of the inner complexity and workings at the cellular level.  For purposes of disease modeling, researchers can create and screen genetic mutants in the zebrafish that are linked to human immune diseases.  Neurological assessments using the live, transparent, zebrafish larvae allow visualization of the mechanisms of myelination.  In conclusion, the zebrafish preclinical model owes much of its popularity to the transparent nature and relevant ease of imaging of vertebrate larvae.  Optimization of data analyses for these varied indications is ongoing.

Source:  Genetic Engineering and Biotechnology News

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Dried Blood Spot Analysis: Preclinical Considerations

Posted by cdavenport on Tuesday Jun 14, 2011 Under FDA, Preclinical, Techniques

A previous entry detailed Dried Blood Spot Analysis: Preclinical Pros and Cons.  Additional preclinical considerations include the ambiguity of acceptance by global regulatory agencies, none of which have issued definitive rulings on how they’ll handle New Drug Applications (NDA) that use the technique.  Furthermore, although validation standards and regulatory guidance exist for liquid assays, many of the suggested parameters (e.g., reproducibility after freezing and thawing of samples) are not applicable to dried blood spot analyses, where samples are dried and stored at room temperature.

Physical parameters also affect dried matrix spotting.  Blood spot size is partly dependent on hematocrit, the percentage of the blood volume composed of red blood cells.  Hematocrit is not only variable between individuals but also varies daily within a given individual.   Therefore given sample dilution based on variable hematocrit, analyte levels can vary widely between individual samples.   As a further development, the heightened analytical sensitivity used in nonclinical drug development (relative to the more traditional clinical uses) has mandated more stringent standards for blotter paper.

Another preclinical use for this technique is analysis of other limited-volume body fluids (e.g., synovial fluid, tears, and cerebrospinal fluid), some of which have not been routinely sampled preclinically in the past due to inefficient methodology.  For example, arthritis mostly affects biomarkers in synovial fluid.  In rodent preclinical models, however, only a few microliters of synovial fluid exist in each joint.  This has forced preclinical scientists to rely on surrogate markers in the animal’s plasma to monitor drug efficacy/toxicity.  By utilizing dried matrix spotting, rodent joints can now be sampled directly.  Furthermore, due to the generally colorless nature of alternate fluids, proprietary paper treatments have been identified to allow for color changes that facilitate spot identification.  As an additional benefit, alternate fluid analyses lack the inherent variability due to hematocrit.

Dried matrix spotting is quickly overcoming perceived challenges.  It remains to be seen whether the heralded FDA Strategic Priorities for 2011-2015, which include advancing the field of Regulatory Science, will promote advancement/acceptance of dried matrix spotting as part of it’s mandate to develop new tools, standards, and approaches to assess the safety, effectiveness, quality, and performance of FDA-regulated products.  Stay tuned…!

Source: Drug Discovery and Development.

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