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Tag Archives: University of Calgary

Monday Biotech Deal Review: May 9, 2011

Welcome to your Monday Biotech Deal Review for May 9, 2011.  Biotech activity was a bit slow last week.  Of note however is the minority shareholder oppression litigation launched against WEX Pharmaceuticals in the wake of the recent takeover by Pharmagesic (Holdings) Inc.  Read on to learn more.   Read more of this post

Friday Science Review: March 18, 2011

Alum Explained

University of Calgary ♦ Published in Nature Medicine, Mar. 13, 2011

During the administration of a vaccine, an antigen is delivered along with another substance, known as an adjuvant, which arouses the immune system and increases overall effectiveness. The most common adjuvant in use today is alum, a trivalent aluminum-containing salt in crystal form.

Many questions related to alum’s mechanisms of action remain unanswered, or were mostly unanswered until the emergence of recent findings from the lab of Dr. Yan Shi at the University of Calgary. Dr. Shi and his lab group discovered that alum interacts with dendritic cells, a specific cell-type in the immune system that specializes in digesting antigenic material and presenting it on the cell surface. There is no specific receptor for alum however, instead it interacts with lipids on the plasma membrane eliciting a lipid sorting mechanism. Sorting of lipids induces a phagocytic response causing an influx of antigen into dendritic cells and an increase in affinity for CD4+ T cells.

Alum has massive implications for human health given the size and importance of the vaccine market. This new insight into dendritic cell response to alum will likely be leveraged to improve upon the efficacy of future vaccines.

Suicide Gene Delivers the Blow

Jewish General Hospital ♦ McGill University ♦ Published in Cancer Gene Therapy, Mar.11, 2011

Combination treatment paradigms for cancer have been under investigation for some time, but the suicide gene approach outlined in this recent research exemplifies the advances that have been made in the area. In this approach a tumour-specific oncolytic virus delivering a fusion construct is paired with a non-toxic prodrug. When the prodrug enters an infected cell containing the suicide transgene it is broken down by the cell’s machinery into toxic metabolites. In essence, the cell commits suicide.

Oncolytic viruses target cancer cells by taking advantage of their genetic abnormalities. A perfect example is vesicular stomatitis virus (VSV), a single stranded RNA virus that grows like wildfire in cancer cells but is unable to populate healthy cells. How? VSV is extraordinarily sensitive to type-1 interferon mediated immune responses. In normal cells that have interferon signaling cascades intact the virus cannot replicate. However, in cancer cells, which have genetic alterations affecting the interferon pathway, the virus survives with relative ease. Researchers utilized a suicide gene (CD::UPRT) in combination with 5-FC, a non-toxic prodrug that is metabolized to the toxic 5-flourocytosine (5-FU) form in the presence of cytosine deaminase. The deamination of 5-FC leads to its conversation to 5-FU, a small molecule drug commonly used in chemotherapeutic regimes for the eradication of cancer. The introduction of 5-FU into the cellular system prevents normal DNA replication, and hence causes cell cycle arrest. In this study researchers showed that the suicide gene strategy was able to trigger oncolysis in a number of VSV-resistant cell strains, including prostate PC3, breast MCF7, B-lymphoma Karpas, and melanoma B16-F10.

The combination scheme investigated here allows for the targeted removal of tumour cells while preserving healthy cells. As such, it circumvents one of the primary barriers associated with the development of efficacious cancer therapeutics − non-selective toxicity. 5-FU is also highly soluble, which causes detriment to neighbouring tumour cells that have been weakly infected, producing a particularly powerful treatment.

Friday Science Review: December 10, 2010

CD8+ Cytotoxic T-cells, Weapons of Selective Destruction

McMaster University ♦ Published in Molecular Therapy (npg), Nov. 30, 2010

Oncolytic viruses (OVs) are being investigated as a means to destroy tumour cells. They exert their cytotoxic effects either directly through infection, or indirectly, if they have been engineered to flag down cancer cells by delivering tumour-associated antigens for later destruction by cytotoxic T-cell lymphocytes. After an OV infects and bursts a cancer cell, a cascade of anti-tumour immune events is initiated. Antigens that are liberated by the destruction of cancer cells are internalized by a cell-type known as an antigen presenting cell (APC), broken down once inside, and then re-expressed on the surface of the APC. After migrating to the lymph nodes the APC ‘presents’ this protein signature to T-cells which deliver the final blow. Recognition of tumour antigens by T-cells drives the expansion of T-cell populations into cytotoxic T-lymphocytes (CTLs) and memory populations that seek out cancer cells. Upon finding cancer cells, CTLs latch on to their surface and release granules containing perforin and granzyme inducing cell breakdown. In recent work coming from the lab of Dr. Karen Mossman at McMaster University, researchers showed that a replication-defective Herpes Simplex Virus (HSV) possesses oncolytic properties in a breast cancer model. New work by this lab group stresses the importance of choosing appropriate in vitro models to study oncolytic viruses. Mossman found that the sensitivities of different cancer cell lines to in vitro oncolysis did not correlate well with in vivo oncolysis in more than one virus under study. These findings illustrate the importance of adaptive antiviral CD8+ cytotoxic T-cells in producing effective oncolytic viruses for virotherapy. Examples of such a therapies in late-stage clinical development include the OncoVEX technology being developed by BioVex for advanced melanoma and JX-594, an oncolytic virus being developed by Jennerex for the treatment of hepatocellular carcinoma.

Insulin Expression Driven by Synthetic Promoter

University of Calgary ♦ Published in Molecular Therapy (npg), Nov. 30, 2010

A step forward for gene therapy in the diabetes arena as researchers have engineered an adenovirus containing the insulin gene under the expression of a highly active and liver-specific promoter. Following IV delivery of the virus into a diabetic mouse model normal glycemia was maintained for greater than 30 days. Glucose tolerance tests also showed that diabetic mice were able to produce insulin and clear exogenous glucose from the bloodstream in a fashion similar to healthy mice. Scientists chose the liver as a target for gene therapy because hepatocytes are particularly sensitive to glucose. The strength of these preclinical findings is in part due to the promoter used to stimulate expression of the insulin DNA component. Dr. Hee-Sook Jun and his team generated a synthetic promoter library and scanned it for promoter components and arrangements that had the strongest transcriptional activity.

Friday Science Review: October 22, 2010

Some great research to touch on this week in top-notch journals including Science, Cell, and NEJM. The first publication really emphasizes the strength of collaborative research projects around the globe.

Understanding Endometriosis: Ovarian clear-cell carcinomas are less common than high-grade serous carcinomas (12% and 70% of total respectively), but still remain the second leading cause of death from ovarian cancer. It is important that the mechanisms behind the formation of this rare subtype are elucidated because it is not responsive to conventional platinum-taxane chemotherapeutic regimes that are currently the first-line treatment for ovarian cancer. In a comprehensive study published in The New England Journal of Medicine, researchers sequence the entire transcriptomes of 18 ovarian clear-cell carcinomas  and identify frequent somatic mutations in the tumor suppressor gene ARID1A (the AT-rich interactive domain 1A). ARID1A encodes the protein BAF250a which in turn is part of the chromatin remodeling complex SWI-SNF that regulates a diversity of cellular processes including DNA repair and tumor suppression. Interestingly, the mutation appears specific to the clear-cell and endometrioid subtypes. After identifying the ARID1A mutation, researchers carried out targeted re-sequencing in a mutation-validation cohort consisting of an additional 210 carcinoma samples from all subtypes. Combining the discovery cohort and validation cohort, the ARID1A mutation was found in 55 of 119 clear cell carcinomas (46%), 10 of 33 endometrioid  carcinomas (30%), but not one of 76 high-grade serous ovarian carcinomas. These findings strongly implicate ARID1A mutation in the early transformation of endometriosis into cancer and the genesis of clear-cell and endometrioid ovarian carcinomas. This exhaustive work was carried out by some 45 researchers in a dozen or so institutions found in Canada, the United States, and Australia.

Danger Signaling: Physical injury to tissue leads to cell necrosis and the release of special patterning molecules, including proteins, nucleic acids, extra-cellular matrix proteins, and various lipids as a complex milieu of chemotaxic signals. Neutrophils are able to use these unique signals to guide themselves to the site of a wound, and play an important role in recycling debris from dying cells. In a study published in Science, led by Dr. Paul Kubes of the Immunology Research Group at the University of Calgary, researchers used a mouse model of sterile injury and an in vivo imaging technique known as spinning disk confocal microscopy to observe the kinetics of eGFP-expressing neutrophils in response to thermal induced necrotic injury. Experiments revealed that necrotic cells activated a multistep hierarchy of cues that lured neutrophils to the site of danger. Another interesting finding of the study is that neutrophils appear to travel to the site of injury intravascularly as opposed to taking the most direct route through tissue. The group proposes that danger sensing and recruitment mechanisms may have evolved to prioritize intravascular travel in order to reduce the collateral damage incurred if neutrophils were to migrate directly through healthy tissue.

In Pursuit of Perfection: The fundamental limit of minimally invasive surgery is at the level of the single cell. In principal, lasers are capable of operating at this spatial resolution however efforts to achieve this have been limited by thermal and shock wave induced collateral damage to surrounding tissue. The long-held promise of a fine surgical laser has been delivered by two investigators in the Toronto research community with the creation of a novel laser source – the Picosecond IR Laser (PIRL). As a cutting modality the PIRL has a shorter pulse duration than conventional surgical lasers, vaporizing tissue on the picosecond timescale rather than burning on the nanosecond, and exploits a new cutting mechanism that selectively energizes water molecules. Researchers created full thickness wounds in CD1 mice using PIRL to demonstrate that it caused neither cavitation or any associated shock wave induced damage, and also showed that PIRL greatly reduced scar formation by comparison to conventional surgical laser or scalpel. The technology is expected to be useful in surgical procedures where scarring is particularly debilitating. Dr. Benjamin Alman, Head of the Division of Orthopedic Surgery at Sick Kids, and Dr. Dwayne Miller, in the Department of Chemistry at the University of Toronto, were co-principal investigators in this study published in PloS ONE.

At the Junction: The RAS/MAPK signaling pathway contributes to a number of important cellular processes including proliferation, differentiation, and survival. In its most basic form the pathway is regulated by the small GTPase RAS, and the three core kinases RAF, MEK, and ERK/MAPK. Like most signaling pathways, the RAS/MAPK pathway is controlled by a diversity of post-translational modifications but much less is known about regulation of its core protein components at the mRNA stage. Using a genome-wide RNAi screen in Drosophila S2 cells, researchers set out to identify other proteins involved in the pathway that could modulate MAPK protein levels. In doing so they identified the Exon Junction Complex (EJC) as a regulator of mapk transcripts. The complex is believed to contribute to the regulation of exon definition and suggests that the EJC has a key role in early regulation the RAS/MAPK pathway. This study, published in Cell, was led by Dr. Marc Therrien at the University of Montreal.

Friday Science Review: September 4, 2009

Potential future therapeutic options…

Dabigatran versus Warfarin: Dabigatran (PRADAX®, Boehringer-Ingelheim) was compared with warfarin (a commonly used anti-coagulant) in a large scale study for the treatment of patients with atrial fibrillations.  The trial demonstrated that the group of patients taking the higher dose of Dabigatran had significantly reduced risk of stroke compared to patients on warfarin but with similar risk of hemorrhaging.  With a lower dose of Dabigatran, they achieved protection from strokes that was similar to that afforded patients using warfarin but with a significantly reduced risk of major bleeding.  Dabigatran is the first alternative therapy option to warfarin treatment showing efficacy and improved safety to patients.  The global study was headquartered out of Hamilton at McMaster University and Hamilton Health Science Centre and appears in this week’s The New England Journal of Medicine.

Drug combo for Bell Palsy: Combinatorial therapy may be a better treatment method to improve the facial paralysis symptom of Bell Palsy patients. In the study lead by Dr. John de Almeida at Sunnybrook Health Science Centre, they compared the standard treatment with corticosteroids alone versus corticosteroids supplemented with antiviral drugs.  It is thought that a herpes infection is likely the cause of the disorder.  As the patients appeared to have experienced a slight incremental benefit from the combo therapy, the researchers will continue their study to provide a definitive answer.  The report was published in the current issue of the Journal of the American Medical Association (JAMA).

Key finds from studying protein structure:

  • The RAF family of proteins is an integral component of the RAS signaling module involved in cell growth, differentiation and survival.  This new structural study on BRAF revealed that its catalytic function is regulated by a “side-to-side” dimerization mode.  Interestingly, a mutation found in oncogenic versions of BRAF is located in this dimerization interface and promotes aberrant activation.  Surely, the side-to-side dimer interface of BRAF will be a potential target for therapeutic intervention against BRAF-dependent tumorigenesis.  This exciting research was lead by a collaborative effort between Dr. Frank Sicheri at the Samuel Lunenfeld Research Institute in Toronto and Dr. Marc Therrien at Université de Montréal and published in the early edition of Nature.
  • New insight into how bacteria can steal iron from its host was revealed through structural studies of the bacteria’s transferrin receptor.  The bacterial transferrin receptor binds to the host’s iron containing transferrin protein, extracts the iron and transports it across the membrane.  When they mutated a critical residue at the interface of this interaction, binding was completely abolished.  Perhaps these results from Dr. Anthony Schryvers’ research team at the University of Calgary will lead to future directions for antimicrobial therapeutics.  The study was published in the recent edition of Molecular Cell.

Nervous system development in today’s issue of Cell…

  • Researchers revealed how the neural-specific SR-related protein of 100 kDa (nSR100) is responsible for facilitating alternative transcript splicing specifically in the nervous system.  nSR100 is required for neural cell differentiation and contributes to the greater complexity of the vertebrate nervous system.  The research was lead by Dr. Benjamin Blencowe at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research.

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Friday Science Review: January 30, 2009

Interesting science developments in and from Canada this week:

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