The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Monthly Archives: April 2012

Monday Biotech Deal Review: April 30, 2012

Welcome to your Monday Biotech Deal Review for April 30, 2012.  It was a slow week last week, with a couple of private placement closings, a business unit purchase and some commercial activity.  Read on to learn more.  Read more of this post

Friday Science Review: April 27, 2012

All vertebrates share a general brain structure, featuring a forebrain, midbrain, and hindbrain, something that is most evident during embryogenesis. However, it is the size and structure of the forebrain and most notably the cerebral cortex that differentiates mammals from the other vertebrates.

As might be expected, the process by which the mammalian forebrain develops is a hugely complicated and fortunately tightly regulated process that involves the expansion of neural progenitor cells, followed by coordinated asymmetric divisions and differentiation to produce the specialized neuronal subtypes that make up the six layers of the cortex.

Regulation of this process is achieved through a combination of internal cellular programs and modulation by external signaling factors.  Neurogenic transcription factors were obvious actors in the intrinsic cellular programs, however, observations that mutations in genes encoding chromatin remodeling proteins caused neurodevelopmental disorders has implicated a role for epigenetics in brain development. It is to our understanding of this epigenetic mechanism to which researchers at the Ottawa Hospital Research Institute and the University of Ottawa have contributed with their recent paper in Developmental Cell.

They sought to determine the in vivo roles of the mammalian ISWI chromatin remodeling protein Snf2l in murine forebrain development by using a conditional targeting approach to remove Snf2I’s ATP-binding motif, thereby impairing its chromatin remodeling activity. Mice containing the mutated Snf2I showed enhanced neural progenitor cell expansion and forebrain hypercellularity that arose from an increased progenitor cell cycle rate and enhanced self-renewal. The hypercellularity was caused by perturbation of the progenitor cell cycle kinetics and delays in the initiation of differentiation and neurogenesis. Expression profiling of the mutant mice, identified increased expression of Foxg1/Brain factor-1, a forkhead homeodomain transcription factor, and the researchers were able to show that Snf2I’s normal role is to reduce Foxg1/Brain factor-1 expression, thereby resulting in the increase in activity of p21 and terminal differentiation of the progenitor cells.

Other Publications:

  • Structure of an intermediate state in protein folding and aggregation. Science. University of Toronto
  • Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells. PLoS One. University of Toronto

Deloitte and Thomson Reuters Follow Up on R&D Value

An interesting follow-up study conducted by Thomson Reuters & Deloitte delving into what many in the industry have sought to understand better.  Last year Deloitte and Thomson Reuters conducted an analysis into value measurement at the “whole R&D business” level using Internal Rate of Return (IRR). This year, they have extended their analysis, looking at the same cohort of companies one year on.

This year’s analysis has highlighted the following key points:

  • R&D leaders are under continued pressure to justify the investment in the ‘business of R&D’ as many companies show a reduction in static IRR
  • Year on year (static) IRR measures reflect the productivity challenges within the industry but also conceal some underlying successes.
  • Analysis of dynamic returns allows us to identify encouraging signs within the industry, but also shine a light on areas of concern which should remain a focus for R&D leaders.
  • For a fair account of R&D performance, dynamic return measures need to be viewed over a four to five year timeframe, yet after one year some companies are demonstrating superior dynamic returns with respect to their peers.

Click here for the full report (pdf).

[ed. Welcome to Christian Hartmann, a new author here at the blog. He’ll be blogging from the upcoming BIO 2012 conference in Boston.]

Monday Biotech Deal Review: April 23, 2012

Welcome to your Monday Biotech Deal Review for April 23, 2012.  Deals from the past week were slow, but included a $10M brokered private placement by Allon Therapeutics and the completion of Warnex’ new credit facility.  Read on to learn more.  Read more of this post

Friday Science Review: April 20, 2012

This week’s Friday science review covers a Nature paper from a large international collaboration – 19 affiliated institutes no less – with the lead author from the University of British Columbia/British Columbia Cancer Research Centre. They present results from the study of somatic mutations in triple negative breast cancer (TNBC) patients.

TNBCs are a subset of breast cancers (~16%) that do not express the estrogen receptor, progesterone receptor or HER2; cannot be treated with endocrine therapy or the HER2-targeting Herceptin (trastuzumab); and are associated with relatively poor outcomes. They show that at the time of diagnosis for 104 TNBC cases the tumours exhibited a wide and continuous range of genomic evolution spanning from a few somatic alterations to hundreds of somatic genomic aberrations. Looking deeper in to the clonal variation within an individual tumour they found significant differences, which meant that at diagnosis the TNBCs already displayed a widely varying clonal evolution. As expected, known drivers such as p53, PIK3CA and PTEN were amongst the highest clonal frequencies, indicating that they were early events in the clonal evolution, however, this was not always the case and in some cancers another unidentified driver of early clonal expansion must have been present.

Ultimately this work adds to the growing sense that to really understand the mechanics driving tumour growth and to predict therapeutic responses will require looking into the individual tumour clonal genotypes.

Other publications:

  • Gastrointestinal-sparing effects of novel NSAIDs in rats with compromised mucosal defence. PLoS One. McMaster University
  • Aberrant Localization of FUS and TDP43 Is Associated with Misfolding of SOD1 in Amyotrophic Lateral Sclerosis. PLoS One. University of British Columbia
  • TOR Is Required for the Retrograde Regulation of Synaptic Homeostasis at the Drosophila Neuromuscular Junction. Neuron. McGill University
  • Engagement of β-arrestin by transactivated insulin-like growth factor receptor is needed for V2 vasopressin receptor-stimulated ERK1/2 activation. PNAS. Université de Montréal
  • Road crash fatalities on US income tax days. JAMA. University of Toronto

Monday Biotech Deal Review: April 16 2012

Welcome to your Monday Biotech Deal Review for April 16, 2012. Highlights include deals by Bioniche, Valeant and Bunge and $5 million of equity financings.  Read on to learn more.  Read more of this post

Friday Science Review: April 13, 2012

Intrinsically disordered proteins, i.e. proteins or regions of proteins that do not adopt defined structural folds, but rather exist as a dynamic ensemble of structures, are a fascinating and important area of biology. Members of this class of proteins are enriched in cell signaling, transcription and translation, where their lack of fixed structure must be conferring a functional advantage.  Often involved in multiple interactions and subject to complex control through post-translational modification, these proteins have immense biomedical relevance, however, their very nature and complexity complicates attempts to characterize them.

Results reported in PNAS by researchers from the Ontario Cancer Institute are gradually filling in the details for one such protein, FOXO3a. This ubiquitously expressed protein activates transcription of genes responsible for differentiation, DNA repair, cell cycle regulation, stress resistance and apoptosis, which it achieves by binding to specific elements in DNA, followed by recruitment of the coactivator CBP/p300. Using nmr on peptides from the intrinsically disordered region of FOXO3a in the presence of the cognate binding partner domain from CBP/p300, they confirmed that two regions of FOXO3a are involved in the interaction, but unexpectedly that the complex is dynamic and exists in two conformationally distinct states. Furthermore, recruitment of CBP/p300 is promoted by interactions with other domains of CBP/p300 and the interaction can be further enhanced by phosphorylation at a specific position within the disordered CBP/p300 binding region of FOXO3a.

These findings help to build a model of the dynamic, promiscuous and multivalent interactions that underlie the functions of intrinsically disordered proteins and can help us to understand why an intrinsic lack of structure can have advantages in both recruiting binding partners and providing mechanisms to modulate those interactions.

Other Publications:

  • Critical Evaluation of Imprinted Gene Expression by RNA-Seq: A New Perspective. PLoS Genetics. University of Toronto
  • Blockade of Fatty Acid synthase triggers significant apoptosis in mantle cell lymphoma. PLoS One. University of Alberta and Cross Cancer Institute
  • EGF-Induced EMT and Invasiveness in Serous Borderline Ovarian Tumor Cells: A Possible Step in the Transition to Low-Grade Serous Carcinoma Cells? PLoS One. University of British Columbia
  • Real-time visualization and quantitation of vascular permeability in vivo: implications for drug delivery. PLoS One. Innovascreen, Inc.
  • Lentivector Transduction Improves Outcomes Over Transplantation of Human HSCs Alone in NOD/SCID/Fabry Mice. Molecular Therapy. University Health Network, Toronto

Friday Science Review: April 6, 2012

Mutations in the CFTR gene, which encodes a chloride channel expressed on the apical membranes of surface epithelial cells, can lead to dysregulation of ion conduction and solute trafficking in these cells. This dysregulation manifests as the accumulation of thicker than normal mucus in the lungs, digestive tract and other areas and it is the inability to clear this mucus that leads to the health consequences for cystic fibrosis (CF) patients.

Over 1900 different mutations and sequence variations in the CFTR gene have been identified and this increase in understanding will allow the development of treatments that target the underlying molecular defect, as demonstrated by the recent approval of Vertex Pharmaceuticals’ Kalydeco, a CFTR potentiator, which increases chloride flux through CFTR channels containing the G551D mutation found in ~4% of CF patients.

However, even in individuals that share the same molecular change to the CFTR gene, there are substantial variations in the disease severity and in the organs affected. The disease pathophysiology is therefore being modulated by variations in other genes. Researchers at the Biostatistics division of the Dalla Lana School of Health and the Department of Statistics of the University of Toronto sought to identify the variations that are associated with meconium ilius (MI), a severe intestinal obstruction at birth that is highly indicative of CF, by carrying out genome wide association studies. Using SNP’s from thousands of CF sufferers born with MI they found associations with variations in three genes that encode members of the solute carrier family of secondary transporter proteins (SLC6A14, SLC26A9, and SLC9A3) and association of MI with multiple other genes that are constituents of the apical plasma membrane.

Identification of these genes helps further develop understanding of the molecular mechanism of the disease i.e. how is the system level function perturbed by the altered chloride levels, as well as opening up new avenues for treating CF by pharmacological modulation of the epithelium as a whole.

Other publications:

  • Differences in the Mechanisms of Proapoptotic BH3 Proteins Binding to Bcl-XL and Bcl-2 Quantified in Live MCF-7 Cells. Molecular Cell. McMaster University
  • PARP1 Parylation Promotes Silent Locus Transmission in the Nucleolus: The Suspicion Confirmed. Molecular Cell. Centre de recherche du CHUQ-Pavillon CHUL
  • Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERα- breast cancer. PNAS. Toronto General Research Institute

Monday Biotech Deal Review: April 2, 2012

Welcome to your Monday Biotech Deal Review for April 2, 2012.  There have been few large transactions over the previous weeks, but there have been some private placement financings and M&A activity, including the announcement of a takeover by Valeant of Russian-based Natur Product International for approximately $180M.  Read on to learn more.  Read more of this post


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