The Cross-Border Biotech Blog

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

Monthly Archives: March 2012

Friday Science Review: March 30, 2012

Fans of bad horror films will know that Ebola and other hemorrhagic viruses are definitely something to be avoided. For those not in the know, infection by Ebola begins with flu like symptoms but leads to mortality in 90% of cases. While outbreaks are thankfully rare, the inability to determine the natural maintenance host of the 4 Ebola disease causing viruses, its endemic state in certain geographical regions and the potential threat from its use as a terror weapon means that it is the subject of some substantial research efforts. However, its classification as a biosafety level 4 agent means that studies on the virus can only be carried out in only a small number of facilities worldwide. Hence this week’s research comes from a different centre than we normally cover in the Friday Science Review – the Special Pathogens Program at the National Microbiology Laboratory of the Public Health Agency of Canada, the operator of Canada’s only biological safety level 4 lab (BSL-4).

Their paper in PLoS Neglected Tropical Diseases evaluates the protective efficacy of 8 different monoclonal antibodies (mAbs) directed against Ebola’s surface glycoprotein in preventing lethal Ebola infections in mice and guinea pigs. All 8 of the mAbs were able to protect mice against lethal Ebola virus challenge when administered within 1 day. However, these mAbs were only able to achieve partial protection for guinea pigs under the same conditions, indicating that a sole agent therapeutic targeted at the surface glycoprotein of the virus might not be possible. Encouragingly, administering combinations of 3-4 of the antibodies was able to provide significant protective effects even if administration was delayed by up to 3 days. This study demonstrates a potential therapeutic for post-exposure treatment of Ebola virus infections, something that is sorely lacking to date.

Other Publications:

  • Superoxide dismutase is dispensable for normal animal lifespan. PNAS. McGill University
  • Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nature Medicine. McGill University
  • Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics.Cancer Cell. University of British Columbia

Friday Science Review: March 23, 2012

When the human genome was sequenced there was surprise that only 23 thousand protein-encoding genes were found. However, it was followed by an added emphasis on the other mechanisms used by eukaryotic organisms to generate proteome diversity and especially the creation of different protein isoforms through alternative splicing of exons in precursor mRNA transcripts. Indeed, in humans it is estimated that 95% of genes containing more than one exon are subject to alternative splicing and splicing of the same gene varies by tissue type.

Given its importance, characterizing the molecular mechanism by which tissue specific splicing occurs and its effect on downstream function is therefore an important area of research and the study carried out by researchers from McGill University and Laval University is helping to fill some of the current gaps. Alternative splicing is regulated by RNA binding proteins, one of which is Sam68, a member of the signal transduction activator of RNA (STAR) family. Sam68-/- mice are leaner than normal mice and are protected from obesity, insulin resistance and glucose intolerance. In their paper published in Molecular Cell, they explored the alternative splicing events regulated by Sam68 to explain its unexpected physiological roles.

By carrying out genome-wide exon usage profiling in the white adipose tissue, they were able to show that Sam68-/- mouse cells had lower levels of mTOR, which resulted from the introduction of a premature termination codon due to intron 5 from the mTOR gene not being excised. The lower levels of mTOR had downstream consequences, including reduced insulin-stimulated S6 and Akt phosphorylation, which reduced adipogenesis.

mTOR inhibitors are of course in the clinic (and in multiple clinical trials) for use in immune suppression and cancer, but is weight loss about to be added to that list? A recent paper from the University of Geneva shows that the chronic exposure to the mTOR inhibitor rapamycin does result in reduced specific fat mass in rats, but at the cost of rather serious systemic consequences including skeletal muscle insulin resistance.

While probably not initiating the rush for development of the new perfect diet pill, this research on tissue specific gene-splicing continues to add to our understanding of the various levels at which signaling pathways are regulated and their tissue dependence.

Gairdner Awards

This week also saw the announcement of the 2012 Canada Gairdner Awards, which recognized contributions to our understanding of the genetic control of circadian rhythms; of how sensory and motor neurons communicate; and the role of Fc receptors in immune response and autoimmune diseases. The awards also recognized the efforts of two scientists for their role in reducing the toll of infectious diseases. Details can be seen on the Gairdner website here.

Other Publications:

  • Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nature Medicine. University of Calgary
  • Cell-Surface Proteomics Identifies Lineage-Specific Markers of Embryo-Derived Stem Cells. Developmental Cell. University of Toronto
  • Direct observation of multiple misfolding pathways in a single prion protein molecule. PNAS. University of Alberta

Friday Science Review: March 16, 2012

I have spent much of this week looking into cancer metabolism, where the recent partnership successes of Forma and fund raising by Agios have shown how hot this area has become. Many cancer cells it turns out switch their metabolism to aerobic glycolysis, a phenomenon known as the Warburg effect. An important regulator of the switch to glycolytic metabolism is the transcription factor HIF-1 (hypoxia inducible factor 1), which, in response to low oxygen conditions or cytokines, growth factors and ROS amongst others up-regulates a whole host of elements involved in stimulating glycolytic flux, including the glycolysis enzymes and regulators, as well as glucose transporters etc.

The cellular rationale above seems clear, in low oxygen conditions cells up-regulate their ability to carry out anaerobic energy production. However, coincidentally, the recent research led by Dr Michael Ohh at the University of Toronto, reveals an interesting new facet to the adaptations: HIF-1 also increases the expression of Caveolin-1 (CAV1), a structural component of caveolae – small flask shaped invaginations in the plasma membrane that have roles in cell signaling and endocytosis. Their research shows that the HIF-1 induced CAV-1 expression leads to increased caveolae on the cell surface and significantly, as a result, increased activation of the EGF signaling pathway even in the absence of ligand due to dimerization of EGF receptors within the caveolae. HIF-1 dependent up-regulation of CAV-1 thereby enhanced the oncogenic potential of tumour cells and increased tumour cell proliferation.

HIF-1 over-expression is commonly seen in tumors, either due to hypoxic tumor conditions, or due to aberrant regulation resulting from mutations in upstream tumor suppressors such as TSC2, PTEN, p53, and VHL and this new finding emphasizes the complexity of the changes seen in cancer signaling and metabolism. The enhancement of glycolysis and the increase in oncogenic potential from ligand independent EGF signaling are related, but how does one attempt to integrate these very different changes? Are changes like the ligand independent EGF signaling encouraging the switch to glycolysis, or is it glycolysis itself that is favorable (for which there are multiple opinions on the possible cellular rationale)?

Other publications:

  • Lung adenocarcinoma of never smokers and smokers harbor differential regions of genetic alteration and exhibit different levels of genomic instability. PLoS One. British Columbia Cancer Research Centre
  • Mechanistic Insight into the Microtubule and Actin Cytoskeleton Coupling through Dynein-Dependent RhoGEF Inhibition. Molecular Cell. University of Toronto
  • Cell-Type Specific Roles for PTEN in Establishing a Functional Retinal Architecture. PLoS One. University of Calgary
  • HIV-1 Promotes Intake of Leishmania Parasites by Enhancing Phosphatidylserine-Mediated, CD91/LRP-1-Dependent Phagocytosis in Human Macrophages. PLoS One. Université Laval

The Partnering Process – Before Crunching The Numbers: Part 17 of Valuation and Other Biotech Mysteries

[Ed. This is the seventeenth part in Wayne’s series. You can access the whole thing by clicking here. Please leave comments or questions on the blog and Wayne will address them in future posts in this series.]

Assuming that all interested potential partners know that you have a specific asset for sale, how does a licensing deal get completed?

Sellers should place themselves in the chair of the person at the potential licensing partner. From the potential partner’s perspective, there are four basic criteria which would need to be met before licensing a product or technology. Read more of this post

Monday Biotech Deal Review: March 12, 2012

Welcome to your Monday Biotech Deal Review for Monday March 12, 2012.  Following a break, the Monday Biotech Deal Review is back with summaries of biotech transactions over the previous weeks.  Activity has been impressive over the past month, with pharma-giant Valeant Pharmaceuticals syndicating $600M in senior secured indebtedness under its existing senior credit facility to fund (among other things) future acquisitions, Alexion Pharmaceuticals completing its acquisition of Enobia Pharma for $610M and Futuremed Healthcare Products Corporation was acquired by Cardinal Health Inc.  Also of note was the recent $80.5M equity financing by YM BioSciences as well as the reverse takeover of The Atman Co. by Biotonix.  Read on to learn more.   Read more of this post

Friday Science Review: March 9, 2012

An accidental neural theme for this weeks Canadian life science research highlights, beginning with…

…higher-order gyrenphalic non-human primates…

Stroke is currently the second leading cause of death here in the West and might surpass heart disease to become the number one killer. In ischemic stroke, the treatment is focused on restoring the restricted blood flow through the use of surgical or pharmacological removal of the causative blood clot. Ischemia causes neuronal damage through initiation of the ischemic cascade, a series of biochemical events that ultimately leads to neuronal death. A promising therapeutic avenue is therefore to block events in this cascade, thereby eliciting a neuroprotective effect.

However, despite promising data in cell and rodent models, a shocking number – over 100 in fact – experimental approaches have failed to demonstrate a neuroprotective effect in clinical trials. While part of this failure rate can be attributed to the poor selection of candidates to advance (from the >1000 reported pre-clinical experimental approaches), poor pre-clinical studies and poor trial design, it has resulted in a general sentiment that neuroprotection in humans is not possible.

However, research by the Tymianski lab at Toronto Western Hospital Research Institute, reported in Nature should help reinstil some much needed optimism. Rather than a rodent model, Cook and colleagues conducted their study in cynomolgus macaques, a higher-order gyrenphalic non-human primate i.e. an animal that possesses a brain more similar to that of humans. Using two experimental models of ischemia, they demonstrated the neuroprotective ability of a PSD-95 inhibitor using a broad set of measures including MRI assessed infarct volumes, retention of transcriptional ability (normally lost in ischemic cells) and retention of neurological function in neurobehavioral assays.

The target PSD-95 is a synaptic scaffolding protein that links NMDA receptors to neurotoxic signaling pathways and while their peptide based inhibitor Tat-NR2B9c had already been shown to be neuroprotective in rats, it is the first time that neuroprotection has been demonstrated in a species so close in complexity to humans. Hopefully with this model there will finally be a path to clinical success and the long sought-after realization of neuroprotection as a treatment modality for ischemic stroke.

Other publications:

  • Developmental transcriptional networks are required to maintain neuronal subtype identity in the mature nervous system. PLoS Genetics. University of British Columbia
  • Ex vivo and in vivo neuroprotection induced by argon when given after an excitotoxic or ischemic insult. PLoS One. Université Laval

Friday Science Review: March 2, 2012

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. However, current treatments e.g. dopamine precursors, monoamine oxide inhibitors and COMT inhibitors, do not aim to address the underlying loss of dopamine containing neurons, but rather, most focus on modulating the extant dopamine metabolism.

In studying PD, familial PD cases have been useful in adding to the understanding of pathophysiology. Importantly, they revealed the association of mutations in mitochondrial proteins with PD, thereby implicating mitochondrial dysfunction in the causes of the disease. One of the identified mitochondrial proteins, PTEN-induced putative kinase 1 (PINK1) is usually trafficked to the interior of mitochondria, where it is rapidly degraded. However, in dysfunctional mitochondria, the reduction in proton electrochemical gradient is associated with the failure of PINK1 to traffic to the mitochondrial interior. Instead, PINK1 accumulates on the surface of the cytoplasmic face of the outer mitochondrial membrane, where it recruits another familial PD-implicated protein Parkin. It is the recruitment of Parkin to the depolarized mitochondrion that sets in motion mitophagy and clearance of the dysfunctional mitochondrion. As such, the PINK1-Parkin pathway represents an important quality control mechanism, helping cells to remove dysfunctional mitochondria and the deleterious effects they cause due to the release of reactive oxygen species or pro-apoptotic factors.

A key question in this mechanism becomes, what is regulating PINK1? The article by the Fon lab at McGill university helps answer part of this question. By selectively screening mitochondrial proteases using RNA-mediated interference, they were able to identify mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP as being involved in the degradation of PINK1. Of these, MPP appears to be the major factor in PINK1 turnover, with even slight reductions in MPP activity resulting in PINK1 accumulation at the mitochondrial surface. The authors suggest that potentiation of the PINK-1-Parkin pathway, possibly by low level inhibition of MPP, could be an avenue to explore in treating PD by increasing the stringency for mitochondrial function and thereby reducing oxidative stress in dopaminergic neurones. While a single eukaryotic cell has over 1000 mitochondria, one has to assume that altering the fundamental balance of mitochondrial turnover is going to be fraught with perils.

However, as highlighted by the rather sparse KEGG PD pathway map, all advances that elucidate the proteins and events in PD are vital in the search for a unified, global understanding of PD, be it familial or idiopathic, and the hope for a therapy that can address the underlying molecular mechanism.

Other Publications

  • Repression of a Potassium Channel by Nuclear Hormone Receptor and TGF-β Signaling Modulates Insulin Signaling in Caenorhabditis elegans. PLoS Genetics. University of British Columbia
  • Charged and hydrophobic surfaces on the a chain of shiga-like toxin 1 recognize the C-terminal domain of ribosomal stalk proteins. PLoS One. University of Toronto
  • Lack of functional selectin ligand interactions compromises long term tumor protection by CD8 T cells. PLoS One. University of Ottawa

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