The Cross-Border Biotech Blog

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

Monthly Archives: February 2011

Monday Biotech Deal Review: February 28, 2011

Welcome to your Monday biotech deal review for February 28, 2011.  In addition to the usual reviews of biotech corporate activity, this week featured the announcement of Theratechnologies’ U.S. IPO, the closing of a $40M bought deal by Paladin Labs, Angiotech’s recapitalization amendment and the appointment of a Receiver for LAB Research.  Read on to learn more.   Read more of this post

Friday Science Review: February 25, 2011

Fusion Construct Promotes Erythropoietic Development from Human Embryonic Stem Cells

McMaster University ♦ The Ottawa Hospital ♦ British Columbia Cancer Agency

Published in Stem Cells, Feb. 15, 2011

The homeobox (Hox) genes encode a group of highly conserved transcription factors that have been known to regulate hematopoietic differentiation. As a result of their involvement in hematopoietic proliferation and lineage commitment, Hox genes have also been implicated in leukemogenesis. Researchers from Dr. Mick Bhatia’s lab have created a fusion construct that alters the hematopoietic differentiation program of human embryonic stem cells (hESCs). They chose the homeobox gene HOXA10, and partnered this with NUP98, a gene that is often found fused to Hox genes in human leukemias. After introduction of the fusion construct into undifferentiated hESCs or early-stage blood progenitors there was a marked increase in the level of erythroid progenitors founds in culture. Introduction of the construct to later-stage cells already committed to the hematopoietic lineage had no effect on the yield of erythropoietic cells. Apparently, unlike some of the fusion constructs observed in leukemias, the combination of HOXA10 and NUP98 does not lead to malignant expansion. Given the interest Dr. Bhatia and his group have in the production of blood cells, it is foreseeable that this fusion construct could be used in future differentiation protocols to bias the differentiation of hESCs towards the erythropoietic lineage.

Ubiquitination Factor E4B, A Novel Target for Brain Cancer

University of Alberta ♦ Published in Nature Medicine, Feb. 13, 2011

The tumour supressor gene TP53 and its protein product p53 are at the root of many cancers. TP53 is inactivated in 50% of human tumours. The resulting deficiency in p53 allows fledgling cancer cells to circumvent apoptotic programs and proliferate wildly. Deficiency in p53 protein may result from a mutation in the TP53 gene, or as is more frequently the case, inactivation of the p53 protein. Inactivation is often the result of ubiquitination. A specific class of enzymes in the body has the ability to add ubiquitin to proteins which marks them for degradation by other protein machinery. However, the molecular mechanisms behind inactivation of p53 in the brain remain largely understood.  Dr. Roger Leng and his team at the University of Alberta have identified a novel mechanism of inactivation in brain tumours: a ubiquitination factor (UBE4B) that directly interacts with the p53 protein destabilizing it and marking it for destruction. The factor was found to interact with an enzyme (Hdm2) that is also involved in ubiquitination. Silencing UBE4B in xenotransplanted tumours led to impaired tumour growth while over-expression of the factor was associated with amplification of its gene suggestive of a positive feedback mechanism. This discovery elucidates a potential target for treating medulloblastoma and ependymoma, two brain cancer types that exhibit inactivation of the p53 protein.

Monday Biotech Deal Review: February 21, 2011

Welcome to your Monday Biotech Deal Review for February 21, 2011.  Among other news, Angiotech made some progress this week in CCAA proceedings with respect to its recapitalization, and Merck Canada has made another investment in Quebec’s biopharma sector, investing $6.8M.  Read on to learn more.   Read more of this post

Friday Science Review: February 18, 2011

Mapping the Development of the Pancreatic Lineage

McEwen Centre for Regenerative Medicine ♦ Published in Development, Mar. 2011 (Epub ahead of print)

Human pluripotent stem cells (PSCs) are being investigated as a means to produce insulin-positive cells for the treatment of diabetes. The most efficient mode of producing functional cell types in vitro is to navigate the signaling pathways and temporal cues that lead to their formation during embryonic development. In the case of insulin-producing cells the key is to recreate the pivotal steps in pancreatic development including the induction of definite endoderm, specification of endoderm to the pancreatic fate, and finally the generation of mature endocrine/exocrine cells. Despite the scientific community having a grasp on pancreatic development, current differentiation protocols suffer from low efficiency and an inability to produce homogenous results across a variety of PSC lines using identical treatments. We have yet to identify the optimal signaling pathways that must be leveraged to produce insulin+ cells. Robust differentiation protocols are also hampered by variations in the characteristics of PSC lines which lead to variability in the quality of differentiation cultures. Dr. Gordon Keller and his lab team ambitiously probed this issue by mapping the pancreatic development of several different PSC lines in order to identify the optimal signaling pathways and temporal requirements essential for producing cells of the pancreatic fate.

Keller’s team found that temporally modulating activin/nodal signaling early in the differentiation protocol was crucial for the development of definite endoderm and ultimately for pancreatic differentiation. Wnt signaling and inhibition of BMP signaling at various stages was also prerequisite for the production of insulin+ cells, noting that the degree of BMP inhibition required for efficient differentiation varied extensively amongst PSC lines. By implementing this stage-specific optimization approach for different cell lines, Keller and his colleagues were able to increase insulin expression in cell cultures by a whopping 250 times; some populations contained as much as 25% C-peptide+ cells (prior to C-peptide being cleaved from the pro-insulin molecule, it acts as a linker between the A and B chains of insulin).

This is the second, recent, body of research from Gordon Keller’s lab that emphasizes the importance of identifying the crucial temporal steps that must be satisfied for highly efficient differentiation to terminal cell fates. This paper also reminds us that individual PSC lines will likely require unique treatments in culture to produce maximal results for transplantation therapy.

IL-7 Therapy: A Stimulus Package for the Immune System

Campbell Family Institute for Cancer Research ♦ Published in Cell, Feb. 18, 2011 (Epub ahead of print)

After the immune system succumbs to uncontrollable viral turnover, it eventually fails, leaving the host prone to any number of opportunistic infections. This is the case with HIV infection. One of the primary focuses of HIV research today is the modulation of immune response to encourage the clearance of chronic viral infections. It appears that a certain cytokine, interleukin-7 (IL-7), may be able to prop up the immune system allowing it to move around mechanisms that circumvent immune response during times of chronic infection. In this study led by Dr. Tak Mak, researchers hypothesized that cytokines supporting homeostatic proliferation would be promising candidates for promoting immune response. Indeed, IL-7 did just that.

After administering IL-7 to mice that were chronically infected with lymphocytic chorimeningitis virus (LCMV) variant clone 13, researchers observed an increase in size of the naive T-cell pool, and an enhanced function and cytokine output in LCMV-specific T-cells. IL-7 therapy resulted in clearance of LCMV from chronically infected mice. The cytokine also appears to serve a second function — bolstering levels of the cytoprotective cytokine IL-22. An increase in IL-22 levels has the added benefit of protecting the liver from viral infection, an organ that is particularly prone to damage under the circumstances. Researchers believe IL-7 exerts its effects by downregulating suppressor of cytokine signaling 3 (Socs3) expression in T-cells through the suppression of the FoxO transcription factors.

Monday Biotech Deal Review: February 14, 2011

Welcome to the Monday Biotech Deal Review for February 14, 2011.  Aside from the usual assortment of corporate and regulatory announcements over the week, the highlights include SemBioSys’ proposed $4M secured 7% bond issuance, Angiotech’s fifth extension to deadlines under its recapitalization support agreements (and definitive agreements in respect of up to $28M in DIP financing), Med Biogene is being accused of breaching confidentiality and exclusivity agreements and former biotech Bradmer Pharmaceuticals is migrating to the oil and gas industry via a proposed reverse takeover.  Read on to learn more.   Read more of this post

Friday Science Review: February 11, 2011

Cardiac Differentiation: A Customized Approach

McEwen Centre for Regenerative Medicine ♦ University of Toronto ♦ SickKids

Published in Cell Stem Cell, Feb. 4, 2011

Dr. Gordon Keller of the McEwen Centre for Regenerative Medicine has been a pioneer in the stem cell world and was the first researcher to produce functioning cardiomyocytes from embyronic stem cells. These cells form clusters in the petri-dish that beat in unison, a rather marvelous sight to behold. The efficient differentiation of embryonic stem cells to cardiac cells requires monitoring the very earliest stages of their development. Monitoring the expression of one gene, Flk-1, has been instrumental in recognizing the formation of cardiac mesoderm, an early step in the developmental path of cardiomyocytes. A problem that remains however, is that Flk-1 is expressed in different forms of mesoderm, not all of which lead to the cardiac lineage. A second gene, PdgfR-α, can be used to separate cardiac and hematopoietic lineages when monitored in conjunction with Flk-1. Fractions of differentiating cells that coexpress the two genes have greater cardiomyocyte potential. Keller’s lab group used these two genes to study the stage-specific effects that Activin/Nodal and BMP signaling have on the development of cardiomyoctyes. They found that very small changes in the amount of Activin/Nodal or BMP had profound effects on the proportion of Flk-1+/PdgfR-α+ cells that appeared early on in the differentiation protocol, and that optimization of these concentrations in cultures of human pluripotent stem cells could give rise to structures that contain more than 50% Flk-1+/PdgfR-α+ cells. A major finding by Keller’s team is that different mouse and human pluripotent stem cell lines required unique optimization to produce maximal results, stressing the importance of using differentiation protocols that are in effect customized to individual pluripotent stem cell lines.

β-Catenin Maintains Pluripotency of Stem Cells with Two Divergent Signaling Cascades

Stem Cell and Cancer Research Institute ♦ McMaster University ♦ University of Guelph

Published in Cell Stem Cell, Feb. 4, 2011

It is widely assumed that β-catenin, a key molecule in the Wnt/β-catenin signaling pathway, helps sustain pluripotency through its interaction with TCL/LEF transcription factors. However, recent research shows that β-catenin also promotes pluripotency by complexing with and stabilizing Oct-4, a key member of the transcriptional network that maintains the pluripotent nature of stem cells. Glycogen synthase kinase-3 (GSK-3) has emerged as an important regulatory of pluripotency, in part because β-catenin is one of its primary substrates. After GSK-3 phosphorylates β-catenin it is degraded, which encourages stem cells to exit the pluripotent state and differentiate to other cell types. Dr. Bradley Doble and his colleagues previously showed that mouse embryonic stem cells (mESCs) that are entirely deficient in GSK-3 express very high levels of β-catenin and exhibit a severe impairment in their capacity to differentiate into the three germ layers. In this recent work, Doble and his team hypothesized that hyperactivated β-catenin/TCF was responsible for the pluripotent “lock” that was imposed on mESCs lacking GSK-3 expression. To the surprise of researchers, GSK-3α/β double knock out mESCs still maintained pluripotency even when they stably expressed a dominant negative form of the TCF transcription factor. How were they doing this? Apparently β-catenin can maintain pluripotency independent of functioning TCF. Researchers showed that β-catenin promotes the maintenance of pluripotency by interacting with Oct-4 in a divergent signaling cascade.

Next Generation Gene Therapy for Hemophilia A: Pre-clinical Progress

Queen’s University ♦ Published in Molecular Therapy, Feb. 1, 2011

Researchers pursuing therapies for Hemophilia A have turned to gene therapy for answers but have struggled to provide convincing pre-clinical results. Patients with the disorder have vastly decreased plasma concentrations of FVIII, a clotting factor that prevents blood loss after injury. Although viral vectors can produce the protein following system injection into animal models, its efficacy is compromised by the introduction of neutralizing anti-FVIII antibodies. Researchers hypothesized that the development of neutralizing antibodies was the result of transgene expression in the antigen presenting cells of mice. The solution to this problem was to “hide” the transgene by placing it under the control of a liver-specific promoter. This approach worked in normal mice, however researchers studying mice with hemophilia B still found that an anti-FVIII immune response was mounted in the presence of the new tissue-specific promoter. As a second layer of defense against this response researchers incorporated target sequences into the transgenic construct that had perfect complementarity to hematopoietic-specific miRNA sequences. These target sequences led to suppression of the transgene specifically in hematopoietic cells, including antigen expressing cells, limiting the neutralizing response. Dr. David Lillicrap and his team at Queen’s University have now used a similar approach to produce some very promising results in a mouse model of hemophilia A. A combination of a liver-restricted promoter, a miRNA regulated FVIII transgene, and a pseudotyped viral envelope seemed to do the trick.

2010 Canadian Healthcare Review: Success and Momentum Building

We had just finished the Q3 2010 report when I attended BioContact Québec in early October and the mood was discouraging. My co-author on these reports (James Smith, VP-Healthcare at Equicom) was in San Francisco in January for the annual JP Morgan conference and he described the overall mood as optimistic. What happened in those three months?

The subtitle for the 2010 Canadian Healthcare Review (pdf) is “Successes and Momentum Building.” The momentum building comes partially from the increased financing which occurred in Q4, and which appears to be continuing in 2011 – Bioniche’s Australian tranche and Paladin Labs’ bought deal.

The momentum also comes from the clinical and regulatory successes in 2010. Three novel products developed by Canadian companies were approved – Cardiome’s IV BRINAVESS (vernakalant), Theratechnologies’ EGRIFTA (tesamorelin), and one which we tend to forget because it was acquired by Medtronic in 2008 is CryoCath’s Arctic Front cryoablation system. Cipher and Labopharm also had specialty pharma products approved and many companies were successfully progressing products through Phase 2 and 3 clinical trials.

These successes are usually dwarfed by the failures but this was not the case in 2010. There were only two Phase 2 or 3 products for which development was terminated. There were three other products which had Phase 2 hiccups but for which product development is continuing. On balance, 2010 was a successful year for product development and regulatory approvals.

In any discussion of successes, we cannot forget the investors, who measure success by increases in share price. From a group of 105 companies we assessed, there were 17 companies with share price increases of 40% or more in 2010 (actually 18 as Nightingale Health Care should be added to the list). This is balanced by 32 companies which had share price decreases of 40% or more.

Success for the industry in 2011 will be defined by its clinical, regulatory and financing successes, and by share price performance of the companies. Some of the companies which made progress in 2010 with their Phase 2 and 3 clinical trials and regulatory filings will have data or decisions in 2011, while others will still be advancing their programs. If the industry is able to repeat the clinical and regulatory success rate of 2011, we expect that financing and share price performance will likely follow.

Monday Biotech Deal Review: February 7, 2011

Welcome to your Monday Biotech Deal Review for February 7, 2011.  It was a fairly busy week for Canadian biotech – Angiotech has followed suit in the U.S. on the heels of last week’s CCAA filing, a number of acquisitions were announced, and there was some activity in biotech licensing.  Read on to learn more.  Read more of this post

Friday Science Review: February 4, 2011

Precious GEMMs: Mouse Models Simulate Metastatic Disease for Tomorrow’s Cancer Therapeutics

Sunnybrook Health Sciences Centre ♦ Published in Nature Reviews Cancer, Feb., 2011

Before cancer therapeutics are moved to the clinic for testing in humans, they must first be assessed in laboratory animals for both safety and efficacy. Developing efficacious therapeutics for cancer treatment is a challenge, by any standard of the word. The process requires animal models of disease that closely simulate similar disease conditions in humans. The introduction of the xenograft mouse model was a large step forward in the development of new treatment regimes for cancer. When carrying out xenograft experiments in mice, researchers transplant human cancer cells into a specific location in the mouse, often subcutaneously, to observe tumour formation and how the tumour responds to treatment with different therapeutics.

Dr. Robert Kerbel and his colleagues at the Sunnybrook Health Sciences Centre reiterate the importance of improving the mouse model for the generation of more effective cancer treatments. With respect to the selection of new drugs for cancer treatment, the predictive abilities of xenograft models suffer from the fact that they fail to adequately simulate the corresponding disease in humans. Human cancer cells, when transplanted subcutaneously into the mouse, grow considerably faster than they do in humans. As a result, xenograft tumours are somewhat hyper-sensitive to chemotherapeutics, which have been designed to target rapidly dividing cells. The location of transplantation plays an important role in how a tumour will respond to treatment. As an example, a tumour found in a human breast will respond differently to cancer treatment than a breast cancer tumour beneath the skin of a mouse. The biological niches in which these tumours reside are quite different, and given the importance the cellular niche plays in cell processes, a difference in niche will translate to a difference in response to therapeutics.

Genetically engineered mouse models (GEMMs) provide a solution to at least some of the problems encountered with the more simple xenograft model. The genetic code of these mice can be altered through the deletion or over-expression of genes that are involved in the tumorigenic processes of specific cancer types. These genetic alterations give rise to tumours in selected tissues such as the breast and lung that are composed of cells and vasculature that are the host’s own. Although GEMMs are a one-up on xenograft models, and have proven valuable for the study of formation and early onset of different cancers, they fall short on one cylinder — primary tumours found in GEMMs rarely metastasize — a hallmark of many cancers. Thus, the clinical predictive power of GEMMs is higher than xenograft models, but is still fundamentally limited.

Dr. Kerbel and his team have addressed this issue using an in vivo selection technique to generate melanoma and breast cancer cells lines that exhibit extensive metastatic capacities following their transplantation into the skin or breast respectively. The selection protocol is rather logical. To create a breast cancer cell line with metastatic abilities a breast cancer cell line is transplanted into the mammary fat pads of an immune compromised mouse. Roughly 4-6 months later some mice will have tumour metastases in the lung. These tumours are dissected, a new cell line is established in vitro, and these cells are then transplanted into the mammary tissue of a second mouse. After two rounds of this selection, mice exhibit extensive metastases to the lung and in some cases, at later stages, the brain. So why is this clinically relevant?

Well, beyond mimicking the normal “metastatic cascade”, treatment of mice that have primary tumours and distant metastases has actually mirrored observations we have made in the clinic for some time. Dr. Kerbel provides a nice example using two monoclonal antibodies. Treating mice with trastuzumab as a monotherapy potently inhibited primary tumours but had very little effect on metastases. Similarly, treatment of mice with a VEGF receptor 2 antibody (DC101) inhibited primary tumour growth but failed to elicit a reduction in the growth of metastases. On the contrary, mice treated with the chemotherapeutic CTX in combination with DC101 inhibited primary tumour growth and the appearance of metastases. This finding is in keeping with the clinical observation that treatment with trastuzumab or DC101 alone as monotherapies has very little clinical benefit for cancer patients, and a combination of antibody and chemotherapy is required for successful treatment in a metastatic setting. We have come a long way with animal disease models and as their predictive powers continue to rise, so should our ability to chose the most effective cancer therapies for the clinic.

TrkC & PTPσ, the Velcro at Neural Junctions

University of British Columbia ♦ Published in Neuron, Jan. 27, 2011

The development of healthy synapses requires a confluence of biological events to occur in harmony at the site where the axon and dendrite meet. The axon of one neuron extends from its cell body towards a dendrite, a short projection radiating from the cell body of an adjacent neuron. Once these two neural components are in close proximity, two key events must occur to drive synaptogenesis. Firstly, “synapse organizing” proteins must help locally recruit pre-synaptic and post-synaptic elements to the ends of the axon and dendrite respectively, and secondly, the axon and dendrite must come into physical contact, a process that is mediated by cell-adhesion molecules. Researchers at the University of British Columbia have discovered a new complex that spans the synapse to bridge axon and dendrite. Dr. Ann Marie Craig and her team used a functional expression screen to identify TrkC, a post-synaptic adhesion molecule, and PTPσ, a high-affinity pre-synaptic receptor of TrkC, which when bound maintain tight synaptic junctions. Neurotrophin receptor tyrosine kinases (Trks) have been known to contribute to nervous system development by interacting with soluble neurotrophins at the post-synaptic membrane. Activation of Trks by neurotrophins leads to signaling cascades that modulate synaptic development. The finding that TrkC interacts with PTPσ on the pre-synaptic membrane is currently the best explanation for why Trks, which are typically catalytic proteins, have cell-adhesion domains and non-catalytic isoforms.

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