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

Monthly Archives: March 2011

Flow-Through Shares for Healthcare Part 2 of 3: Flow-Throughs in Mining and Oil & Gas

In Part 1 of this series, we mentioned two flow-through share financings completed in 2010 (chosen at random for illustrative purposes). The following discussion examines those financings in more detail, and puts them in the context of overall funds raised by the mining industry in recent years.

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Monday Biotech Deal Review: March 29, 2011

Welcome to your Monday Biotech Deal Review for March 28, 2011.  There was a flurry of financing activity last week, with over $76M raised or announced in biotech funds (not including the $60M Genome Canada investment announced by the Government of Canada).  Double-digit million-dollar deals included MethylGene’s $34.5M private placement announcement, Medicago’s $17M private placement announcement, and the closing of Novadaq’s $15M private placement.  Read on to learn more.  Read more of this post

Friday Science Review: March 25, 2011

Beware of Repeats

The Hospital for Sick Children ♦ University of Toronto ♦ Published in PLoS Genetics, Mar. 10, 2011

Trinucleotide repeats are known to be associated with the onset of many diseases including Huntington’s disease and fragile X syndrome. These unstable elements can be transcribed bidirectionally and are dynamic, meaning their numbers can change within individuals and across generations. Particularly worrisome elements include CAG and CTG repeats. In this recent review, Dr. Christopher Pearson describes a process known as Repeat Associated Non-ATG translation (RAN-translation) wherein portions of DNA containing blocks of CAG repeats can be transcribed in the absence of a conventional ATG transcriptional start site. 

Repetitive tracts of DNA can be transcribed in all three reading frames giving rise to RNA transcripts that produce polymeric proteins composed of repeating amino acid building blocks. Unstable repetitive genetic elements may be toxic to the body in several ways, leading to loss-of-protein expression, over-expression of normal proteins, and toxic gain-of-protein function. Due to the functionality of proteins, diseases are often physically manifested at the protein level. Interestingly, when it comes to diseases caused by unstable trinucleotide repeats, RNA transcripts can get in the mix aswell. Transcripts containing repeating CUG or CGG elements can have toxic gain-of-function effects. It is even possible for diseases to be caused through the combined action of a toxic gain-of-function RNA and related toxic polymeric protein.

Acetylcholine, Turning Down the Action

University of Western Ontario ♦ Published in PLoS ONE, Mar. 10, 2011

It has been difficult to assess the contribution that acetylcholine (ACh) has on locomotion. As a major peripheral neurotransmitter it has a vital role in controlling movement, emotional behaviour, and is also involved in memory and learning. Dysfunction in cholinergic activity is involved in the development and onset of many different disorders of the brain, including, but not limited to, Alzheimer’s, schizophrenia, Parkinson’s disease, epilepsy and ADHD. The first attempts at recreating cholinergic dysfunction used non-selective means that were either too destructive, causing destruction of neural types beyond cholinergic, or not destructive enough, failing to eradicate all cholinergic neurons. This short coming left room for significant variation in previous studies, making it difficult to elucidate the effects that ACh has on the various nervous systems.

The alternative to mimicking cholinergic dysfunction was to approach the situation from the standpoint of genetics. This is what Dr. Vania Prado and her lab team have been working on in recent times. This was no easy feat though. To impair cholinergic signaling they chose to target the vesicular acetylcholine transporter (VAChT), a protein that is involved in sequestering acetylcholine and accumulating it within vesicles for transport. The VAChT gene, however, is located within the first intron of the acetylcholine transferase (ChAT) gene in a nested formation. In order to knock down expression of VAChT they flanked it with short “lox” sequences that are used to remove the gene.

What the group found was that the new mutant mice strains they had generated exhibited hyperactivity when exposed to new environments. A similar trait is observed in patients suffering from Alzheimer’s, schizophrenia, and ADHD. Rescuing VAChT expression alleviated that hyperactive phenotype suggesting that acetycholine serves the purpose of toning down the nervous system to control locomotion and other peripheral body functions.

Flow-Through Shares for Healthcare Part 1 of 3: What Are Flow-Through Shares?

The extension of flow-through tax incentives to development stage biotech and healthcare companies has been discussed for many years, including twice previously on this blog (here and here). One of the most recent articles supporting this change was written by David Allan, a former investment banker who is a founder and current Chairman of YM Biosciences (Biotechnology Focus, March 2011). In order to properly assess what impact this action might have on our industry, we need to first understand how flow-through shares work. Read more of this post

Monday Biotech Deal Review: March 21, 2011

Welcome to your Monday Biotech Deal Review for March 21, 2011.  There was some interesting investment and commercial transactions announced and closed last week, including the $15M private placement announced by Novadaq, the $4M bond financing closed by SemBioSys and Pacgen’s announcement of a corporate makeover to accommodate its recent investments in the products of General Biologicals Corporation.  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.

Monday Biotech Deal Review: March 14, 2011

Welcome to your Monday Biotech Deal Review for March 14, 2011.  This week was a fairly slow week for Canadian biotech, but there were nevertheless a couple of interesting announcements.  Pharmagesic acquired over 90% of the restricted voting shares of WEX Pharmaceuticals marking the conclusion of its bid, and Theratechnologies has backed away from its previously announced U.S. IPO due to unacceptable pricing conditions.  Read on to learn more.  Read more of this post

Friday Science Review: March 11, 2011

Insulin + Pancreatic Stem Cells, Proof of Life

University of Toronto ♦ Published in Cell Stem Cell, Mar. 4, 2011

The origin of insulin-producing pancreatic β-cells has been a matter of contentious debate. Some research groups have produced findings that would suggest β-cells duplicate themselves and that new β-cells do not arise from the differentiation of a more primitive pancreatic progenitor. Other groups have proven the existence of pancreas-derived multipotent progenitors (PMPs) that are capable of giving rise to a spectrum of cells from both the pancreatic and neural lineage. So where do β-cells come from?

New results from the lab of Dr. Derek van der Kooy point in the direction of PMPs. Lineage labeling experiments in mice showed that PMPs originate from the embryonic pancreas, as opposed to the neural crest, which has often been cited as the source of pancreatic progenitors. These findings are in conflict with previous studies which could not provide evidence of pancreatic progenitors in the developing embryo or the adult. Convincingly, Dr. van der Kooy’s group was able to show that PMPs express insulin in vivo, an attribute that has often been considered prerequisite for the production of β-cells.

Analysis of human islet tissue showed that PMPs also exist in humans, and, similar to the mouse PMPs under observation, were capable of differentiation to both the pancreatic and neural lineages. Both mouse and human PMPs were able to alleviate diabetic conditions in mice and may provide another avenue to explore in the pursuit of therapeutic cells for transplantation therapy.

Selective Pressures Shape the Genomic Integrity of Human iPS Cells During Reprogramming

Samuel Lunenfeld Research Institute ♦ Ontario Institute for Cancer Research ♦ The Hospital for Sick Children ♦ University of Toronto

Published in Nature, Mar. 3, 2011

Coercing fibroblasts to revert to an embryonic stem cell-like state places a good deal of stress on the genome. The consequences of reprogramming can affect the development of safe populations of cells for therapeutics, which is why researchers at the Samuel Lunenfeld Research Institute have been interested in understanding how the reprogramming process affects genomic integrity. The integrity of a genome can be measured using copy number variation (CNV) within a population of cells. CNVs arise from deletions or duplications in DNA; as variation increases, the integrity of the genome declines.

In this study supervised by Dr. Andras Nagy and Dr. Timo Otonkoski, researchers characterized the CNV content of 22 human iPS cell lines and 17 human ES cell lines using Affymetrix SNP arrays. Induced pluripotent cell lines were created by way of retroviral transduction or with the use of a transposon known as piggybac. The number of CNVs in iPS cells was roughly twice that found in ES cells on average and many CNVs found in iPS cells were undetectable in ES cells suggesting that CNVs are generated during the reprogramming process. To the surprise of the group the number of CNVs in iPS cells was greatest at early stages, and decreased as cells were passaged in culture.

Researchers hypothesized that the reduction in copy number variation could be the result of two things, firstly, a DNA repair mechanism that corrects deletions and additions as the cells grow and divide in vitro, or mosaicism in early cultures followed by selection of iPS cells that have lower variation and greater genomic stability; a survival of the fittest in a way. It is unlikely that a DNA repair mechanism could operate fast enough to account for the rapid reduction of CNVs observed in iPS cells in culture and indeed, after using fluorescence in situ hybridization (FISH), it was confirmed by the lab group that mosaicism did exist in early cultures of iPS cells. In order to prove that selection was driving the decrease in CNVs researchers focused on deletions that cannot be corrected by DNA repair mechanisms. They found that several of these deletions were selected against during passaging of iPS cell lines. This pressure was bidirectional however, as some CNVs were selected for, not against.

CIITA, A Promiscuous Partner in Lymphoid Cancers

Centre for Translational and Applied Genomics ♦ BC Cancer Agency ♦ University of British Columbia

Published in Nature, Mar. 2, 2011

Chromosomal translocation events are a common abnormality leading to the development of cancer but few have been described as contributors to the development of lymphoid cancers. A new chromosomal translocation event has been implicated in the development of Hodgkin lymphoma and primary mediastinal B-cell lymphoma (PMBCL). Large scale mutations of this nature occur when non-homologous chromosomes transiently stick together and cause breakages that lead to the exchange of genetic information. If genes are placed next to one another following the translocation event, fusion transcripts are created which can lead to cellular abnormalities and malignant expansion.

Genome-wide mapping of translocation events can be carried out using paired-end sequencing of expressed transcripts. Researchers used such a platform to analyze two Hodgkin lymphoma cell lines. Analysis uncovered a highly expressed gene fusion between the MHC class II complex (CIITA) and an uncharacterized gene. Further analysis of 263 B-cell lymphoma cell lines went on to show that the CIITA translocation was highly recurrent in PMBCL (38%) and Hodgkin lymphoma (15%). The genetic event appears to be quite specific to PMBCL as it was observed in only 3% of diffuse large B-cell lymphoma cell lines.

Researchers note that although certain translocation events of very specific rearrangements are key contributors to some B-cell lymphomas, resulting in unique clinopathological features, many well characterized B-cell lymphomas still lack identifiable translocations that define the disease. Translocations in B-cell lymphomas are a rare occurrence, and until the publication of this research, no translocations had ever been reported in PMBCL.

Stability at the Top: A Look at Top Biotech VC Deals from 2007-2010

FierceBiotech published the top 15 biotech VC deals of 2010 last week, measured by dollars invested. Since they noted an overall uptick in investments in 2010, it seemed like a worthwhile time to look back. Here’s what U.S. VC investment in biopharma and medical devices looked like from 2007 to 2010 (normalized to 2007 levels):

Not unexpectedly, a huge decline between 2007 and 2009, though not as big as the overall decline in VC investments. Here’s the really interesting part — the average amount invested (±1σ) among the top 15 deals each year:

Remarkably stable. Even during a period of steeply declining investment there will be standouts that generate real excitement, proving that as FierceBiotech said in 2008 “[g]ood science will attract funding in any market.”

It’s not a surprise that good ideas always get some funding, but why do the top investees always attract the same amount?  The price of admission to the top 15 between 2007 and 2010 has ranged only between $39 and $42 million.

It must be that (once a concept reaches a certain stage) the amount of money needed to really propel a life sciences company to success is constant — apparently an average of $50 – $60 million — and recognizing that, VCs will fund their best prospects to that level even at the expense of other investments.  So the next time you’re contemplating a $10 million C round, keep in mind that you’re more than two standard deviations off the mean investment made when VCs really mean it. It’s an interesting idea the other way too: Pacific Biosciences, which IPO’d in the middle of its range at $16/share last October, was the top deal twice in four years (including the +2.4σ variant of $109m in 2010). It’s currently trading at $15.74, giving it  a market cap of $831.43 million, just over double the reported $370 million of VC that it raised prior to the IPO.

Check out FierceBiotech’s list of the top VC investments from 2010, 2009, 2008 and 2007 and apply your own 20:20 hindsight to your heart’s content. Also, keep your fingers crossed that a 3% increase stops feeling like such a victory when we see the 2011 data.

Monday Biotech Deal Review: March 7, 2011

Welcome to your Monday Biotech Deal Review for March 7, 2011.  It was a busy week with numerous private and public investments, offerings by biotech companies (see Stem Cell Therapeutics and Adherex Technologies), as well as some interesting licensing activity.  Read on to learn more.  Read more of this post

Friday Science Review: March 4, 2011

The Origin of Meier-Gorlin Syndrome

Dalhousie University ♦ University of Montreal ♦ University of British Columbia

Published in Nature Genetics, Feb. 27, 2011

Researchers have mapped a locus for Meier-Gorlin syndrome (MGS), a rare genetic condition characterized by short stature, small ears, and reduced or absent kneecaps. A mutation in the ORC4 gene seems to be at the root of the disorder. ORC4 is a component of the eukaryotic origin recognition complex.

To map the locus responsible for MGS researchers performed high density genome-wide SNP genotyping using a panel of 600,000 markers provided by Illumina. The next stop involved PLINK, a whole genome analysis toolset, which was able to identify a haplotype on chromosome 2 within a number of affected individuals. Sequencing of coding exons located in the ORC4 gene led to the identification of a missense mutation that causes a tyrosine (residue 174) to cysteine switch in the ORC4 protein. The tyrosine residue affected in MGS is completely conserved across eukaryotes suggesting it has an important function; the amino acid is also believed to interact with a conserved arginine residue on a nearby helix motif in the protein structure. In the absence of this interaction the structural integrity of the protein could be compromised in part.

The origin recognition complex consists of six proteins in humans and is essential for DNA replication. It plays a critical role in recognizing origin sites on DNA and in the formation of DNA replication forks. This is the first report of an inherited mutation in any gene of the origin recognition complex in the vertebrate literature.

The Human Serum Metabolome

University of Alberta ♦ National Institute of Nanotechnology

Published in PLoS ONE, Feb. 16, 2011

Human biofluids are very important from a clinical standpoint given the insight they can provide into the disease conditions of a human being. The study of metabolomics attempts to identify, on a large scale, the composition of metabolites found in these biofluids. The advent of advanced analytical techniques along with mounting pressures for scientists in the metabolomics community to document the entire human metabolome, led to the development of the Human Metabolome Project. The project is supported by Genome Alberta and Genome Canada, the latter of which is a private, non-profit, corporation that received $600 million in funding from the Canadian government to develop and implement a national strategy in genomics and proteomics.

The most recent contribution to the project is a comprehensive multicentre study led by Dr. David Wishart at the University of Alberta. Using a diversity of metabolomics platforms researchers were able to identify, and quantify, metabolites found in human serum. The use of different methods, including nuclear magnetic resonance (NMR), and various mass-spectrometry platforms (GC-MS, LC-MS), increased the overall coverage of the serum metabolome. Data gathered via these platforms was linked to computer-aided literature mining which allowed for the development of a virtually complete set of metabolites. In total the group found 4,229 metabolites, but this number may increase in coming years as more powerful characterization techniques are developed.

Dr. Wishart and his colleagues previously characterized the human cerebrospinal fluid metabolome.


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