Friday Science Review: October 21, 2011

CD34: Beyond A Stem Cell Marker

Biomedical Research Centre, Vancouver ♦ University of British Columbia ♦ Sprott Centre for Stem Cell Research, Ottawa ♦ Others..

Published in Stem Cells, October 13, 2011

Despite the fact that the cell surface marker CD34 is typically used to identify a diversity of adult stem cell types, no regeneration-related function has been attributed to it. In attempts to broaden our understanding of the protein’s contribution to regenerative biological processes, researchers at the University of British Columbia probed the effect that it has on muscle regeneration in mice. Knockout mice lacking the protein still developed properly, however exhibited an inability to regenerate muscle following both acute and chronic skeletal muscle injury. Researchers attribute this defect to a shortcoming in satellite cells; a small and rare progenitor cell type found in muscle that migrates to the site of injury to proliferate and restore muscle mass. In the absence of CD34, it appears that satellite cells are unable to migrate along muscle strands to relocate themselves and stimulate the growth of new tissue.

Black Death Reconstructed

McMaster University ♦ University of Tübingen ♦ Max Planck Institute of Evolutionary Anthropology ♦ University of South Carolina ♦ Others..

Published in Nature, October 12, 2011

Scientists working out of McMaster University’s Ancient DNA Centre have managed to reconstruct the genome of Yersinia pestis. The rod-shaped microbe was responsible for the epidemic that killed an estimated 30-50% of the European population between the years 1347 and 1351; the infection was appropriately given the name the Black Death. The advent of high-powered sequencing technologies has allowed us to quickly and accurately map the genomes of ancestral microbes. Not only do these genomes provide valuable insight into their biology, they allow us to plot the evolution of pathogens and adaptations they have gathered over time. DNA samples were collected from the teeth of skeletons unearthed from old burial grounds in London. Contrary to what was originally believed, the sequenced genome revealed that the ancestral microbe was no more virulent than strains in existence today. Researchers believe the severity of the 14th century pandemic was brought on by the generally malnourished and immuno-compromised state of the population at that time. Poor hygiene and particularly wet conditions are likely to have exacerbated the spread of the microbe as well.

Monday Biotech Deal Review: October 17, 2011

Welcome to your Monday Biotech Deal Review for October 17, 2011.  This week’s deal review is a double feature following last Monday’s Canadian thanksgiving holiday.  Of note from the past two weeks were the acquisition of Labopharm by Paladin Labs, and its announcement that it is ceasing its hostile takeover pursuit of Afexa. 

Friday Science Review: October 14, 2011

Ubiquitin Ligase Sweeps Aggregates

University of British Columbia ♦ Published in Nature Cell Biology, October 9, 2011

It seems that ubiquitin ligase may play a critical role in preventing diseases characterized by protein aggregation. The enzyme acts by fusing a polyubiquitin chain to misfolded proteins that sit in the cytoplasm. Once tagged, these faulty proteins are degraded by other enzymes in the proteasome. Researchers at the University of British Columbia utilized heat-shock to create short-term stores of misfolded proteins in yeast cells and demonstrated that a specific ubiquitin ligase, Hul5, is responsible for ubiquitylation and removal of low-solubility proteins. Pin2, a protein involved in the development of prion disease, was also observed to be removed by Hul5.

Key Determinant of Osteoporosis Discovered

University of Montreal ♦ McGill University ♦ Laval University ♦ Washington University School of Medicine

Published in Cell Metabolism, October 5, 2011

Researchers have discovered a factor that controls the differentiation of osteoclasts, the cell type responsible for bone resorption. Bone resorption is one of two processes that act in concert to ensure a constant bone mass in the human body. When this balance is broken the result is loss of bone density, otherwise known as osteoporosis. When resorption occurs osteoclasts break down releasing calcium into the bloodstream which in turn regulates bone formation. Inppb4α seems to regulate osteoclastogenesis by repressing the differentiation of osteoclasts. Mice deficient in Inppb4α exhibit accelerated osteoclast differentiation and bone loss. An important finding in this study was that the human gene, INPP4B, was found to be a susceptibility locus for osteoporosis, confirming the functional analysis carried out in mice.

Antisense Oligos for Huntington Disease

University of British Columbia ♦ Isis Pharmaceuticals ♦ University of Copenhagen

Published in Molecular Therapy, October 4, 2011

Huntington disease (HD) is characterized by a CAG nucleotide expansion in the Huntington gene (HTT). Hence, targeting the HTT gene has been a desirable therapeutic approach. However, the wild-type (normal and healthy) HTT gene is crucial for neuronal development and survival so down regulating its expression can have deleterious effects. To circumvent this researchers created gene-silencing antisense oligonucleotides (ASOs) that target small variable regions known as single nucleotide polymorphisms (SNPs) found in the HD population. ASOs were modified with S-constrained ethyl (cET) motifs to ensure selectivity of target sites. Delivery of ASOs to the mouse brain demonstrated allele-specific knockdown of the HTT protein in vivo.

Optimizing Lipid Nanoparticles for Delivery of Therapeutic Payload

University of British Columbia ♦ Published in Molecular Therapy, October 4, 2011

One of the most effective means to deliver therapeutic payloads is to drop them into lipid nanoparticles (LNPs) for in vivo delivery. LNPs are easier to manufacture than viral vectors and have lower immunogenicity, making LNP delivery systems an attractive option. In this study researchers investigated the potency of RNAi on primary bone macrophages and dendritic cells using any one of four cationic lipids to build LNPs. Of the four lipids used, DLinkC2-DMA provided the most potent intracellular delivery in vitro and in vivo. To demonstrate the efficacy of DLinkC2-DMA-containing LNPs researchers loaded them with GAPDH-siRNA and administered them intravenously to mice. Significant inhibition of GAPDH and CD45 was observed in spleen and peritoneal macrophages and dendritic cells in relation to LNPs containing other lipid types.

Long Non-Coding RNAs, Dark Matter Comes into Light

British Columbia Cancer Agency Research Centre ♦ University of British Columbia

Published in PLoS ONE, October 3, 2011

Researchers have had a change of heart with respect to the contribution that long non-coding RNAs (LncRNAs) have to cancer formation. LncRNAs do not code for proteins, instead serving structural and functional roles in the cell. Due to the fact that they are not actually translated to proteins, LncRNAs have been dubbed the ‘dark matter’ of the transcriptome. Conservative estimates put their numbers somewhere in the vicinity of 23,000 transcripts. LncRNAs have been implicated in at least two cancer types, breast cancer and lung cancer, but this paper is the first large scale analysis of their contribution to human cancers. By comparing 26 different normal human tissues and 19 human cancers, researchers show that in many cancers LncRNAs are aberrantly expressed and may not be as innocuous as most think. Today’s current commercial microarrays used for transcriptome profiling focus on coding regions of the transcriptome. We may now have to place more emphasis on non-coding regions in order to capture a more comprehensive view of how the transcriptome can contribute to the development of cancer.

Assessing Potential Market Share for a New Drug: Part 14 of Valuation and Other Biotech Mysteries

[Ed. This is the fourteenth 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.]

In the previous post, we looked at epidemiology and pricing to estimate the market size for a new drug. As we continue to look at the potential rewards from successful drug development, we need to consider market share.

A new drug product which is being assessed will probably share its market with:

• currently approved drugs;
• some drugs currently at the same or later stage of development; and
• some drugs which are at an earlier stage of development. 

An assessment of market share is not static and should be continuously updated as new information becomes available. Until all of the Phase 3 data is available on a new drug, market share assessments are really guesstimates. Phase 3 data from two new drugs which were compared to either a placebo or an older standard of care, but not to each other, might not be sufficient to allow a winner to be selected. A major pharma licensing deal with a product that is two years behind might change your ranking of that drug.

Potential Rewards from Successful Drug Development: Part 13 of Valuation and Other Biotech Mysteries

[Ed. This is the thirteenth 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.]

Finally we have reached the point of looking at the potential rewards from successful drug development. The potential reward can be estimated using the following step-wise analysis.

Friday Science Review: October 7, 2011

Cell Polarity Dictated by Phosphatidylserine

Hospital for Sick Children ♦ Published in Nature Cell Biology, October 2, 2011

The enzyme Cdc42 is responsible in part for cell polarization during asymmetric cellular events. In the case of the yeast S. cerivisiae, polarization is essential during the process of budding and the formation of projections in response to mating factors. Polarization is also crucial to the operation of mammalian cells. In this Nature paper researchers show that phosphatidylserine, a type of phospholipid, is required for the correct dispersal of Cdc42 during polarization events. In an event that precedes the movement of Cdc42, phosphatidylserine is sent via secretory vesicles to the plasma membrane where it accumulates. Yeast mutants lacking phosphatidylserine synthase exhibited impairment in the polarization of Cdc42 and difficulty in budding and mating, suggesting it is at the core of regulating cellular polarization and some very important cellular processes.

Embryonic Stem Cell-Specific Splicing Event Promotes Pluripotency

University of Toronto ♦ Mount Sinai Hospital ♦ Columbia University Medical Centre ♦ Published in Cell, September 30, 2011

There are a host of genes that are upregulated in embryonic stem cells which promote stem cell-like characteristics, namely pluripotency, or the ability to give rise to all cell types in the human body. These genes include Sox2, Oct4, and Nanog, among others, and are associated with primitive cell types. Much time has been invested in researching the transcriptional networks promoting pluripotency, and how the various stem cell-specific transcription factors cross-talk with one another to ensure stem cells do not differentiate. Although these transcription factors can cross-regulate each other, on a more fundamental level they are controlled by the forkhead box (FOX) transcription factors. In this study, researchers discovered that FOX transcription factors do not always operate in the same manner. In stem cells, the FOXP1 mRNA transcript is alternatively spliced in such a manner that the FOXP1 protein has a greater affinity for the DNA promoter regions that control transcription of stem cell factors like Sox2, Oct4, and Nanog. FOXP1 also represses genes that cause differentiation. Interestingly, the FOXP1 isoform studied here could not be found in more differentiated cells, suggesting that alternative splicing is an important mechanism by which stem cells maintain their primitive status.

 

Monday Biotech Deal Review: October 3, 2011

Welcome to your Monday Biotech Deal Review for October 3, 2011.  Last week witnessed a flurry of financing activity, with over $50M closed.  As well, the competing take-over bids between Paladin and Valeant for Afexa heated up with both Valeant and Paladin sweetening their offers to Afexa shareholders.  Read on to learn more.