Welcome to your Monday Biotech Deal Review for September 3, 2012. A slow week was capped by today’s announcement that Valeant Pharmaceuticals International Inc. will acquire dermatology specialist Medicis Pharmaceuticals Corporation. The deal, which pushes Valeant’s total 2012 acquisition spending to over $3.5 billion, continues Valeant CEO Michael Pearson’s strategy of “using M&A as a surrogate for R&D.” Read on to learn more. Read more of this post
Welcome to your Monday Biotech Deal Review for August 27, 2012. Highlights from the previous two weeks include Miraculins Inc’s grant of stock options and distribution agreement with London Drugs, Microbix Biosyetem’s licensing of a thrombolytic biopharmaceutical to Zydus Cadila, and BIOREM’s closing of its private placement. The Monday Deal Review for August 13, 2012 also marked the last Review authored by Jacob Cawker. We’d like to thank Jacob for his hard work and years of service! For more about me, please see my Bio, here. Read on to learn more. Read more of this post
Reduced blood flow to organs and peripheral tissue, as might be expected, leads to cell necrosis and death. The nature of the resulting ischemic disease depends upon the specific tissue affected and spans the range from acute conditions such as acute coronary syndrome or acute kidney injury, to chronic conditions such as peripheral artery disease and angina. Despite the development of both pharmacological and surgical treatment strategies, ischemic disease remains a leading cause of morbidity and mortality. As such, therapies that will reduce ischemia by promoting the regeneration of damaged vasculature are an active area of active research and cell-based therapies represent one avenue being pursued.
In a paper in Stem Cells, researchers at the University of Western Ontario show that by selecting for a rare population of aldehyde dehydrogenase expressing cells from human umbilical cord blood they could promote vascular regeneration in an animal model of ischemic disease. This rare population of cells (<0.5%) is enriched for early myeloid and stem cell-associated cells and displays a pro-angiogenic transcription profile, including the hallmark angiogenic signaling factors ANGPT1 and VEGFA. In vitro cell culture efficacy was demonstrated in experiments that showed that this cell population was able to promote human umbilical vein endothelial cell (HUVEC) survival and tube-like cord formation, both being indicators of pro-angiogenic activity. Interestingly, permanent engraftment of the cells was not required for the vascular regeneration, which increases the clinical development potential by potentially avoiding the need for long-term immune suppression of a patient receiving this allogeneic cell therapy approach.
Public Canadian healthcare companies raised over $1 billion in equity and convertible debt financings in the first half of 2012. Before anybody wonders whether another biotech boom has suddenly appeared, a closer look at the details shows a different reality.
Large equity and convertible debt financings by profitable Canadian healthcare service companies in the first half of 2012 totaled $1,048 million. These are profitable companies, three of which do monthly distributions to shareholders. These companies fit the current risk profile of many investors, who are looking for profits, value and yield.
SXC Health Solutions $541.8 million
Chartwell Seniors Housing REIT $339.3 million (equity and convertible debt)
HealthLease Properties REIT $110.0 million (IPO)
Leisureworld Senior Care $ 56.4 million
The total for the rest of the sector was about $288 million for equity and convertible debt deals closed in H1 2012. A financing over $10 million indicates that a company, especially one developing a novel therapeutic, may have a chance to plan its future, as opposed to just survive. This list includes:
YM BioSciences $80.5 M
Novadaq Technologies $40.3 M
Oncolytics Biotech $21.3 M
Bioniche Life Sciences $20.0 M (debt)
BELLUS Health $17.3 M (includes plan of arrangement proceeds)
Merus Labs $17.3 M (equity plus debt)
Removing these large financings leaves about $127 million for the remaining over 100 companies in the sector to share. A small amount of additional funding came from exercise of warrants, government grants and milestone payments from partners.
The financing numbers in this post were compiled from the Q2 2012 Canadian Healthcare Review (pdf), co-authored by myself and Ross Marshall, Senior Vice President, The Equicom Group Inc., a wholly-owned subsidiary of TMX Group Inc.
Welcome to your Monday Biotech Deal Review for August 13, 2012. Highlights from the previous two weeks include the announcement of an interim order for a plan of arrangement between QHR Technologies Inc. and Open EC Technologies and the announcement of a support agreement for the takeover of Life Bank by Insception Biosciences. Read on to learn more. Read more of this post
Antibiotic resistance is an increasingly pressing public health problem. While the prevalence of resistance is increasing, there is a simultaneous dearth of newly approved or in development drugs. For those that are in development the majority are natural products or derivatives thereof. Most of these represent improved variants of marketed compounds rather than a new mechanistic class, which increases the risk of the rapid appearance of resistance. The small pipeline and current lack of diversity therefore means the identification of novel antibiotics is an important task.
Cationic antimicrobial peptides (CAMPs) represent one such class and are produced by all living species. These peptides have varied structures, but share the feature of a segregation of cationic and hydrophobic resides and it is this gross physiochemical property that underlies the antibiotic effects. Multiple mechanisms can be involved in the bactericidal activity, including membrane disruption, binding of DNA and other cellular components. However, the ability to translate the promise of CAMPs into antibiotics is hampered by their pharmacokinetic properties and especially their susceptibility to degradation by serum proteases.
Various strategies are available to address the stability problems of potential peptide therapeutics and this week’s paper by the Schweizer lab at the University of Manitoba focuses on examining the potential of the incorporation of peptoid residues into CAMP’s to improve their stability. Encouragingly their peptoid analogues had similar activities to the parent peptides, again supporting the idea that CAMPs work through gross physical chemical properties rather than specific structural features. The next step for the researchers is to show that the retained activity is bolstered by improved serum stability.
Welcome to your Monday Biotech Deal Review for Monday July 30, 2012. Highlights from the previous weeks include the closing of the $13 million public offering by Trimel Pharmaceuticals and $7.5 million loan, as well as the M&A activity involving Functional Technologies Inc. and Medifocus Inc. Read on to learn more. Read more of this post
TDP-43 and its C. elegans ortholog, TDP-1 are DNA and RNA binding proteins that have multiple functions in repressing transcription, splicing pre-mRNA and regulating translation. TDP-43 is found to be a constituent of stress granules, cytosolic RNA/protein aggregates that form in response to cellular stress, be it from heat, oxidative or osmotic.
TDP-43 has also been found to be mutated and accumulated in multiple neurodegenerative disorders, including ALS (Lou Gehrig’s disease), frontotemporal dementia (a form of pre-senile dementia second in prevalence only to Alzheimer’s disease) and chronic traumatic encephalopathy (including dementia pugilistica).
Given TDP-1/TDP-43’s role in cellular stress response the Parker lab at the Université de Montréal asked whether TDP-1 participated in C. elegans’s cellular stress response and longevity pathways and whether it was through participation in the Insulin/IGF-signaling (IIS) pathway, a major axis of stress-response signaling and longevity in worms.
They found that the tdp-1 gene is responsive to stress and participates in the Insulin/IGF signaling pathway to regulate lifespan, as well as to respond to oxidative stress. While worms that lack tdp-1 were more sensitive to external stresses, over-expression of tdp-1 was itself toxic. Furthermore, tdp-1 expression was induced by the introduction of mutant TDP-43 due to increased oxidative stress and that this led to increase neuronal degradation and reduced lifespan. This leads to the model that tdp-1 was intended to protect from unfavourable conditions, but is now becoming aberrantly activated and is contributing to proteotoxicity and oxidative stress in the cell. If this malfunction is present in humans it may explain why TDP-43 is found to be associated with an increasing number of neurodegenerative conditions and would support the exploration of TDP-43 as a therapeutic target.
Oncolytic viruses are a promising therapeutic approach that may finally be approaching the market; Amgen’s recently acquired OncoVEX GM-CSF is in phase III for melanoma with results expected in 2013 and Canada’s own Oncolytics has recently completed the first stage of its phase III trial for the treatment of platinum-refractory head and neck cancers.
For tumour types that are permissive to these viruses much of the promise arises from the specific replication in cancer cells and subsequent lysis. However, another activity that can help improve complete responses and prevent recurrence even when the virus has been cleared from the patient is the induction of antitumor immunity. This immunity is greatly stimulated by the viral replication and lysis process. Aiming to harness this effect, the recent paper in Molecular Therapy by researchers at the University of Ottawa describes an approach to generate a broad anti-tumour immunity against a multitude of tumour antigens through the use of an infected cell vaccine (ICV) platform, which is even applicable for tumours that are not permissive to oncolytic viruses.
The oncolytic VSV-Δ51 virus is able to induce a strong anti-tumour immunity in tumour cell lines, but only when viral replication occurs in the tumour cells. To overcome this, the researchers chose an ex vivo approach, whereby infection of isolated tumour cells with their oncolytic virus construct (the VSV-Δ51 virus, but expressing GM-CSF similar to the BioVEX approach) could be ensured in vitro by a high multiplicity of infection. A vaccine could then be prepared from this population of infected cells. With this approach mice were protected from subsequent tumour challenge and the induced innate and adaptive immune response was robust enough to control the growth of established tumours.
This approach offers a personalized vaccine comprising the full range of a patient’s tumour-specific antigens improving the hope for complete response and effective control of recurrence, albeit with a significant commercialization challenge arising from the inherently unscalable manufacturing, operational complexity and high production costs that is currently being faced by Dendreon’s Provenge.
Welcome to your Monday Biotech Deal Review for July 9, 2012. Highlights from the previous two weeks include the announcement of a $13.25 million prospectus offering by Trimel Pharmaceuticals, and the announcement of a $200 million exchange offer by Angiotech on its Senior Floating Rate Notes due 2013. Read on to learn more. Read more of this post
While there are a surprisingly low number of genes in the human genome, 95% of the multi-exonic genes are subject to alternative splicing and therefore the role of alternative splicing in permitting increased cellular and functional complexity should be more widely appreciated.
In different cell types and in response to different conditions, coordinated splicing regulation leads to the specific use of alternative exons and these regulated exon networks can be assumed to play important roles in specific processes and pathways – why else would it occur and be conserved. However, while this regulated behaviour is well known, there is a current lack of understanding of the functional effects imparted by the tissue-regulated alternative exons. A desire to fill in some of this gap motivated the research by a collaborative trio of labs at the University of Toronto. In their Molecular Cell paper, they show that proteins containing regulated exon networks tend to have more interactions in protein-protein interaction networks and that these regulated exons, together with their flanking constitutive exons, are enriched in sequences predicted to be highly disordered.
In a specific example of an alternative exon network regulated by nSR100/SRRM4 (neural-specific Ser/Arg-repeat related protein of 100 kDa), which is responsible for the inclusion of ~11% of brain specific exons, they show that the inclusion of the regulated exons could result in more or fewer protein-protein interactions, depending on the specific gene. Therefore, introduction of a regulated exon and the corresponding additional protein segment does not merely have an additive effect on the range of interactions in which an alternatively spliced protein can engage. Continuing on to a deeper level of detail, the authors show that the inclusion of one of these regulated exons in Bin1 promotes the interaction with the GTPase Dnm2 and that this interaction was needed for efficient endocytosis in neural cells, linking the splicing regulation all the way to cellular function.
Changes in exon splicing are known to be both causes and consequences of multiple human diseases, including tauopathies, spinal muscular atrophy and familial dysautonomia; adding to the functional understanding of alternative splicing will surely allow the identification of more, and the increased chance for the development of a treatment.
Welcome to your Monday Biotech Deal Review for June 25, 2012. Highlights from the previous week include the closing of the second tranche of Medifocus’ private placement for gross proceeds of $3.3 million. Read on to learn more. Read more of this post
On the heels of the U.S. government’s recent report: National Bioeconomy Blueprint , Battelle and BIO have released: State Bioscience Industry Development 2012.
The report highlights how the bioscience industry has excelled in terms of job growth. Even during tough economic times and an uneven recovery of the global economy, the industry has generally been an employment generator, well above the U.S. national average.
The report goes on to examine the bioscience industry by state. To read the report, click here
The Dick lab at the Campbell Family Institute of the Ontario Cancer Institute has been instrumental in the field of cancer stem cells. The central tenet of the cancer stem cell hypothesis is that there is a small population of cells within a tumour that are able to self-renew and also differentiate into the full range of cell types found within that tumour. In addition to their role at the head of the tumour cell hierarchy, these cancer stem cells (also known as cancer initiating cells, or tumour initiating cells) have increased resistance to chemotherapeutics, leading to an unfortunate ability to cause both relapse and metastasis.
In their Cancer Cell paper, the Dick lab and collaborators investigated the genes that are involved in controlling this combination of abilities. They determined that the proteins ID1 and ID3 were responsible for controlling the self-renewal of colon cancer stem cells. ID1 and ID3 are members of the DNA-binding protein inhibitor family of proteins that heterodimerize with basic helix-loop-helix transcription factors to prevent their ability to bind DNA. ID1 and ID3 appeared to be exerting their effect by increasing levels of p21, a cell-cycle inhibitor and regulator of self-renewal. p21 itself has previously been linked to protecting cancer cells from stress and DNA damage and it was also found that knocking down ID1 and ID3 led to increased sensitivity to oxaliplatin, thereby linking the phenomenon of increased resistance to chemotherapy and self-renewal.
As an official blog site for BIO 2012, Cross Border Biotech had the opportunity to participate in a fantastic new program known as the “BIO Buzz Center” which enables official bloggers to do webcasts over BIO’s website. During the convention, traffic to BIO’s websites surges – with the audience increasing by 2-3 times the normal size therefore increasing visibility.
Not being shy of the camera I jumped at the opportunity and had the privilege of interviewing Mr. Sanj Singh, President and CEO of Ade Therapeutics
Aside from the fact that my mike level was a bit low and I probably should have hit the makeup chair before taping, the 4 minute interview went very well.
A big thank-you to Sanj, Tracy Wemett and Gayle Kansagor for making this happen.
In light of the Canadian government’s review of the R+D tax credit regime in Canada and the hand wringing around the fallout should the recommendations from the Jenkins report be implented, it was refreshing to hear about the State of Maryland’s approach.
The Maryland government decided to create a unique approach to tax credits for early stage bio and tech companies resulting in “InvestMaryland”. The program has been highlighted in the “BIOtechNOW” event daily : BIOtech_Issue1_17 (2) from the BIO 2o12 convention.
The state program has been well received and local governments like Montgomery county have stepped up to provide additional support .
Welcome to your Monday Biotech Deal Review for June 18, 2012. Highlights from the previous week include the $10 million subscription receipt financing by Allon Therapeutics, the elimination of $11.8 million in debt by MedMira and the syndication of $600 million in debt by Valeant under its existing senior secured credit facilities. Read on to learn more. Read more of this post
BIO 2012 has officially kicked off in the beautiful city of Boston.
Social Media has moved front and centre during the convention with a full range of bloggers and tweeters. This year BIO is re-broadcasting blog posts via: http://convention.bio.org/ . Cross Border Biotech is listed as an official blog site so please check back for the latest updates and news from the convention floor. Speaking of convention floor, the Canadian Pavilion (booth 735) occupies a very large piece of real estate (7200 sq. ft.) and although not officially open is attracting a steady flow of people. The Pavilion houses companies from every province looking to promote, connect and partner.
[Ed. This is the nineteenth 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.]
The deal structure as outlined in Part 18 of this blog series is not meant to be a perfect, detailed model, or even realistic. However, this is a model which can be easily used to change assumptions and see what the impact is on the cash flow and NPV. Here are two examples.
Cisplatin was the first platinum based chemotherapy and remains the most widely used. Through an alkylating-like mechanism of action, cisplatin kills cells by binding, cross linking and damaging their DNA, thereby stimulating apoptosis through failed DNA repair attempts.
Platinum based chemotherapy is a standard first line therapy following surgery for many of the most common cancers (e.g. lung, ovarian, cervical). While cisplatin is able to produce positive responses in many patients, with time many will suffer from disease progression due to the development chemoresistance. While targeting cancer stem cells may prove to be a successful (and topical) approach, other approaches that seek to overcome the mechanisms of chemoresistance are important. These mechanisms will depend upon the agent to which resistance is conferred, but include increased efflux, mutation in the therapeutically target enzyme, decreased drug activation, increased drug metabolism, drug inactivation, enhanced DNA repair and mutation of the apoptosis pathway.
In this weeks post, the Lu lab at the University of Waterloo sought to boost the DNA-damaging activity of cisplatin. Based upon the authors’ previous studies, where they demonstrated the importance of a dissociative electron-transfer mechanism for reductive DNA damage by cisplatin, the authors proposed that addition of a biological electron donor to cisplatin treatment would increase its activity and potentially overcome resistance. N,N,N’,N’-tetramethyl-p-phenlenediamine (TMPD) is one such donor and in combination with cisplatin it was shown to increase plasmid DNA double strand breaks (a simple measure for DNA-damage activity); increase cisplatin sensitivity in both HeLa cells and in the cisplatin resistant ovarian cancer cell line NIH:OVCAR-3. A key feature of the combination is that it led to synergistic rather than additive effects. Furthermore, the authors proposed that the presence of TMPD actually suppressed the mechanism conferring cisplatin resistance to the NIH:OVCAR-3 cells, however, demonstration of that will require further work.
Indeed, much remains to be done to demonstrate the broad applicability and robustness of the results, but cisplatin’s immense importance in the formulary and its frontline use in a wide range of cancers means that the rapid development of a TMPD adjunctive therapy is one to be hoped for.
Welcome to your Monday Biotech Deal Review for June 11, 2012. The Monday Biotech Deal Review is back with Norton Rose Canada summer law student Jennifer Ng, who has agreed to assist with the deal review over the summer months. A very warm thanks to Keldeagh Lindsay for his dedication and contribution to the blog! The below covers transactions in the biotech space since since May 14, 2012. Highlights include the closing of the first tranche of Stellar Pharmaceuticals’ debt financing, as well as private placements each worth approximately $6 million closed for each of MedMira Inc. and Lorus Therapeutics. Read on to learn more. Read more of this post
The cancer stem cell (CSC) hypothesis – the concept that a small population of stem cell-like transformed cells is important for cancer initiation, progression and relapse – has gained quite a bit of attention in both academia and industry. It is proposed that these populations of cells have the unfortunate combination of being able to reinitiate tumour growth following treatment, as well as being more resistant to treatment, which explains the development of therapy resistance, minimal residual disease and tumour recurrence.
An attractive therapeutic rationale is therefore to develop drugs that either selectively target the cancer stem cells. However, any such treatment would need to have a therapeutic window between killing the cancer stem cells and killing an individual’s healthy stem cells, a population of cells that play important roles in tissue maintenance and repair. One approach is to discourage the proliferative self-renewal role that CSC’s favour and encourage their differentiation, thereby reducing their tumour growth potential. However, despite exactly this mechanism being used by Vesanoid, a treatment for acute promyelocytic leukemias developed over 20 years ago, no similar treatments for other cancers exist. However, the research by the Bhatia lab and collaborators at McMaster University is aimed at reinvigorating this approach.
They developed a discovery platform that can be used to screen molecules for their ability to induce the differentiation of a model of human CSC’s (a variant human pluripotent stem cell line) and but not normal pluripotent human stem cells. Applying their platform in a proof-of-concept screen, initially with well established, annotated compounds from the NIH Clinical and Canadian Compound collections they identified several candidates that induced morphological changes in the CSC model cells, but had no effect on normal stem cells. Unexpectedly a compelling hit arose from the antipsychotic drug thioridazine, with the apparent activity arising from the molecules action as a dopamine receptor antagonist.
With a paper that presents both a powerful screening tool, a potential repurposing of an approved molecule and a new potential target for the selective treatment of CSC’s, there is certainly no shortage of avenues to pursue and hopefully it will not be another 20 years before the we see the addition of another cancer therapy using the differentiation approach.
Divergent Genomic and Epigenomic Landscapes of Lung Cancer Subtypes Underscore the Selection of Different Oncogenic Pathways during Tumor Development. PLoS One. British Columbia Cancer Research Centre
Inhibition of Serine Palmitoyl Transferase I Reduces Cardiac Ceramide Levels and Increases Glycolysis Rates following Diet-Induced Insulin Resistance. PLoS One. University of Alberta
Assessment and implication of prognostic imbalance in randomized controlled trials with a binary outcome – a simulation study. PLoS One. McMaster University
Most people take for granted that given a little resolve at the gym they can induce their muscles to grow, however, most people have probably not considered the complexity of the underlying cellular and biochemical processes. In response to exercise or injury, normally quiescent muscle satellite cells are activated and divide to produce progeny myogenic precursor cells that will themselves undergo multiple rounds of division before differentiating and fusing to the multinucleated muscle myofiber, thereby increasing the size and strength of the muscle. Key to the regulation of the satellite cell function is expression of the paired box transcription factors Pax3 and Pax7. These transcription factors are highly related (>85% sequence identity) and play overlapping, but mostly nonredundant roles in the specification and progression of the adult satellite cell lineage. Lineage tracing has suggested that Pax3 is required in cells that contribute to embryonic myoblasts and to the endothelial lineage, but Pax7 cells contribute to fetal myoblasts.
Given their sequence similarity, researchers at the University of Ottawa investigated how the functional differences were achieved. By profiling the global gene expression of satellite cell-derived myoblasts, alongside determining the genome-wind binding sites of Pax3 and Pax7, they showed that Pax3 and Pax7 have intrinsic differences in DNA binding and it is the differential binding that drives the differential downstream gene activation. Specifically, they showed that Pax3 and Pax7 are both able to activate gene expression by binding to combined prd/hbox motifs, but Pax7 can also activate gene expression by binding to the hbox motif alone. Due to this difference in binding ability, over 400 genes are regulated by Pax7, that are not subject to regulation by Pax3 and these genes have diverse functions from cell adhesion to muscle cell differentiation. This work adds to the transcriptional network underpinning muscle cell differentiation and also cautions us by showing how large functional differences can occur in transcription factors with only small differences in sequence.
Hyperphosphorylation and cleavage at d421 enhance tau secretion. PLoS One. Université de Montréal
Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1. PNAS. Structural Genomics Consortium, Toronto
Muramyl Dipeptide Induces NOD2-Dependent Ly6C(high) Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection. PLoS One. Laval University
The development and application of large scale studies of pathways, metabolites and interactions is clearly hugely important for biomedical advances and today’s paper from the University of Toronto and the University of Ottawa is concerned with acetylomics (a relatively recent addition to the rapidly growing omeome).
Lysine acetylation of histones has long been known to be involved in regulation of gene expression. However, acetylation has only recently come to be appreciated as having a wider role outside of histones and may be as extensive a post-translational modification as phosphorylation, with over 2500 mammalian proteins being subject to acetylation. Normal cell proliferation, growth, and differentiation requires the function of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) to maintain the appropriate levels of histone acetylation and abnormal function of these proteins is found in cancer. Therapeutically, KDACs are the targets of the histone deacetylase inhibitors (e.g. Vorinostat) and also include Sirtuin-1, the proposed target for the much hyped Resveratrol.
In their study, the Andrews lab and collaborators determined a network of 463 synthetic dosage lethal interactions for two classes of KDACs in budding yeast, thereby identifying which cellular pathways were subject to regulation by the different KDACs. The identified genes were enriched for diverse cellular processes, indicating that acetylation has a wide, and currently under-appreciated, role within cells that means we should hope to hear a lot more from acetylomics in the future (whether you be a fan of that particular neologism or not).
TLR Tolerance Reduces IFN-Alpha Production Despite Plasmacytoid Dendritic Cell Expansion and Anti-Nuclear Antibodies in NZB Bicongenic Mice. PLoS One. Toronto Western Research Institute
Translational Homeostasis via the mRNA Cap-Binding Protein, eIF4E. Molecular Cell. McGill University
Multiple roles of integrin-linked kinase in epidermal development, maturation and pigmentation revealed by molecular profiling. PLoS One. University of Western Ontario
Welcome to your Monday Biotech Deal Review for May 14, 2012. Highlights from the previous week include the $5 million private placement announced by Lorus Therapeutics and other equity financing announcements, but otherwise the week has generally been a slow one. Read on to learn more. Read more of this post
The tumour suppressor p15ink4b is a cyclin-dependent kinase (cdk) inhibitor, which functions to cause cell cycle arrest and whose functional presence in tumour cells is often lost through mutation or deletion. The expression of p15ink4b can be rapidly induced by transforming growth factor beta (TGF-β) and regulation of p15ink4b levels occurs primarily at the level of transcription. DNA methylation is one of the mechanisms known to repress transcription of p15ink4b, however, the mechanism by which DNA methylation is reversed for the regulation of transcription is relatively poorly understood. In this week’s Molecular Cell paper, the Torchia lab at the University of Western Ontario sought to determine the mechanism of DNA methylation and demethylation of the p15ink4b in response to TGF-β.
Using chromatin immunoprecipitation-sequencing (ChIP-seq), they showed that the p15ink4b gene is a target for the ZNF217/CoREST complex and that along with the action of specific DNA (cytosine-5)-methyltransferase enzymes e.g. DNMT3A, the p15ink4b gene is hypermethylated and repressed. Overcoming the repression in response to TGF-β induced signaling was shown to require removal of the DNMT3A/ZNF217/CoREST complex and replacement by SMAD2/3, the CBP acetyltransferase, and TDG or MBD4. Base excision repair then occurred, demethylating the DNA and thereby removing the transcriptional repression. They further showed that ZNF217 overexpression, a feature of some cancers, was shown to inhibit recruitment of the demethylation complex.
While focused on the specific regulation of p15ink4b, these results add more generally to our knowledge of methylation-based epigenetic regulation and the important association of abnormal DNA methylation patterns with malignant transformation.
Monomeric site-specific nucleases for genome editing. PNAS. University of Western Ontario
TRADD contributes to tumour suppression by regulating ULF-dependent p19(Arf) ubiquitylation. Nature Cell Biology. University of Toronto
[Ed. This is the eighteenth 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 a partnering deal is signed, what are the usual financial components?
Up-front cash usually has no conditions and is a non-dilutive financing. Big pharma generally does not want equity as it just clutters up their balance sheets and is an even bigger problem if the partnership gets terminated.
Clinical and regulatory milestone payments are fairly standard. The basic milestones are the initial U.S. and E.U. approvals but may include approvals of additional indications if they increase the market potential.
Sales milestone payments have become more common in the last decade. If the pharma partner does not believe the market potential, milestones can be included for reaching certain annual or cumulative sales milestones.
Royalties on sales are generally no longer a simple X% on net sales. They can be tiered, increasing after annual or cumulative sales milestones are reached.
If there is an R&D program, who conducts it and who pays for it?
Who executes and pays for the clinical and regulatory programs?
Some companies would like to retain or have an option on some sales and marketing rights in specific territories. These rights may cease to exist if there is a change of control at the smaller company.
The only way to learn about deal structures is to create a fictional deal, make the spread sheet and start looking at the impact of structural changes on the product NPV. The following assumptions have been used to create the attached Excel workbook. Read more of this post
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