Pullan Consulting
Biotech Business Development Consulting
www.pullanconsulting.com and www.lindapullan.com
email: lpullan@msn.com 805-558-0361
Issue #30
Pullan's Pieces
Commentary on Science & Business of Drug Development
For Business Development & Others
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No bad news – just a bit of science and warm wishes!
I decided that for this holiday season, I would write nothing on the economy, but I’d love to hear what you would like to read about in 2009.
With this issue, I want to thank all my clients, business colleagues, and readers, and wish you all a lovely holiday season and good times in 2009!
Linda
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Twins with a lipid storage disease may shed light on Alzheimer’s – a touching story, with hope from foundations and a patient-funded virtual biotech
A story in The Scientist (http://www.the-scientist.com/templates/trackable/display/article1.jsp?type=article&o_url=article/display/55136&id=55136) of young twins afflicted with Niemann-Pick Disease (NPC) brings together the touching drama of illness, and the reach for innovation that makes biotech special.
Young twin girls face a devastating prospect of what has been termed “Childhood Alzheimer’s” in Niemann-Pick (NPC) disease. Mutation of the gene that produces NPC1, a protein that helps transport lipids such as cholesterol to the endoplasmic reticulum and the plasma membrane, results in accumulation of lipids and neuronal cell death, with symptoms ranging from difficulties in coordination and walking, to cognitive decline.
Their rare disease has spurred work, funded by the parents and the Ara Parseghian Foundation, on screening already approved drugs to reverse the phenotype in fibroblast cells from NPC kids. The young girls in the story are already taking curcumin, identified as effective in NPC mice by a group of researchers known as SOAR-NPC, or Support of Accelerated Research for Niemann-Pick disease type C. SOAR-NPC is managed by Collabrx, a new patient-funded "virtual" biotech that facilitates collaborations between researchers (written about in prior Pullan’s Pieces).
Some researchers are studying NPC in hopes of finding leads for Alzheimer’s. In NPC, cholesterol is not trafficked properly. High cholesterol appears to increase the risk of Alzheimer's, and apoE4, a variant of the protein apolipoprotein E, influences the development of both NPC and Alzheimer's. The brains of NPC children get the neurofibrillary tangles of hyperphosphorylated tau seen in Alzheimer’s patients. Some NPC cells get primitive plaque-like structures, mimicking in part the other hallmark of Alzheimer’s. A recent genome-wide expression analysis of fibroblasts with mutated NPC1 revealed higher expression levels of genes that help generate amyloid. Neurons affected by both diseases experience dramatic accumulations of autophagic vacuoles and lysosomes, and cells affected by both disorders have enlarged endosomes. One new therapeutic strategy for Alzheimer’s is identifying why NPC mice are protected from the hyperphosphorylation of tau and the tangles.
But all involved hope that a means to prevent the loss of brain functioning in these young kids can be found quickly.
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Most cases of relapse in Acute Lymphoblastic Leukemia can be traced back to a cell with a mutation existing at diagnosis
An analysis (Mullighan et al, Science 322: 1377, 2008) of gene copy number changes in Acute Lymphoblastic Leukemia (ALL) samples at time of diagnosis and at time of relapse may change the way we think about cancer relapse. It is not yet clear how broadly these findings apply as this study was focused on changes in gene copy number (not other mutations), and not on a more heterogeneous solid tumor, but it already raises new questions about the biomarkers of tumors and treatment of relapse.
The study found that, by specifically seeking in the diagnostic samples those changes seen at relapse, 52% of the relapse cases arose from a mutated cell already present in the sample at time of diagnosis of ALL. This suggests that relapse is often not further mutation of the diagnostic clone, but rather that effective treatment of the diagnostic clone leaves a small number of cancer clones ready to expand upon new mutations. The new mutations found at time of relapse were most commonly in tumor suppressors, cell cycle control and genes for B cell development, not in mechanisms of drug resistance such as drug import, export, or metabolism or in drug receptors. Relapse was not drug-induced resistance. The diversity of the genes changed, and the presence of a minor clone at diagnosis that escapes drug treatment means that treating relapsed ALL is likely to be hard. If more broadly applicable, it may be that gene changes in rare tumor cells are important to track and that drug-induced resistance is less important than we thought.
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New doubt on cancer stem cell hypothesis, at least in melanoma
Past studies on diverse cancers, including melanoma, have indicated that only rare human cancer cells (0.1–0.0001%) form tumors when transplanted into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Now, use of an even more immunocompromised animal (NOD/SCID interleukin-2 receptor gamma chain null (Il2rg -/-) mice) showed that in single-cell transplants, an average of 27% of unselected single melanoma cells (from four different patients) formed tumors. Tests did not show any of the markers for cancer stem cells on these single cells able to form tumors. (Nature 456, 593-598, 4 December 2008). The findings suggest that all cancer cells, not just rare cancer stem cells, can form tumors.
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Cheaper proteins may reduce the costs of biologic drugs; Merck sees yeast production as enabling biogenerics business
Producing proteins more cheaply has long been on the horizon, with transgenic goats and other alternatives to mammalian cell culture. Now, a clinical study has begun with insulin produced in the oil storage bodies of safflower seeds. This sequestration in the seed organelles makes the proteins easier to purify from the plants. It is estimated that 3 commercial farms could supply all the insulin. SemBioSys Genetics says it is the largest production of proteins in plants yet. (http://www.newswire.ca/en/releases/archive/December2008/03/c6526.html ).
Cheaper production in humanized yeast cells (with the carbohydrate side chain engineering of the Glyco-Fi platform acquired in 2006) was a key driver in Merck’s recent decision to enter the biologics and biogenerics business. Merck is expecting the Obama administration to create a regulatory pathway for the follow-on biogenerics. Merck also believes the unique production platform will mean that it can avoid patent infringement and compete successfully with Amgen’s Epogen (The Wall St. Journal, Dec. 10th). Merck needs to do something new, as it has announced guidance for no-growth in earnings for 2009 (http://www.bizjournals.com/triangle/stories/2008/12/01/daily35.html?ana=from_rss ).
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Pullan Consulting
Linda M. Pullan, Ph.D.
Biotech Business Development
www.pullanconsulting.com and www.lindapullan.com
e-mail: lpullan@msn.com
805-558-0361
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