Published on Feb 27, 2013
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Published on Feb 27, 2013
Symposium summary: Swine cells could power artificial liver
Feb. 27, 2013 - Chronic or acute, liver failure can be deadly. Toxins take over, the skin turns yellow and higher brain function slows.
“There is no effective therapy at the moment to deal with the toxins that build up in your body,” said Neil Talbot, a Research Animal Scientist for the USDA Agricultural Research Service. “Their only option now is to transplant a liver.”
Talbot thinks a line of special liver cells could change that. In an interview with the American Society of Animal Science, he discussed how a line of pig liver cells called PICM-19 could perform many of the same functions as a human liver.
In 1991, Talbot created PICM-19 from the cells of an 8-day-old pig embryo. The cell line is significant because it is “immortal,” meaning the cells can divide an infinite number of times. Many immortal cells lines continue dividing because they are derived from cancer cells; however, PICM-19 cells are derived from epiblast cells, the embryonic stem cells that form in the early stages of embryo development.
This immortal cell line has helped Talbot study how cells differentiate. Cells from the PICM-19 lines naturally differentiate into bile duct cells or hepatocytes. Hepatocytes do the bulk of the work in a liver. Hepatocytes form and secrete bile, store glycogen, control blood glucose, process vitamin D, and metabolize cholesterol and fat.
“The PICM- 19 cells are the cells that really do all the metabolic functions of the liver,” said Talbot.
Hepatocytes also “scrub” toxins from the blood. Talbot said PICM-19 cells could do the same thing inside an artificial liver. There have already been several in vitro tests of artificial liver devices, and the ARS scientists are working on ways to grow the PICM-19 cells without needing “feeder cells.” Feeder cells are mouse cells that hold PICM-19 cells in place and provide important molecules for PICM-19 cell growth and maintenance.
Artificial livers are still in development, but Talbot pointed out other applications for PICM-19 cells. Talbot and fellow scientists have used PICM-19 to study malaria, toxoplasmosis and hepatitis viruses. Researchers could also use the cells to study certain cancers of the liver or investigate the changes in the bile duct associated with cystic fibrosis.
Talbot recommends future studies on how PICM-19 cells respond to selective pressures. He said scientists could select for more efficient liver cells by exposing PICM-19 cells to toxins in culture.
“A lot of cells would die, but the survivors would really be tough,” Talbot said.
Those tougher cells could make artificial liver devices more effective. Scientists could also use genetic modification to prompt PICM-19 cells to behave like other cells in the body.
“Maybe we want to enable it to make insulin,” Talbot said. “It will be like a pancreas.”
With PICM-19 cells filling in for livers or other organs, the transplant list could get a lot shorter.
Tom Caperna, an ARS Research Biologist and collaborator with Talbot, presented their work on PICM-19 during the Growth and Development Symposium at the 2012 Joint Annual Meeting. The full symposium summary is titled “Growth and Development Symposium: Development, characterization, and use of a porcine epiblast-derived stem cell line: ARS-PICM-19.” It can be read in full at journalofanimalscience.org.
USDA Agricultural Research Service
301-504-8216 / firstname.lastname@example.org
Source - http://www.asas.org/membership-services/press-room/press-release-interpretive-summary-archive/swine-cells-could-power-artificial-liver
Spring Bank Pharmaceuticals Closes $10.5 million Series A Financing to fund Phase I Clinical Trials in HCV-infected Patients
Published: 28 February 2013 12:01 PM
MILFORD, Mass., Feb. 28, 2013 /PRNewswire/ -- Spring Bank Pharmaceuticals, Inc., a biopharmaceutical company developing innovative medicines for the treatment of viral infections, today announced it has closed on a $10.5 million Series A financing. Proceeds will be used to fund Phase I clinical development of SB 9200, a novel, orally available treatment for Hepatitis C virus (HCV) infection and to further the preclinical pipeline. The Company plans to conduct a Phase I safety and antiviral efficacy study of SB 9200 in healthy, HCV-infected patients beginning in the first quarter of 2013. This financing was led by Brock Securities LLC with participation from Gilford Securities.
"This financing represents a major milestone for SBP," said Douglas Jensen, CEO and Co-founder of Spring Bank, "as it will enable us to move SB 9200 through an important Phase I clinical study that will provide both safety and early antiviral activity data. SB 9200 is an entirely new agent for the treatment of chronic HCV infections and is based on our proprietary Small Molecule Nucleic Acid Hybrid (SMNH) technology platform. We thank our investors for their enthusiastic support and together we look forward to the initiation of our first clinical program and the advancement of our strong pipeline of additional SMNH programs for Hepatitis B virus (HBV), Respiratory Syncytial Virus (RSV), Broad Spectrum Antiviral and COPD."
SB 9200 has a unique mechanism of antiviral action involving the selective activation of the host-immune response in HCV-infected cells. "Unlike other classes of drugs for HCV infection that act directly on the virus, SB 9200 targets host cytosolic sensor proteins, RIG-I and NOD2," states Dr. Kris Iyer, CSO and Co-founder of Spring Bank. "This leads to the selective activation of the host immune response in the presence of viral infection. By virtue of this novel mechanism of action, SB 9200 is ideally suited for combination with other classes of HCV antivirals. In preclinical studies, SB 9200 has shown synergistic antiviral activity when combined with other anti-HCV compounds and has demonstrated an excellent safety profile. Moreover, this novel mechanism of action suggests it could have pan-genotypic activity, as well as potentially a high barrier to resistance. These attributes could potentially lead to the use of SB 9200 as part of an Interferon-free, all-oral regimen for HCV therapy."
About Spring Bank Pharmaceuticals
Spring Bank Pharmaceuticals is engaged in the discovery and development of an entirely new class of safer and more effective medicines based on the Company's proprietary SMNH, "Small Molecule Nucleic Hybrid" technology program. SB 9200, a potential breakthrough drug for the treatment of HCV and HBV, is the Company's most advanced drug under development. The Company also has programs for the development of antivirals against Respiratory syncytial virus (RSV) infections; the development of a Broad spectrum antiviral; and therapies to treat Chronic obstructive pulmonary disease (COPD).
Contact: Douglas Jensen (508)-473-5993 x105
Wonder drug warning: Health Canada describes deaths from Hep C pills
Serious skin reactions to Incivek in chronic Hepatitis C patients a sign they should seek “urgent” medical care, Health Canada says.
By:Lesley Ciarula Taylor
News reporter, Published on Thu Feb 28 2013
A chronic Hepatitis C wonder drug that has caused death and serious skin reactions has been hit with a serious warning and alert by Health Canada, two months after the same urgent message in the U.S.
The Incivek capsules are the flagship product of Vertex Inc., a Massachusetts pharmaceutical company with a branch in Laval, Que.
Health Canada warned people to seek “urgent” medical treatment if they develop a serious skin reaction while taking Incivek, the trademark name of the drug teleprevir produced by Vertex Pharmaceuticals Canada Inc.
Deaths have occurred in people with “progressive rash and systemic symptoms” who kept using the drug, Health Canada said Wednesday.
The U.S. parent company announced the “black box” warnings, the highest cautionary level, in December. The drug was approved in the U.S. and Canada in 2011.
Health Canada’s longer process for issuing such warnings caused the extra two-month lag in announcing the complications, Vertex U.S. spokeswoman Erin Emlock told the Star.
“We had to work through that process” with Health Canada, she said.
“There are a limited group of physicians who prescribe the drug in Canada. There are many, many more patients in the U.S.,” she said.
In December, the U.S. Federal Drug Administration said there had been two deaths and 112 serious skin reactions.
Emlock said she didn’t know if any of those were in Canada.
Ontario doctors last fall questioned why it was taking the province so long to approve the drug.
“The medication can dramatically shorten the treatment time for hep C, limiting the impact of side effects like anemia and rashes, and it has been shown to cure the condition in a majority of new cases,” the Star’s Rob Ferguson reported.
Provincial drug plans in Quebec, Nova Scotia, New Brunswick, Alberta, B.C. and the Yukon and private insurers were paying for the $35,000 cost of a standard 12-week treatment, Ferguson reported.
Health Canada advised patients to talk to their doctors before they stop using the medication.
“Fatal and non-fatal serious skin reactions, including Toxic Epidermal Necrolysis (TEN), Stevens Johnson Syndrome (SJS), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported in patients receiving Incivek combination treatment,” Health Canada said.
Incivek is used only in combination with peginterferon alfa and ribavirin.
At the time of the Health Canada approval, Canadian Incivek investigator Dr. Eric Yoshida of the University of British Columbia said, “Incivek has been shown to help clear the virus for nearly four out of five patients new to treatment.”
Vertex chief medical officer Robert Kauffman said a quarter of a million Canadians suffered from Hepatitis C.
The drug is used to treat genotype 1 chronic hepatitis C in adult patients with compensated liver disease.
Updates @ NATAP
This study is currently recruiting participants
Dose Ranging of NS5A GSK2336805 (vs telaprevir) in Combination Therapy
GSK2336805 is a novel hepatitis C virus (HCV) non-structural 5A (NS5A) inhibitor being developed for the treatment of chronic HCV infection. This Phase II, multicenter, parallel-group, randomized, dose-ranging study will assess the safety and tolerability, antiviral activity, and pharmacokinetics of GSK2336805 at 2 dose levels (40 and 60 mg) in combination with pegylated interferon alfa-2a (PEG) and ribavirin (RIBA) in approximately 100 treatment-naïve subjects with chronic genotype 1 HCV infection.....
NS5A Review - Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein
"NS5A-targeting molecules are probably the most potent antiviral molecules ever discovered"
"At least 4 NS5A-targeting molecules are being evaluated in combination with pegIFN/RBV: BMS-790052, GS-5885, ABT-267, and GSK23368005 (Table 1 and Table 2)."
"BMS-790052 serves as the prototype molecule for this class of HCV inhibitor; defined by exquisite low picomolar EC50 values for HCV genotype 1 (Table 1.). These molecules are over a 1000-fold more potent than the current licensed HCV protease inhibitors in cell culture-based HCV replicon assays ( Flint et al., 2009, Gao et al., 2010 and Lin et al., 2006); they are probably the most potent antiviral molecules ever discovered."
"Both Achillion's and Merck's NS5A inhibitors (ACH-3102 and MK-8742, respectively) retain substantial levels of in vitro potency against NS5A resistance polymorphisms that plague early NS5A inhibitors, such as BMS-790052 and GS-5885 ( Liu et al., 2012 and Yang et al., 2012). Accordingly, they can be viewed as 'second generation' NS5A inhibitors and time will tell whether these favorable preclinical profiles will also translate to superior clinical efficacy."
ClinicalTrials.gov -Updated in the last 30 days
Efficacy and Safety Evaluation of a Treatment Consisting of Peg Interferon Alfa + Ribavirin + Daclatasvir in HCV Genotype 1 and 4 Treatment naïve Patients
Thursday, February 21, 2013, 12:00:00 PM
"Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period"
Dr. Zoe Mariño discusses her article "Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period"
Abstract - http://www.journal-of-hepatology.eu/article/S0168-8278(12)00768-4/abstract
Editorial - Silibinin: An old drug in the high tech era of liver transplantation
Murphy: Hepatitis and the pharmacology of greed
OHSU scientists first to grow liver stem cells in culture, demonstrate therapeutic benefit
PORTLAND, Ore. — For decades scientists around the world have attempted to regenerate primary liver cells known as hepatocytes because of their numerous biomedical applications, including hepatitis research, drug metabolism and toxicity studies, as well as transplantation for cirrhosis and other chronic liver conditions. But no lab in the world has been successful in identifying and growing liver stem cells in culture -- using any available technique – until now.
In the journal Nature, physician-scientists in the Papé Family Pediatric Research Institute at Oregon Health & Science University Doernbecher Children's Hospital, Portland, Ore., along with investigators at the Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, Netherlands, describe a new method through which they were able to infinitely expand liver stem cells from a mouse in a dish.
"This study raises the hope that the human equivalent of these mouse liver stem cells can be grown in a similar way and efficiently converted into functional liver cells," said Markus Grompe, M.D., study co-author, director of the Papé Family Pediatric Research Institute at OHSU Doernbecher Children's Hospital; and professor of pediatrics, and molecular and medical genetics in the OHSU School of Medicine.
In a previous Nature study, investigators at the Hubrecht Institute, led by Hans Clever, M.D, Ph.D., were the first to identify stem cells in the small intestine and colon by observing the expression of the adult stem cell marker Lgr5 and growth in response to a growth factor called Wnt. They also hypothesized that the unique expression pattern of Lgr5 could mark stem cells in other adult tissues, including the liver, an organ for which stem cell identification remained elusive.
In the current Nature study, Grompe and colleagues in the Papé Family Pediatric Research Institute at OHSU Doernbecher used a modified version of the Clever method and discovered that Wnt-induced Lgr5 expression not only marks stem cell production in the liver, but it also defines a class of stem cells that become active when the liver is damaged.
The scientists were able to grow these liver stem cells exponentially in a dish – an accomplishment never before achieved – and then transplant them in a specially designed mouse model of liver disease, where they continued to grow and show a modest therapeutic effect.
"We were able to massively expand the liver cells and subsequently convert them to hepatocytes at a modest percentage. Going forward, we will enlist other growth factors and conditions to improve that percentage. Liver stem cell therapy for chronic liver disease in humans is coming," said Grompe.
Moderate, excessive or heavy alcohol consumption: each is significantly associated with increased mortality in patients with chronic hepatitis C
Z. M. Younossi1,2,*, L. Zheng1,2, M. Stepanova2, C. Venkatesan1, H. M. Mir1
Article first published online: 24 FEB 2013
DOI: 10.1111/apt.12265 © 2013 Blackwell Publishing Ltd
Alimentary Pharmacology & Therapeutics
|Characteristics||CH-C (n = 218) Percent ± S.E.||No CH-Ca (n = 8767) Percent ± S.E.||P-valueb|
|Excessive alcohol consumptionc||28.35 ± 5.48||7.29 ± 0.47||0.0075|
|20–44||79.25 ± 4.97||63.05 ± 1.09|
|45–54||15.06 ± 4.69||14.56 ± 0.62|
|55–64||1.63 ± 0.49||12.02 ± 0.59|
|65–74||4.07 ± 1.52||10.36 ± 0.65|
|Male||67.37 ± 4.92||46.41 ± 0.68||0.0042|
|Non-Hispanic white||63.33 ± 5.59||77.56 ± 2.14|
|Non-Hispanic black||21.80 ± 3.52||10.55 ± 1.16|
|Mexican American||6.61 ± 1.92||4.70 ± 0.78|
|Other||8.26 ± 3.70||7.20 ± 1.15|
|Smoking||83.19 ± 4.96||54.27 ± 1.32||0.0007|
|Obesity||33.22 ± 4.82||31.36 ± 0.90||0.7001|
|Diabetes or insulin resistance||36.13 ± 4.15||16.84 ± 0.83||0.0013|
|Hypertension||18.42 ± 4.46||17.21 ± 0.71||0.7859|
|Characteristics||All-cause mortality||Cardiovascular mortality||Liver-related mortality|
|CH-C: Excessive alcohol consumptiona||5.12 (1.97–13.28)||3.34 (0.55–20.50)||183.74 (15.98–infinity)|
|CH-C: No excessive alcohol consumptionb||2.44 (1.59–3.75)||0.71 (0.23–2.21)||74.25 (19.62–280.92)|
|Excessive alcohol consumption||0.80 (0.60–1.07)||0.57 (0.27–1.20)||0.28 (0.04–2.17)|
|45–54||3.04 (2.03–4.54)||3.56 (1.44–8.84)||1.31 (0.18–9.77)|
|55–64||7.16 (4.95–10.35)||6.87 (3.23–14.61)||7.82 (0.66–92.92)|
|65–74||22.90 (16.15–32.48)||33.61 (16.40–68.90)||30.92 (4.47–214.16)|
|Male||1.33 (1.12–1.57)||1.72 (1.24–2.37)||1.70 (0.45–6.49)|
|Non-Hispanic black||1.26 (1.05–1.52)||1.18 (0.89–1.56)||0.79 (0.29–2.18)|
|Mexican American||0.94 (0.76–1.16)||0.96 (0.67–1.39)||1.01 (0.29–3.63)|
|Other||0.80 (0.51–1.25)||0.39 (0.15–1.05)||0.27 (0.02–3.38)|
|Smoking||2.08 (1.72–2.52)||1.56 (1.15–2.11)||1.36 (0.45–4.12)|
|Obesity: Age 20–44||1.30 (0.84–2.03)||1.34 (0.46–3.90)||8.85 (1.33–59.04)|
|Obesity: Age 45–54||1.63 (1.01–2.61)||1.28 (0.50–3.24)||6.14 (0.80–47.30)|
|Obesity: Age 55–64||0.98 (0.74–1.31)||1.11 (0.63–1.98)||0.49 (0.05–4.94)|
|Obesity: Age 65–74||0.67 (0.53–0.86)||0.60 (0.39–0.93)||0.63 (0.09–4.54)|
|DM/IR||1.66 (1.35–2.03)||1.74 (1.29–2.36)||0.76 (0.30–1.94)|
|Hypertension||1.47 (1.24–1.74)||2.50 (1.72–3.64)||2.64 (0.94–7.42)|
|CH-C and alcohol consumption (number of participants, N)||All-cause Mortality||P-valueb|
|CH-C with a previous history of alcohol consumption (N = 60)||2.33 (1.21–4.49)||0.0116|
|CH-C without previous a history or current alcohol consumption (N = 14)||2.52 (0.87–7.34)||0.0887|
|CH-C with moderate current alcohol consumption <20 g/day (N = 99)||2.29 (1.36–3.88)||0.0023|
|CH-C with excessive current alcohol consumption 20–29 g/day (N = 23)||7.63 (1.48–39.31)||0.0157|
|CH-C with heavy current alcohol consumption ≥30 g/day (N = 22)||3.50 (1.20–10.17)||0.0219|
|Top 3 causes of deatha|
|Controls without CH-C||Cardiovascular disease (32.4%), lung cancer (10.3%), pneumonia or other chronic lower respiratory disease (6.8%)|
|CH-C (the entire cohort)||Liver diseases (20.4%), motor vehicle or poisoning accidents (16.7%), cardiovascular disease (9.3%)|
|CH-C with a history of alcohol consumption||Liver disease (29.4%), cardiovascular diseases (17.6%), diabetes (11.8%)|
|CH-C with excessive current alcohol consumption||Motor vehicle accidents (25.0%), liver disease (16.7%), suicide (16.7%)|