Time filter

Source Type

News Article | December 6, 2016
Site: www.eurekalert.org

A new biopharmaceutical company, Tenaya Therapeutics Inc., will build on discoveries in cardiovascular disease research made at the Gladstone Institutes, concentrating on regenerative medicine and drug discovery for heart failure. The new company combines Gladstone's basic science expertise with the resources and translational know-how of the biotechnology industry. Cardiovascular disease -- including heart attacks and congenital heart defects -- is the world's leading cause of death. Heart failure alone afflicts more than 20 million people around the world. "When heart muscle is damaged, the body is unable to repair the dead or injured cells," explained Deepak Srivastava, MD, director of the Gladstone Institute of Cardiovascular Disease and a co-founder of the new company. "Right now, the only possible cure for heart failure is a heart transplant. We hope that this new venture will bring us closer to a more scalable cure." "There has been limited commercial investment in the cardiac field, despite the remarkable progress made at Gladstone and elsewhere," added Stephen Freedman, PhD, vice president for corporate liaison and ventures at Gladstone. "Tenaya will advance some of the innovative work coming out of Gladstone, with the aim of developing new therapeutics for heart failure." Tenaya is supported by a $50 million Series A financing from The Column Group. David Goeddel, PhD, a managing partner at The Column Group and a pioneer of the biotechnology industry, is the board chair of Tenaya. JJ Kang, PhD, an associate at The Column Group, is a board director and president of the new company. "The key ingredients for a successful company are a great team and great ideas," said Goeddel. "With the stellar group of scientists that we've assembled, we're confident that we will be able to build something transformative from the cutting-edge research of the Gladstone Institutes." Tenaya will leverage Gladstone's pioneering work in cellular reprogramming to search for cures for heart failure. One program will translate cellular reprogramming technology to the clinic to regenerate heart muscle cells in patients with heart failure. Other programs will use cellular models of heart disease created from stem cells to identify potential new drug targets. The new company is the first formed out of BioFulcrum, an entrepreneurial initiative within Gladstone that takes a milestone driven approach to science. BioFulcrum aims to accelerate the discovery of cures by bringing together scientists, multiple non-profit institutions, and industry partners such as Goeddel, who sits on the board of BioFulcrum. "Inspired by the collaborative research at BioFulcrum, we wanted to establish Tenaya to integrate new findings and tools in the cardiac field and advance them towards clinical translation," said Kang. "Our goal is to build a science-focused company that discovers novel therapies for heart failure patients." Scientific co-founders of the company include Srivastava and Gladstone Investigators Benoit Bruneau, PhD, Bruce Conklin, MD, Sheng Ding, PhD, and Saptarsi Haldar, MD, as well as Eric Olson, PhD, from the University of Texas Southwestern Medical Center. Other Gladstone scientists will serve as scientific partners (Katherine Pollard, PhD, Todd McDevitt, PhD, Nevan Krogan, PhD) or founding employees of the company, including Kathy Ivey, PhD, former director of the Gladstone Stem Cell Core and the new director of research operations at Tenaya. "The launch of Tenaya Therapeutics exemplifies Gladstone's fierce dedication to scientific discovery and to putting those discoveries on a path to pioneering new therapeutics," said Gladstone President R. Sanders "Sandy" Williams, MD, who is on the board of Tenaya. "Deepak assembled a group of investigators adept at discovery within Gladstone, and our novel BioFulcrum initiative accelerated their progress. Plus, in Dave Goeddel and JJ Kang from The Column Group, we found the perfect partners for this new enterprise." To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound medical, economic, and social impact--unsolved diseases of the brain, the heart, and the immune system. Affiliated with the University of California, San Francisco, Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease.


News Article | December 15, 2016
Site: www.eurekalert.org

Research on a gene mutation that causes holes in the hearts of infants revealed insights into how the heart develops and how it stays healthy Scientists at the Gladstone Institutes linked a single gene mutation to two types of heart disease: one causes a hole in the heart of infants, and the other causes heart failure. Using cells donated by a family with the mutation, the researchers gained insight into congenital heart disease, human heart development, and healthy heart function. "Studying what goes wrong in disease can provide us with important insights into basic biology and how it's supposed to go right," said Deepak Srivastava, MD, director of the Gladstone Institute of Cardiovascular Disease and senior author on the new study. "The lessons we learned about cardiac gene networks from this family and their mutation will inform the development of treatments not only for their form of heart disease, but for many others." Congenital heart disease afflicts almost one percent of all newborn babies. In a particularly common type, a hole forms in the wall (called the septum) between two chambers of the heart. One cause of these septal defects is a mutation in the GATA4 gene, which is essential for normal heart development and healthy heart function. The GATA4 gene encodes a "master regulator" protein of the same name that activates or silences other genes involved in heart development. The current study, published in the journal Cell, involved a family of patients who suffer from congenital heart disease and carry a mutation in GATA4. The family first approached Srivastava in 2003 after half of the babies in the family were born with a septal defect. Using gene sequencing, the researchers learned that every member of the family with congenital heart disease had the same mutation in GATA4--a change in a single letter in the gene. Seven years later, several of the family members, now adolescents, developed a separate disease of the heart muscle that caused it to pump abnormally. The scientists concluded that the same GATA4 mutation was to blame for the heart muscle dysfunction, but they did not know why. To answer this question, the Srivastava team took skin cells from the family and reprogrammed them using stem cell technology into beating heart cells. This technique enabled the scientists to study heart cells with an identical genetic make-up as the patients to determine how the GATA4 mutation was causing the two forms of disease. The scientists noticed several abnormalities in the heart cells created from the patients: the cells beat weaker than normal, and numerous genes in the cells were abnormally activated or silenced. For example, genes involved in heart formation were not properly turned on, including genes that control septum formation. In contrast, genes involved in the development of other organs were turned on when they should have been off. "By studying the patients' heart cells in a dish, we were able to figure out why their hearts were not pumping properly," explained Srivastava. "Investigating their genetic mutation revealed a whole network of genes that went awry, first causing septal defects and then the heart muscle dysfunction." The researchers discovered that the GATA4 mutation prevented another master regulator protein, TBX5, from being recruited to genes needed for heart development and muscle contraction. GATA4 and TBX5 work together to activate genes responsible for heart formation and function, and silence genes involved in other organs. However, if one protein is mutated, then the other does not work well. Because of the single mutation in GATA4, virtually the entire network of genes regulated by GATA4 and TBX5 were disrupted, resulting in disease. Interestingly, human mutations in TBX5 also result in holes in the heart. "It was surprising how widespread the effect was. We changed one letter in one gene, and the entire cardiac development process was upended," said first author Yen-Sin Ang, PhD, a research scientist at Gladstone. "This work reveals how a single mutation in a key cardiac gene can lead to at least two forms of disease." It is difficult to target master regulator proteins, such as GATA4, with drugs because their influence is so widespread. However, the researchers did find a potential therapeutic target downstream of GATA4 that might be used to treat heart disease. Using computational modeling to extend their research in the cells, the scientists identified a hub of genes controlled by GATA4 that is important for heart function. They think this gene hub could be targeted with drugs to correct some of the damage caused by GATA4 mutations. Notably, a drug that affects this pathway already exists, and the researchers are pursuing it as a potential treatment for heart disease. "It's amazing that by studying genes in a two-dimensional cluster of heart cells, we were able to discover insights into a disease that affects a complicated three-dimensional organ," said Ang. "We think this conceptual framework could be used to study other diseases caused by mutations in proteins that serve as master regulators of whole gene networks." Other Gladstone researchers on the study include Renee Rivas, Janell Rivera, Nicole Stone, Karishma Pratt, Tamer Mohamed, Ji-Dong Fu, Ian Spencer, Molong Li, and Ethan Radzinsky. Rohith Srivas, Michael Snyder, Alexandre Ribeiro and Beth Pruitt from Stanford University, and scientists from the University of California, San Francisco, and Cornell University also contributed to the research.


News Article | November 10, 2016
Site: www.eurekalert.org

Two chemicals improved the speed, quantity, and quality of direct cardiac reprogramming, bringing the technology one step closer to regenerating damaged hearts Scientists at the Gladstone Institutes identified two chemicals that improve their ability to transform scar tissue in a heart into healthy, beating heart muscle. The new discovery advances efforts to find new and effective treatments for heart failure. Heart failure afflicts 5.7 million Americans, costs the country $30.7 billion every year, and has no cures. When heart muscle is damaged, the body is unable to repair the dead or injured cells. Gladstone scientists are exploring cellular reprogramming--turning one type of adult cell into another--in the heart as a way to regenerate muscle cells in the hopes of treating, and ultimately curing, heart failure. It takes only three transcription factors--proteins that turn genes on or off in a cell--to reprogram connective tissue cells into heart muscle cells in a mouse. After a heart attack, connective tissue forms scar tissue at the site of the injury, contributing to heart failure. The three factors, Gata4, Mef2c, and Tbx5 (GMT), work together to turn heart genes on in these cells and turn other genes off, effectively regenerating a damaged heart with its own cells. But the method is not foolproof--typically, only ten percent of cells fully convert from scar tissue to muscle. In the new study, published in Circulation, Gladstone scientists tested 5500 chemicals to try to improve this process. They identified two chemicals that increased the number of heart cells created by eightfold. Moreover, the chemicals sped up the process of cell conversion, achieving in one week what used to take six to eight weeks. "While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient," said senior author Deepak Srivastava, MD, director of the Gladstone Institute of Cardiovascular Disease. "With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process." The first chemical inhibits a growth factor that helps cells grow and divide and is important for repairing tissue after injury. The second chemical inhibits an important pathway that regulates heart development. By combining the two chemicals with GMT, the researchers successfully regenerated heart muscle and greatly improved heart function in mice that had suffered a heart attack. The scientists also used the chemicals to improve direct cardiac reprogramming of human cells, which is a more complicated process that requires additional factors. The two chemicals enabled the researchers to simplify the process bringing them one step closer to better treatments for heart failure. "Heart failure afflicts many people worldwide, and we still do not have an effective treatment for patients suffering from this disease," said Tamer Mohamed, PhD, first author on the study and a former postdoctoral scholar at Gladstone. "With our enhanced method of direct cardiac reprogramming, we hope to combine gene therapy with drugs to create better treatments for patients suffering from this devastating disease." Other Gladstone scientists on the study include Nicole Stone, Emily Berry, Ethan Radzinsky, Yu Huang, Karishma Pratt, Yen-Sin Ang, Pengzhi Yu, Haixia Wang, Shibling Tang, Sheng Ding, and Kathy Ivey. Researchers from the University of California, San Francisco (UCSF) also took part in the research. To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound medical, economic, and social impact--unsolved diseases of the brain, the heart, and the immune system. Affiliated with the University of California, San Francisco, Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease.


Chen K.,Wuhan University | Gao L.,Institute of Cardiovascular Disease | Liu Y.,Wuhan University | Zhang Y.,Wuhan University | And 9 more authors.
Basic Research in Cardiology | Year: 2013

Cardiac hypertrophy is the heart's response to hypertrophic stimuli and is associated with increased mortality. Vinexin-β is a vinculin-binding protein that belongs to a family of adaptor proteins and mediates signal transduction and actin cytoskeleton organisation. A previous study has shown that Vinexin-β is ubiquitously expressed and that it is highly expressed in the heart. However, a critical role for Vinexin-β in cardiac hypertrophy has not been investigated. Therefore, to examine the role of Vinexin-β in pathological cardiac hypertrophy, we used Vinexin-β knockout mice and transgenic mice that overexpress human Vinexin-β in the heart. Cardiac hypertrophy was induced by aortic banding (AB). The extent of cardiac hypertrophy was quantitated by echocardiography and pathological and molecular analyses of heart samples. Our results demonstrated that Vinexin-β overexpression in the heart markedly attenuated cardiac hypertrophy, fibrosis, and cardiac dysfunction, whereas loss of Vinexin-β exaggerated the pathological cardiac remodelling and fibrosis response to pressure overload. Further analysis of the in vitro and in vivo signalling events indicated that beneficial Vinexin-β effects were associated with AKT signalling abrogation. Our findings demonstrate for the first time that Vinexin-β is a novel mediator that protects against cardiac hypertrophy by blocking the AKT signalling pathway. © Springer-Verlag Berlin Heidelberg 2013.


Grube E.,University of Bonn | Chevalier B.,Institute Hospitalier Jacques Cartier | Smits P.,Maasstad Ziekenhuis | Davk V.,Toronto General Hospital | And 6 more authors.
JACC: Cardiovascular Interventions | Year: 2011

Objectives: The SPIRIT V (A Clinical Evaluation of the XIENCE V Everolimus-Eluting Coronary Stent System in the Treatment of Patients With De Novo Coronary Artery Lesions) study is a post-market surveillance experience of the XIENCE V (Abbott Vascular, Santa Clara, California) everolimus-eluting stent (EES) in patients with higher-risk coronary anatomy. Background: Previous pre-approval studies have shown the safety and efficacy of EES in highly selected groups of patients. Methods: The SPIRIT V trial is a prospective, open label, single arm, multicenter study. Two thousand seven hundred patients with multiple de novo coronary artery lesions suitable for treatment with a planned maximum of 4 EES were enrolled at 93 centers in Europe, Asia Pacific, Canada, and South Africa. Lesions had a reference vessel diameter between 2.25 and 4.0 mm and a length of ≤28 mm by visual estimation. An independent clinical events committee adjudicated all end point-related events. The primary end point was the composite rate of all death, myocardial infarction (MI), and target vessel revascularization at 30 days. Secondary end points included stent thrombosis and acute success (clinical device and procedure success). Results: At 30 days, the primary composite end point of all death, MI, and target vessel revascularization was 2.7%. At 1 year, rates of cardiac death, overall MI, and target lesion revascularization were 1.1%, 3.5%, and 1.8%, respectively. The cumulative rate of definite and probable stent thrombosis was low at 0.66% at 1 year. Conclusions: Use of EES in patients with multiple, complex de novo lesions yielded 1-year major adverse cardiac events, stent thrombosis, and target lesion revascularization rates that are comparable to those of the more controlled SPIRIT II and SPIRIT III trialswhich included patients with restricted inclusion/exclusion criteriaand other all-comer population, physician-initiated studies like the X-SEARCH (Xience Stent Evaluated At Rotterdam Cardiology Hospital) and COMPARE (A Randomized Controlled Trial of Everolimus-eluting Stents and Paclitaxel-eluting Stents for Coronary Revascularization in Daily Practice) trials. © 2011 American College of Cardiology Foundation.


Luo Y.,Tianjin University | Luo Y.,Institute of Cardiovascular Disease | Zhao Y.,Tianjin University | Li X.,Tianjin Third Central Hospital | And 3 more authors.
Molecular and Cellular Biochemistry | Year: 2014

ZNF580 is a novel C2H2 zinc-finger nuclear transcription factor with potential involvement in the transforming growth factor-β1 (TGF-β1) signal transduction pathway. Emerging evidence suggests that TGF-β1 can regulate endothelial nitric oxide synthase (eNOS) expression in endothelial cells. This study aimed to determine if ZNF580 mediated eNOS expression and participated in endothelial cell migration and proliferation via the TGF-β1/Smad2/ZNF580/eNOS signaling pathway. Overexpression/downexpression of ZNF580 in EAhy926 cells leads to the enhancement/decrease of eNOS expression. TGF-β1 downregulated both ZNF580 and eNOS at the mRNA and protein levels in concentration- and time-dependent manners. ZNF580 and eNOS downregulation induced by TGF-β1 was blocked by the specific TGF-β1 type I receptor ALK5 inhibitor, SB431542. Overexpression of ZNF580 attenuated TGF-β1-induced inhibition of EAhy926 cell growth and mobility, and vice versa. These results suggest that ZNF580 mediates eNOS expression and endothelial cell migration/proliferation via the TGF-β1/ALK5/Smad2 pathway, and thus plays a crucial role in vascular endothelial cells. © 2014 Springer Science+Business Media.


News Article | November 11, 2016
Site: www.sciencedaily.com

Scientists at the Gladstone Institutes identified two chemicals that improve their ability to transform scar tissue in a heart into healthy, beating heart muscle. The new discovery advances efforts to find new and effective treatments for heart failure. Heart failure afflicts 5.7 million Americans, costs the country $30.7 billion every year, and has no cures. When heart muscle is damaged, the body is unable to repair the dead or injured cells. Gladstone scientists are exploring cellular reprogramming -- turning one type of adult cell into another -- in the heart as a way to regenerate muscle cells in the hopes of treating, and ultimately curing, heart failure. It takes only three transcription factors -- proteins that turn genes on or off in a cell -- to reprogram connective tissue cells into heart muscle cells in a mouse. After a heart attack, connective tissue forms scar tissue at the site of the injury, contributing to heart failure. The three factors, Gata4, Mef2c, and Tbx5 (GMT), work together to turn heart genes on in these cells and turn other genes off, effectively regenerating a damaged heart with its own cells. But the method is not foolproof -- typically, only ten percent of cells fully convert from scar tissue to muscle. In the new study, published in Circulation, Gladstone scientists tested 5500 chemicals to try to improve this process. They identified two chemicals that increased the number of heart cells created by eightfold. Moreover, the chemicals sped up the process of cell conversion, achieving in one week what used to take six to eight weeks. "While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient," said senior author Deepak Srivastava, MD, director of the Gladstone Institute of Cardiovascular Disease. "With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process." The first chemical inhibits a growth factor that helps cells grow and divide and is important for repairing tissue after injury. The second chemical inhibits an important pathway that regulates heart development. By combining the two chemicals with GMT, the researchers successfully regenerated heart muscle and greatly improved heart function in mice that had suffered a heart attack. The scientists also used the chemicals to improve direct cardiac reprogramming of human cells, which is a more complicated process that requires additional factors. The two chemicals enabled the researchers to simplify the process bringing them one step closer to better treatments for heart failure. "Heart failure afflicts many people worldwide, and we still do not have an effective treatment for patients suffering from this disease," said Tamer Mohamed, PhD, first author on the study and a former postdoctoral scholar at Gladstone. "With our enhanced method of direct cardiac reprogramming, we hope to combine gene therapy with drugs to create better treatments for patients suffering from this devastating disease."


PubMed | Institute of Neurology, Vinča Institute of Nuclear Sciences, Institute of Cardiovascular Disease and Institute of Medical Biochemistry
Type: Journal Article | Journal: EJIFCC | Year: 2016

Combinations of multiple predisposing polymorphisms and their interactions with modifiable factors may result in synergistic effects on early ischemic stroke risk. We evaluated the potential interaction of apolipoprotein (apo) E and angiotensin I-converting enzyme (ACE) gene polymorphisms and hypertension on early ischemic stroke risk in Serbian population. We analyzed 65 stroke patients (mean age 35 yrs) and age- and body mass index matched 330 controls. ACE genotypes were determined by polymerase chain method (PCR) and apoE genotypes by PCR appended by HhaI restriction fragment-length polymorphism/MADGE analysis. Odds ratios (ORs) for stroke were 1.35 (95% confidence interval (CI) 0.50-3.62) in subjects with one studied polymorphism and 3.78 (95% CI, 1.28-11.18) in those with two. Compared with nonhypertensive subjects bearing no polymorphisms, ORs were 2.73 (95% CI 0.32-17.55) and 4.80 (95% CI 0.50-28.12) for nonhypertensive subjects with one and two polymorphisms, 8.53 (95% CI 1.04-62.47) and 30.00 (95% CI 3.21-186.45) for hypertensive. These data suggest a gene-dose effect of the examined gene variants and a synergistic effect of these polymorphisms and hypertension in the pathogenesis of early ischemic stroke.


PubMed | Institute of Neurology, Vinča Institute of Nuclear Sciences, Institute of Cardiovascular Disease and Institute of Medical Biochemistry
Type: Journal Article | Journal: EJIFCC | Year: 2016

The possible association of ACE polymorphism with ischemic stroke (IS) was evaluated in 65 patients with IS and 330 age and BMI-matched controls. ACE genotypes were determined by polymerase chain reaction (PCR). There was no significant difference in ACE genotype/allele frequencies between case and control group (p>0.05). Patients with D allele had 4,7 times higher risk for large vessel IS than healthy persons D allele possessors. Persons with D allele had 9.2 times higher risk for large vessel disease than small vessel disease. These data suggest a possible association of ACE gene polymorphism with pathogenesis of large vessel IS.

Loading Institute of Cardiovascular Disease collaborators
Loading Institute of Cardiovascular Disease collaborators