Genes and Cardiovascular Function
Students will be introduced to the primary research literature and will consider articles of current interest to analyze for their assignments.
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Develop the skills to consider the role of genes and environment in shaping cardiovascular health. Achieve proficiency in reading, analyzing and evaluating current scientific literature in the field of cardiovascular pathophysiology. Undergraduate subjects Graduate subjects Research subjects. Breadth search Breadth tracks. About this subject Overview Eligibility and requirements Assessment Dates and times Further information Timetable opens in new window Single page view for printing Contact information Please refer to the specific study period for contact information.
Intended learning outcomes On completion of this subject, students should be able to: define and describe cardiovascular structure, function and development at both organ and cellular levels describe and critically evaluate how blood pressure is controlled and regulated, and factors involved in development of cardiovascular diseases describe the important endocrine bases for maintenance of cardiovascular homeostasis develop skills to evaluate and consider the role of genes and environment in shaping cardiovascular health.
Generic skills Develop the skills to consider the role of genes and environment in shaping cardiovascular health. Next: Eligibility and requirements. Gene therapy treatments are in development for a wide array of illnesses, including a dozen or more products in late-stage clinical development for the treatment of cancer, ocular, and cardiovascular disorders.
Family History & Your Risk for Heart Disease | ubabirovli.gq
One therapy that may soon get EU approval is from GSK and treats patients with adenosine deaminase for severe combined immunodeficiency syndrome. A recent market research report identified a total of gene therapy molecules in the market or clinical pipeline, most in early development. There are a handful of gene therapies approved for use in China, Russia, and the Philippines.
Optimal heart function is dependent on, among other things, healthy cardiomyocytes. Progressive changes in cardiomyocyte phenotype are a central feature in chronically stressed and failing hearts, as is cell death. Damage to the cardiomyocyte population comes in several forms. Regenerating or repairing damaged myocytes has been an important theme in cardiovascular research. Unfortunately, the heart is one of the least regenerative organs in the body. Traditionally, the heart has been thought of as a terminally differentiated postmitotic organ in which the number of cardiomyocytes is established at or near birth.
Researchers now know that cardiac stem cells reside in the heart and have the ability to differentiate into cardiomyocytes, allowing for some—albeit limited and slow—regeneration. Cell therapy relies on the administration of live whole cells or maturation of a specific cell population to repopulate areas of damaged myocardium. Despite extensive efforts, no cell therapy has been conclusively shown to be effective. Gene therapy, on the other hand, focuses not on replacing lost cardiomyocytes but rather on improving the function of existing myocytes by altering or influencing the expression of specific genes.
Some approaches try to introduce a new gene into the body to help fight a disease.
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Sometimes a combined approach works best, making it hard to categorize an approach as clearly cell or gene therapy. In May, phase II results were presented at Heart Failure showing the potential of a novel non-viral gene therapy that expresses stromal cell-derived factor-1 SDF-1 , a naturally occurring signaling protein that repairs damage by recruiting circulating stem cells to the site of injury. The therapy, called JVS Juventas Therapeutics, Cleveland, OH , is a deoxyribonucleic acid plasmid designed to be delivered directly to the site of injured tissue.
The therapy appeared safe and the development of JVS continues. Calcium cycling is central to cardiomyocyte function and a popular target for gene therapy. Calcium handling in HF-damaged cardiomyocytes is impaired, producing a weak contractile force. Also, impaired calcium uptake to the SR results in incomplete myocyte relaxation after contraction.
Calcium cycling is a popular gene therapy target for HF and the focus of two of the companies profiled below: Celladon and Renova. The field is an interesting mix of traditional academic research and Silicon Valley-type start-ups with bubbly valuations, news-making partnerships, and loads of entrepreneurial spirit. But the level of expertise needed to develop a successful product—expertise not only in gene therapy but also in product development and product registration—makes for a field that demands high performers, generous funding, and the possibility of abject failure.
When biotech companies fall, they fall hard. Unrealistic valuations help, as do politicians trying to score points with voters. But the real issue for these companies is that they often have no sales or revenue and only one or two drugs in the pipeline. Not long ago San Diego-based Celladon was a biotech darling in the gene therapy space.
Its targeted therapy, called Mydicar, was designed to enhance the contractile potential of remaining cardiomyocytes in individuals with HF. We noted above that deficient SR calcium uptake has been identified in failing hearts.
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A decrease in SERCA2a activity has been shown to be responsible for abnormal calcium homeostasis in failing hearts. The concept behind Mydicar was that overexpression of the SERCA2a gene in the myocardium would restore SERCA2a enzyme production in the cardiomyocytes, which would then power the SR, improving contraction and relaxation of remaining cardiomyocytes.
In preclinical models of HF, increasing the expression of SERCA2a in cardiomyocytes by gene transfer restored normal calcium cycling and resulted in improved cardiac function and myocardial energetics.
Family History and Other Characteristics That Increase Risk for Heart Disease
The trial enrolled patients in 56 clinical sites and randomized them to Mydicar or placebo in equal numbers. All patients were prescreened for the presence of AAV neutralizing antibodies. The novel treatment failed to meet any of its primary or secondary endpoints. Mydicar did not reduce HF hospitalizations, all-cause death, or the need for a mechanical circulatory device or heart transplantation Figure 3.
Celladon stock collapsed on the news. In Nov. Renova Therapeutics is another hot gene therapy start-up based in San Diego, CA, but of a very different flavor than Celladon and, obviously, hopeful of a different future.
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The company is supported by a group of high-net-worth individuals and has not taken any venture capital money—as of yet. Reich, PhD. Reich in an interview with CSWN. Our investors and our management are on the same side of the table. They have partnered with the National Institutes of Health NIH to run both an extensive preclinical program on their target gene therapy product and to conduct clinical trials through a public-private partnership between the NIH and Renova Therapeutics.
Hammond was the first to discover that adenylyl cyclase type 6 AC6 was downregulated in patients with HF of any etiology and that regulating AC6 could have a positive effect on said patients. AC6 is a protein found in cardiomyocytes that catalyzed conversion of adenosine triphosphate to cyclic AMP cAMP and, thus, is a central regulator of calcium cycling. RT is designed to upregulate AC6 content and restore heart function. In extensive preclinical study, a single dose improved myocardial function and reversed HF-induced remodeling of the heart.
These early results supported the phase II trial conducted at seven U. During the 1-year trial, there were no differences in HF hospitalization or death between groups. AC6 gene transfer was not associated with myocarditis or liver inflammation, or an increase in implantable cardioverter-defibrillator events. In terms of efficacy, RT given at the two highest doses increased EF significantly at 4 weeks, but because of an insignificant but substantial increase in the placebo group at 4 weeks, the between-group difference was not significant at 12 weeks.
When response was categorized by HF etiology, nonischemic HF patients were the only patients who showed improved EF with the therapy. The ischemic subjects did not improve at all. The investigators also saw a signal that a dose higher than the highest they tested might be beneficial.
And while symptoms improved significantly after RT, a large placebo effect was noted such that the between-group difference was not significant at 4 or 12 weeks. Renova plans to meet with health authorities in the U. There are no trials ongoing presently.https://miparrinila.tk
Gene Therapy in Cardiovascular Disease
Reich, who has vast experience in getting products registered, explained the importance of stepping in sync with regulatory bodies. He should know. He was a co-founder of the first gene therapy company in , Viagene, which was acquired by Chiron in His last company, Collateral Therapeutics, was the first gene therapy company focused on cardiovascular disease and was sold to Schering AG in Reich came out of retirement to lead Renova.
The concept is simple: a single treatment to cure an otherwise chronic and usually progressive lifelong illness. How much should that cost? Heath care professionals and politicians alike continue to weigh in on the topic but often disagree on how to rein in prices that are much higher in the U.