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The next frontier in battle against atherosclerosis: immunetherapies by efwegbe erergeer
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The next frontier in battle against atherosclerosis: immunetherapies |
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New strategies injecting cardiovascular disease (CVD) patients withvaccines and monoclonal antibodies to combat atherosclerosis couldsoon change the treatment landscape of heart disease . Both approaches, Professor Jan Nilsson told delegates at theFrontiers in CardioVascular Biology (FCVB) 2012 meeting, can beconsidered truly ground breaking since for the first time theytarget the underlying cause of CVD. The FCVB meeting, organised bythe Council on Basic Cardiovascular Science (CBCS) of the EuropeanSociety of Cardiology (ESC), was held at the South KensingtonCampus of Imperial College in London. "People at high risk of MI are likely to be the first candidatesfor immune approaches.
Such treatments, since they've totallydifferent modes of action, could be used in addition to the currenttherapies," explained Nilsson, who is professor of ExperimentalCardiovascular Research at Lund University, Sweden, and a keyplayer in the development of immune treatments. Speaking at the session "Atherosclerosis and the immune system:Expanding beyond inflammation" , Nilsson said that with phase 2atrials on recombinant antibodies currently ongoing in the US andCanada and results expected to be announced Quarter IV 2012, suchtreatments could soon become a clinical reality. "If all goes well,the first in class of these treatments could be licensed withinfour to five years," he added. Undoubtedly there is an urgent need for new approaches to tackleCHD, a condition that kills two million people across Europe eachyear. Established therapies against atherosclerosis almostexclusively focus on risk factor modification - that is reductionof dyslipidaemia, hypertension and hyperglycaemia.
"Existing treatments only reduce the risk ofpatients experiencing a CVD event by 40%. Although such results areencouraging, it shouldn't be forgotten that 60% of CVD eventscontinue to occur," said Nilsson. It was in the early 1990s that identification of antibodies againstoxidised low density lipoproteins (LDL) in artery plaques, firstgave rise to the concept that CVD might be an autoimmune diseasewhere the immune system attacks oxidised LDL. To test thishypothesis Nilsson and colleagues conducted experiments immunizingrabbits with high blood cholesterol with their own oxidised LDL. "We had anticipated that immunizationwould result in the atherosclerosis becoming more aggressive, butto our initial disappointment found that immunization appeared tobe activating protection against atherosclerosis.
At the time thismade no sense to us at all," he recalled. The team subsequently discovered that through serendipitous use ofan adjuvant (agent added to vaccines to increase the immuneresponse) they had in fact stumbled upon a way to shift the T cellsfrom pro-inflammatory Th1 responses towards protective Th2 andregulatory T cell responses. "This had the overall effect ofdampening down inflammation and reducing the plaque severity," saidNilsson. Since it is impractical to develop vaccines based on oxidised LDL(due to difficulty of standardising the particle) Nilsson looked toidentify structures within the oxidised LDL that triggered thedesired protective response. Working with Prediman Shah, fromCedars-Sinai Heart Institute (Los Angeles, CA), the team screened anumber of different apolipoprotein (apo) B peptides (the onlyprotein permanently associated with LDL) sequences.
The team wereable to identify three 20 amino acid long apo B peptides, whichwhen formulated with a carrier and adjuvant, reduced development ofatherosclerosis in mice by 60 to 70%. The resulting CVX-210 vaccine, currently in development byCardioVax, involves one of these three amino acid fragments(residues 3136 to 3155). CardioVax are currently awaiting FDAclearance to start phase 1 clinical trials with the vaccine, whichwill be given subcutaneously. Also in development is a secondvaccine using the same amino acid sequence that has been formulatedin a way that makes it possible to give intranasally. Further along the development pathway, and already in clinicaltrials, is an altogether different immune approach involvinginjection of antibodies directly targeting oxidised LDL.
"Therationale is that since oxidised LDL plays a major role in thedevelopment of atherosclerotic plaques and harmful inflammatoryprocesses, directly targeting oxidised LDL should prevent plaqueformation and reduce inflammation," explained Nilsson. Preclinical studies show that administration of the BI-204monoclonal antibody, developed jointly by BioInvent and Genentech,reduced the formation of atherosclerotic plaques and plaquesalready present by 50%. In the phase I study, which took place in80 healthy volunteers with elevated levels of LDL, BI-204 was foundto be safe and well tolerated. Now for the current phase 2a double blind GLACIER (Goal of oxidisedLdl and Activated maCrophage Inhibition by Exposure to aRecombinant antibody) study, BI-204 is being deliveredintravenously to 144 patients with stable coronary artery disease in addition to standard care. The study, which is taking place at20 centres in the US and Canada, has been designed to demonstratereduction in inflammation in the carotid artery quantified byFDG-PET imaging (18Fluoro-2-deoxyglucose positron emissiontomography) at weeks four and 12 following initiation of treatment.At the beginning of March, the companies announced that patientrecruitment was completed.
Looking to the future, Nilsson said it was unlikely that either themonoclonal antibodies or vaccine would be given as "one off jabs"during childhood against CVD. "Both these treatments are far morelike drugs - to be effective they'd need to be given long term. Theantibody therapy in particularly is likely to be expensive so youcould probably only afford to give it to high risk populationsrather than everyone," he said. Additional References Citations. I am an expert from Electric Pans, Deep Fryers, usually analyzes all kind of industries situation, such as water slides inflatables , motorcycle seat foam.
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