The potential of a gene-silencing technique called RNA interference has long enticedÂ biotechnology researchers. Itâ€™s used routinelyÂ in the laboratory to shut down specific genes in cells. Still, the challenge of delivery has held back RNA-based drugsÂ inÂ treating human disease.
RNA is unstable and cumbersome, and just getting it into the body without having it break down is difficult. One that hurdle is met, there is another: the vast majority of the drug is taken upÂ by the liver. Many current RNA-based approaches turnÂ this apparent bug into a strength, because they seek to treat liver diseases. See these articles in The Scientist and in Technology Review for more.
But what if you need to deliver RNA somewhere besides the liver?
Biomedical engineer Hanjoong Joâ€™s lab at Emory/Georgia Tech, working with Katherine Ferraraâ€™s group at UC Davis, has developed technologyÂ to broadenÂ the liver-dominantÂ properties of RNA-based drugs.
Hanjoong Jo, PhD
The results were recently published in ACS Nano. The researchers show they can selectively target an anti-microRNAÂ agent to inflamed blood vessels in mice while avoiding other tissues.
â€œWe have solved a major obstacle of using anti-miRNA as a therapeutic by being able to do a targeted delivery to only inflamed endothelial cells while all other tissues examined, including liver, lung, kidney, blood cells, spleen, etc showed no detectable side-effects,â€ Jo says. Read more
Last week on Friday, Lab Land attended the annual Regenerative Engineering & Medicine center get-together to hear about progress in this exciting area.
During his talk, Tony Kim of Georgia Tech mentioned a topic that Rose Eveleth recently explored in The Atlantic: why arenâ€™t doctors using amazing â€œnanorobotsâ€ yet? Or as Kim put it, citing a recent review, â€œSo many papers and so few drugs.â€
[A summary: scaling up is difficult, testing pharmacokinetics, toxicity and efficacy is difficult, and so is satisfying the FDA.]
TheÂ talks Friday emerged from REM seed grants; manyÂ paired an Emory medical researcher with a Georgia Tech biomedical engineer. All of these projects take on challenges in delivering regenerative therapies: getting cells or engineered particles to the right place in the body.
For example, cardiologist W. Robert Taylor discussed the hurdles his team had encountered in scaling up his cells-in-capsules therapies for cardiovascular diseases to pigs, in collaboration with Luke Brewster. The pre-pig phase of this research is discussed in more detail here and here. Read more
A paper from cardiologist Aloke Finn and colleagues (published Wednesday, Aug. 5 inÂ Nature Communications) describes how the protein CD163, produced by macrophages, puts the brakes on muscle repair after ischemic injury in mice. Here’s why we think this paper is interesting.
*Speculatively, there are connections to the recent wave of “young blood cures old body” parabiosis research. Increased CD163 is a marker of aging in humans. Maybe low levelsÂ of CD163 areÂ part of how young blood is restorative.
*Translational potential — it wouldn’t be too hard to make anÂ antibody against human CD163. Something that blocks CD163Â could possibly be used to treat muscle breakdown, whichÂ occurs in response to injury, inactivity and in diseases such as cancer and diabetes.
*Finn says his team was surprised to find that mice lacking CD163, tested in experiments where blood flow is restricted in one leg, showed increased blood vessel and muscle growth in the otherÂ leg. It looks like part of CD163’s roleÂ is to limit muscle regeneration to the site of injury. Read more
This image submitted by Thalita Abrahao won second place at the Postdoctoral Research Symposium Thursday. Abrahao, a postdoc in Kathy Griendlingâ€™s lab, is studying vesicle trafficking in vascular smooth muscle cells.
Thalita Abrahao — Kathy Griendling lab
Griendlingâ€™s lab has been looking into how the enzyme Nox4 and its partner Poldip2 are involved in cell migration, and Abrahao was investigating if vascular smooth muscle cells that have less Poldip2 have changes in protein processing.
Here, green represents beta-tubulin, a protein making up fine-looking fibers (microtubules) extending through the cell. Purple represents Sec23, part of the process of vesicle trafficking and protein secretion. White indicates when beta-tubulin and Sec23 are both present. Orange marks DNA in the nucleus.
Posted on May 28, 2015
For the last decade, cardiology researchers have been collecting detailed information on the patients who come through Emoryâ€™s catheterization labs.Â The density of data (close to 7000 people) can make it possible to achieve some insights about mortality in American society.
Cardiology research fellow Salim Hayek, MD, presented some provocative findings yesterday in a poster competition at the American College of Physicians meeting in Boston. He has been working with Arshed Quyyumi, MD and colleagues at Emoryâ€™s Clinical Cardiovascular Research Institute.
Their analysis shows â€œcollege education as a discrete indicator of socioeconomic status was an independent predictor of survival.â€
A key thing to remember when looking at this data is that most of the people in the cath lab at a given moment are not actually having a heart attack — just 13 percent are. (Abstract/poster available upon request). However, thereâ€™s enough suspicion or history of heart disease for doctors to take a look inside; most of them have hypertension and coronary artery disease, and many have had a heart attack in the past. The group is mostly men, average age 63. Read more
Posted on May 1, 2015
Emory dermatologist Jack Arbiser discovered the anti-angiogenic properties of honokiol, a compound derived from magnolia cones, more than a decade ago. Since then, honokiol has been found to have anti-inflammatory, anti-oxidant and anticancer properties.
A paper published Tuesday in Nature Communications from researchers at the University of Chicago shows that honokiol inhibits the mitochondrial enzyme Sirt3, which has connections to longevity.Â Manesh Gupta and colleagues demonstrate thatÂ honokiol canÂ blockÂ cardiac hypertrophy in mice, a finding with possible relevance for the treatment of heart failure.
Sirt3 has been linked both genetically to human life span, and until now, the only way to increase levels of Sirt3 was old-fashioned calorie restriction and/or endurance exercise.
The authors write: It is believed thatÂ Sirt3 does not play a role inÂ embryonic development, but rather it fine tunes the activity ofÂ mitochondrial substrates by lysine deacetylation to protect cellsÂ from stress…Â To theÂ best of our knowledge, this is the first report describing aÂ pharmacological activator of Sirt3.
On Thursday, cardiology researcher Leslee Shaw, PhD joined an exclusive club at Emory with her 2015 Deanâ€™s Distinguished Faculty Lecture and Award.* Shaw is the co-director of Emoryâ€™s Clinical Cardiovascular Research Institute and research director of Emory Womenâ€™s Heart Center. Her lecture focused on the utility of coronary artery calcium (CAC) scoring in predicting cardiovascular disease.
Much cardiovascular risk research has focused on finding imaging or biomarker tests that can provide doctors with cost-effective decision-making power. OneÂ prominent question: should the patient take cholesterol-reducing statins? These tests should provide information above and beyond the Framingham Risk Score or its ACC/AHA update, which incorporates information about a patientâ€™s age, sex, cholesterol/HDL, blood pressure and diabetes status.
CAC scoring is a good place to start, Shaw said, since it is a standardized, relatively inexpensive test that measures the buildup of calcium in atherosclerotic plaque, and the radiation dose is low compared with other cardiac imaging techniques. Read more
A risk calculator for cardiovascular disease, developed as a companion for the 2013 American College of Cardiology/American Heart Association cholesterol guidelines, may account for racial differences in sub-clinical vascular function better than the Framingham Risk Score, Emory cardiology researchers say.
Their findings are scheduled for presentationÂ MondayÂ at the American College of Cardiology meeting in San Diego.
African Americans, especially men, tend to have a higher prevalence of cardiovascular disease, but this differences are not reflected in the Framingham Risk score. Arterial stiffness is a sign of heart disease risk that tends to appear more prominently among African Americans than whites. Cardiovascular research fellow Jia Shen, MD, MPH, and Emory colleagues analyzed data on arterial stiffness and structure from 1235 people â€“ 777 whites and 458 African-Americans — enrolled in two large studies (Center for Health Discovery and Well Being and META-Health). Read more
MicroRNAs have emerged as important master regulators in cells, since each one can shut down several target genes. Riding on top of the master regulators is Drosha, the RNA-cutting enzyme that initiates microRNA processing in the nucleus. Drosha and its relative Dicer have been attracting attention in cancer biology, because they are thought to beÂ behind a phenomenon where cancerous cells can â€œinfectâ€ their healthy neighbors via tiny membrane-clothed packets called exosomes.
At Emory, pharmacologist Zixu Mao and colleagues recently published in Molecular Cell their findings that Drosha is regulated by stress (experimentally: heat or peroxide) through p38 MAP kinase.
Although weÂ mention relevance to cancer above, this is one of those basic cell biology findings that may have applicability to several areas of medicine. Alterations in miRNA processing have been linked to neurodegenerative disease (Fragile X-associated tremor/ataxia syndrome, for one example). MicroRNA-packed exosomes are also being studied by biomedical engineers asÂ potential therapeutic tools in regenerative medicine, so knowing what cellular stress does to miRNAÂ production could be useful. Read more